Pharmacology & Therapeutics 223 (2021) 107807

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Pharmacology & Therapeutics

journal homepage: www.elsevier.com/locate/pharmthera

Addiction and the kynurenine pathway: A new dancing couple?

Nuria Morales-Puerto a,b,c,d,1, Pablo Giménez-Gómez a,b,c,d,1, Mercedes Pérez-Hernández a,b,c,d,
Cristina Abuin-Martínez a,b,c,d, Leticia Gil de Biedma-Elduayen a,b,c,d, Rebeca Vidal a,b,c,d,
María Dolores Gutiérrez-López a,b,c,d, Esther O'Shea a,b,c,d,⁎, María Isabel Colado a,b,c,d,⁎
a
Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense, Madrid, Spain
b
Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid, Spain
c
Red de Trastornos Adictivos del Instituto de Salud Carlos III, Madrid, Spain
d
Instituto Universitario de Investigación Neuroquímica (IUIN), Facultad de Medicina, Universidad Complutense, Madrid, Spain

a r t i c l e i n f o a b s t r a c t

Available online 19 January 2021 Drug use poses a serious threat to health systems throughout the world and the number of consumers rises re-
lentlessly every year. The kynurenine pathway, main pathway of tryptophan degradation, has drawn interest in
this field due to its relationship with addictive behaviour. Recently it has been confirmed that modulation of
Keywords: kynurenine metabolism at certain stages of the pathway can reduce, prevent or abolish drug seeking-like behav-
Kynurenine pathway iours in studies with several different drugs. In this review, we present an up-to-date summary of the evidences
Addiction of a relationship between drug use and the kynurenine pathway, both the alterations of the pathway due to drug
Ethanol use as well as modulation of the pathway as a potential approach to treat drug addiction. The review discusses
Nicotine ethanol, nicotine, cannabis, amphetamines, cocaine and opioids and new prospects in the drug research field
Cannabis
are proposed.
Ro 61–8048
© 2021 Published by Elsevier Inc.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Neurobiology of addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Tryptophan metabolism and the kynurenine pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
4. Neuromodulation of brain circuits associated with addiction by kynurenine and its metabolites. . . . . . . . . . 4
5. Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
6. Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
7. Cannabis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
8. Amphetamine and its derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
9. Cocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
10. Opioids: a special case . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
11. Future prospects and new trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Abbreviations: AhR, Aryl hydrocarbon receptor; BBB, Blood-brain barrier; CA, Cinnabarinic acid; CB1/2, Cannabinoid receptor 1/2; CBD, Cannabidiol; CNS, Central nervous system; DA,
Dopamine; EtOH, Ethanol; GABA, γ-aminobutyric acid; GPR35, G protein-coupled receptor 35; 3-HK, 3-hydroxykynurenine; 5-HT, Serotonin; IDO, Indolamine 2,3-dioxygenase; KAT,
Kynurenine aminotransferase; KMO, Kynurenine 3-monooxygenase; KYN, Kynurenine; KYNA, Kynurenic acid; mGluR, Metabotropic glutamate receptor; NAc, Nucleus accumbens;
nAChR, Nicotinic acetylcholine receptor; NMDA, N-methyl-D-aspartate; PFC, Prefrontal cortex; QA, Quinolinic acid; TDO, Tryptophan 2,3-dioxygenase; THC, Tetrahydrocannabinol; TRP,
Tryptophan; VTA, Ventral tegmental area; XA, Xanthurenic acid.
⁎ Corresponding authors at: Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain.
E-mail addresses: estheros@med.ucm.es (E. O'Shea), colado@med.ucm.es (M.I. Colado).
1
Contributed equally.

https://doi.org/10.1016/j.pharmthera.2021.107807
0163-7258/© 2021 Published by Elsevier Inc.
N. Morales-Puerto, P. Giménez-Gómez, M. Pérez-Hernández et al.
1. Introduction
Drug abuse and addiction are a major global health problem, as is re-
vealed in the World Drug Report of 2019 published by the United Na-
tions Office on Drugs and Crime. According to the report, in 2017
about 271 million people declared having used drugs in the previous
year, which represents an increase of 30% compared with 2009. More-
over, currently there are 35 million people diagnosed with drug use dis-
orders all over the world. These data together indicate a high burden of
disease with over half a million deaths and 42 million years of “healthy”
life lost due to drug use (World Health Organization, 2019a). Despite
the devastating impact of addiction on society, pharmacological treat-
ments and behavioral therapies are far from being effective for most
people. Hence, new therapeutic strategies are necessary to combat
these disorders.
The kynurenine pathway, the main route of tryptophan (TRP) degra-
dation, is implicated in several physiological processes, such as neuronal
and immunological functions or ageing processes (Stone, Stoy, &
Darlington, 2013). Furthermore, the kynurenine pathway has been im-
plicated in a wide range of diseases of the central nervous system (CNS),
including neurodegenerative and neuropsychiatric disorders (Platten,
Nollen, Röhrig, Fallarino, & Opitz, 2019). In line with this, during the
last decades it has been proposed that the kynurenine pathway can con-
tribute to or modulate addictive behaviour. These findings open the
door to the study of the involvement of the kynurenine pathway in ad-
dictive disorders and offers a new opportunity to establish the
kynurenine pathway as a new pharmacological target in the treatment
of addictive disorders.
2. Neurobiology of addiction
The key brain area associated with addiction is the limbic system,
which comprises the cingulate gyrus, amygdala, hippocampus, prefron-
tal cortex (PFC), ventral tegmental area (VTA) and the nucleus accum-
bens (NAc). All these areas are related to reward, emotion and
punishment, thus boding critical importance in addiction (Fogaça,
Campos, & Guimarães, 2016a). Reward is defined as any event that in-
creases the probability of a response with a positive hedonic compo-
nent. All known drugs of abuse act stimulating the brain reward
system and changes in this system are key to understanding the devel-
opment of addiction (Koob & Volkow, 2016). Limbic structures give he-
donic value to stimuli and in this effect dopamine (DA), a
monoaminergic neurotransmitter produced in the substantia nigra
and in the VTA, plays a key role. The dopaminergic connection between
the VTA and the NAc is usurped by drugs of abuse (Taber, Black, Porrino,
& Hurley, 2012). In this sense, all drugs produce an increase in DA re-
lease in the NAc, although the exact mechanism by which drugs of
abuse can promote the mentioned DA liberation varies among the dif-
ferent classes of substances of abuse (Fig. 1).
The most accepted theory about the addiction process proposes a
disorder that includes three phases in which users of drugs of abuse
pass from positive reinforcement and voluntary use to compulsive con-
sumption with negative reinforcement in the absence of drug (Koob &
Volkow, 2010). The first stage of these three-stage cycle is the binge
or intoxication stage. This stage is influenced by substance pharmacoki-
netics and administration methods (Fogaça et al., 2016a; Fogaça,
Campos, & Guimarães, 2016b) but relies on the release of DA in the
NAc, crucial for the acute reinforcing effects of drugs, and the perception
of pleasure and enjoyment (Koob & Volkow, 2010). The exact mecha-
nism by which a particular drug produces the release of DA will be de-
scribed in the section corresponding to each drug of abuse.
During the second stage, the withdrawal phase, the brain cannot
regulate its experience of pleasure and reward from the drugs of
abuse independently due to their chronic effects, that include a down-
regulation of reward-related neurotransmitter levels (Koob & Le Moal,
2001). In this phase, a negative emotional state predominates, caused
2
Pharmacology & Therapeutics 223 (2021) 107807
by the activation of the extended amygdala. This brain area is composed
of the central nucleus of the amygdala, bed nucleus of the stria
terminalis and the shell of the NAc and plays a key role in the integration
of stress systems with hedonic processing systems, in order to produce
the negative emotional state that will subsequently establish the nega-
tive reinforcement associated with the development of the addiction
(Koob & Volkow, 2010). The reward obtained after drug consumption
is substituted by a reduction in DA release that decreases motivation
for non-drug stimuli (Melis, Spiga, & Diana, 2005). In addition, in the
withdrawal phase, the activation of the release of corticotropin-
releasing factor and the increase in corticosterone and adrenocortico-
tropic hormone levels in the amygdala promote the engagement of
users in drug consumption in order to avoid this aversive mood
(Koob, 2008).
The last stage of this process is the craving stage. In this last step of
the addiction cycle, an individual has a persistently down-regulated
state and may seek their substance of choice to ameliorate the anhedo-
nia and other unpleasant and undesirable consequences of that state
(Fogaça et al., 2016a). Evidence from animal models show that there
are three possible mechanisms involving different brain areas and,
mainly, the neurotransmitter glutamate by which an individual can re-
instate drug-seeking behaviour. The first one is drug-induced reinstate-
ment, by a dose that can act as a priming and in which the medial PFC/
NAc/ventral pallidum circuit play a key role (McFarland & Kalivas,
2001). The second one involves cue-reinstatement and relies on struc-
tures such as the basolateral amygdala and the PFC (Everitt & Wolf,
2002; Knackstedt & Kalivas, 2009). The last one involves the extended
amygdala and, in addition to glutamate, corticotropin-releasing factor
in a stress-induced reinstatement mechanism (Shaham, Shalev, Lu, De
Wit, & Stewart, 2003).
3. Tryptophan metabolism and the kynurenine pathway
TRP, as an essential amino acid, is acquired from the diet, after which
is either destined to the formation of proteins or undergoes metabolic
degradation. The main metabolic route of TRP degradation is the
kynurenine pathway, which eventually leads to the synthesis of redox
cofactor nicotinamide adenine dinucleotide (Fig. 2). Up to 95% of TRP
is metabolized to kynurenine (KYN), while the remaining 5% is trans-
formed into serotonin (5-HT) (Ikeda et al., 1965; Leklem, 1971). KYN
is formed by the action of the enzymes indolamine 2,3-dioxygenase
(IDO), present in most tissues (Yamazaki, Kuroiwa, Takikawa, & Kido,
1985), and tryptophan 2,3-dioxygenase 2 (TDO2, here TDO), found
mainly in the liver (Rongvaux, Andris, Van Gool, & Leo, 2003). IDO exists
as two different proteins coded for on adjacent genes in humans and
mice (IDO1 and IDO2; Badawy, 2017). Whereas IDO1 is widely
expressed, exhibits high affinity for TRP and has been shown to have
an important role in systemic TRP catabolism in particular when in-
duced by inflammatory stimuli (Larkin et al., 2016), IDO2 shows a
more restricted pattern of expression, a lower affinity for TRP and re-
duced catalytic activity compared with IDO1 (Metz et al., 2007). Al-
though studies indicate a non-redundant role for this form of the
enzyme in the control of inflammation and adaptive immunity, its dele-
tion does not alter plasma concentrations of KYN (Metz et al., 2014),
thus, its contribution to systemic TRP catabolism has yet to be defined.
In the mammalian brain, KYN can be synthesised by IDO1, though
more than half of brain KYN is taken up from the periphery (60%), indi-
cating that it can be transported across the blood-brain barrier (BBB)
(Fukui, Schwarcz, Rapoport, Takada, & Smith, 1991). From KYN, the
pathway splits in two directions: the neurotoxic branch, towards the
formation of quinolinic acid (QA) by the action of the enzyme
kynurenine 3-monooxygenase (KMO) (Guillemin, 2012); and the neu-
roprotective branch, by the action of the enzyme kynurenine amino-
transferase (KAT) leading to the formation of kynurenic acid (KYNA)
(Schwarcz, Bruno, Muchowski, & Wu, 2012a, 2012b). The KYNA/QA
ratio has been proposed recently as a putative neuroprotection index,
N. Morales-Puerto, P. Giménez-Gómez, M. Pérez-Hernández et al. Pharmacology & Therapeutics 223 (2021) 107807

Fig. 1. Sites of action of different drugs in the VTA-NAc connection. Although converging in the release of DA in the NAc, each drug of abuse can act through different mechanisms in order to
promote this circuitry signalling. With the exception of amphetamines, all drugs discussed in this review can alter the activity of glutamatergic afferences to VTA, as well as the activity of
local GABAergic interneurons, causing an increment of the former's and an inhibition in the latter's input. EtOH would act on GABAergic neurons by blockade of glutamatergic receptors, i.e.
AMPA and NMDA, while nicotine, cannabis and opioids would activate nAChR, CB1 and MOR receptors, respectively. EtOH and nicotine have the ability to directly activate dopaminergic
neurons by interacting with G protein-coupled inwardly rectifying potassium channels, in the case of EtOH, or nAChR, in the case of nicotine. In the NAc, cocaine and amphetamines exert
their effects by increasing the presence of DA on the synapse. On the one hand, both drugs diminish DA reuptake by blockade of the dopamine transporter. Additionally, amphetamines
induce reverse transport of DA. On the other hand, cocaine increases the concentration of DA in the synapse by desensibilization of the D2 autoreceptor. AMPA: α-amino-3-hydroxy-5-
methyl-4-isoxazolepropionic acid receptor; CB1: cannabinoid receptor 1; D2R: dopamine autoreceptor 2; DA: dopamine; DAT: dopamine transporter; EtOH: ethanol; GIRK: G protein-coupled
inwardly rectifying potassium channel; MOR: μ opioid receptor; nAChR: nicotinic acetylcholine receptor; NMDA: N-methyl-D-aspartate receptor; VTA: ventral tegmental area.

by which decreases in the ratio can signal inflammation-related pathol-
ogy (Savitz et al., 2015).
QA is one of the most studied metabolites of KYN since its interaction
with the N-methyl-D-aspartate (NMDA) receptor complex, an ionotropic
glutamate receptor, can cause excitotoxic neuronal cell loss and convul-
sions (Stone & Perkins, 1981). In contrast, KYNA is an endogenous
NMDA receptor antagonist, which acts mainly at the glycine site on the
receptor complex (Birch, Grossman, & Hayes, 1988; Kessler, Terramani,
Lynch, & Baudry, 1989; Perkins & Stone, 1982). It is well-known that in
many neurodegenerative disorders, for instance Parkinson's disease and
Alzheimer's disease, and in stroke and epilepsy, the activation of excit-
atory amino acid receptors, such as the NMDA receptor, plays a pivotal
role (Gagliardi, 2000; Greenamyre & Young, 1989; Shaw, 1993). Numer-
ous studies in the literature have attempted to clarify whether KYNA, as
an excitatory amino acid receptor antagonist, can exert a therapeutic ef-
fect in these neurological disorders (Hertelendy, Toldi, Fülöp, & Vécsei,
2018; Mangas et al., 2018; Tanaka, Bohár, Martos, Telegdy, & Vécsei,
2020). Furthermore, KYNA can interact with several other receptors.
Sites of action for this metabolite have been described in the astrocytic
G-protein coupled receptor 35 (GPR35) (Wang et al., 2006). Also, KYNA
is an agonist at the aryl hydrocarbon receptor (AhR) (DiNatale et al.,
2010). Finally, there is one last receptor with which KYNA appears to in-
teract. In the early 2000's, a study using cultured hippocampal neurons
showed that KYNA non-competitively inhibited the presynaptic α7
nicotinic acetylcholine receptor (nAChR), blocking glutamate release,
and regulated the expression of α4β2nAChR (Hilmas et al., 2001)
(Fig. 3). However, further experiments in order to replicate this event
have had mixed outcomes: while some authors could not reproduce the
results, even when using high concentrations of KYNA (Arnaiz-Cot et al.,
2008; Dobelis, Staley, & Cooper, 2012; Mok, Fricker, Weil, & Kew, 2009;
Stone, 2020), the same group in subsequent assays and also other re-
searchers did so, both in vitro and in vivo (Alkondon et al., 2011; Grilli
et al., 2006; Lopes et al., 2007). To this day this interaction continues to ac-
cumulate supporting evidence, although it remains to be unequivocally
confirmed and is thus regarded as dubious by some experts. In the next
section, we will elaborate on the interaction between KYNA and its
brain targets in more detail.
Since KYNA has a very limited ability to cross the BBB (Fukui et al.,
1991), efforts have been made to raise its brain levels in order to pro-
mote its neuroprotective influence. To this end, KYNA derivatives have
been synthesised (e.g. glucosamine-KYNA, 4-chloro-KYNA and 7-
chloro-KYNA), in order to produce compounds similar to KYNA in
their ability to act on the glutamate receptor but better transported
across the BBB (Deora et al., 2017; Gellért et al., 2012). Moreover, at
least three more strategies have been established for the purpose of pro-
ducing increases in the cerebral concentration of KYNA. The use of pro-
benecid, an inhibitor of the transport of organic acids such as KYN and
KYNA, blocks the exit of these compounds out of the brain, thus

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N. Morales-Puerto, P. Giménez-Gómez, M. Pérez-Hernández et al. Pharmacology & Therapeutics 223 (2021) 107807

Fig. 2. Kynurenine pathway of TRP degradation and effect of drugs on KYN metabolites. While a small portion of circulating TRP is destined to the synthesis of proteins or serotonin, 95% of it
is metabolized through the kynurenine pathway, which ultimately generates two main products: the neuroprotective KYNA and the neurotoxic QA. Several drugs of abuse have been
shown to affect the levels of metabolites of this pathway. Cocaine can decrease KYNA and anthranilic acid concentration, while leaving KYN and QA unaltered. EtOH exposure causes
an increase in KYN levels, but it does not affect KYNA. Nicotine raises KYNA levels. Amphetamine reduces both KYN and KYNA. 3-HAO: 3-hydroxyanthranilic acid oxygenase; AADC:
aromatic-L-amino acid decarboxylase; EtOH: ethanol; IDO: indoleamine-2,3-dioxygenase; KAT: kynurenine amino transferase; KMO: kynurenine 3-monooxygenase; KYN: kynurenine; KYNA:
kynurenic acid; KYNU: kynureninase; QA: quinolinic acid; QPRT: quinolinic acid phosphoribosyl transferase; TDO: tryptophan-2,3-dioxygenase; TPH: tryptophan hydroxylase; TRP: tryptophan.

increasing their cerebral concentration (Nilsson, Linderholm, & Erhardt,
2006). The second strategy consists in the administration of exogenous
L-kynurenine to increase both peripheral and central levels of KYN and
KYNA. These studies have been performed pre- and postnatally and
showed that the administration of KYN can cause cognitive deficits
(Alexander et al., 2013; Pocivavsek, Wu, Elmer, Bruno, & Schwarcz,
2012), learning deficits (Pocivavsek, Thomas, Elmer, Bruno, &
Schwarcz, 2014) and a schizophrenic-like phenotype (Goeden et al.,
2017). The third strategy involves the use of enzyme inhibitors which
block the synthesis of the neurotoxic QA and redirect KYN metabolism
towards KYNA. In this sense, Ro 61–8048, a KMO inhibitor (Röver,
Cesura, Huguenin, Kettler, & Szente, 1997), is one of the most promising
strategies for the treatment of neurodegenerative diseases or other pa-
thologies such as drug abuse (Zwilling et al., 2011). The administration
of Ro 61–8048 produces a marked increase in both KYN and KYNA in
plasma and in various brain areas of mice and rats. Since Ro 61–8048 ex-
hibits low blood-brain penetration the increases observed are derived
from the increases in the periphery. Moreover, since KYNA does not
cross the BBB, the increase in KYNA in the brain is due to the conversion
of peripherally-derived KYN. A low brain penetrability could be advan-
tageous by maximizing clinical benefit and managing toxicity in combi-
nation therapies (Reinhart & Kelly, 2011). Although there is concern
that the increase in brain KYN, in the absence of brain KMO inhibition,
might lead to an increased conversion to QA (Muneer, 2020) this does
not appear to be the case since QA levels in the brains of mice were un-
altered following treatment with Ro 61–8048 (Chiarugi & Moroni,
1999) or JM6 (a prodrug of Ro 61–8048; Zwilling et al., 2011). Thus, pe-
ripheral inhibition of KMO appears to be a valuable mechanism for in-
creasing levels of KYN and KYNA in the CNS.
4. Neuromodulation of brain circuits associated with addiction by
kynurenine and its metabolites
In spite of acting through different mechanisms of action involving
several neurotransmitter systems and eliciting varying effects outside
the brain reward circuitry, all drugs of abuse ultimately activate the
mesolimbic pathway after acute administration: i.e. by acting at different
levels, they directly or indirectly increase dopaminergic transmission
from the VTA to the NAc in the ventral striatum (Nestler, 2005). This do-
paminergic transmission mediates the hedonic consequences of a rein-
forcing stimulus, promoting associative learning about the stimulus or
anticipating its rewarding effects (Di Chiara, 1999). Hence, the
mesolimbic circuit is considered the neuroanatomical substrate for drug
dependence. It is widely modulated by several neurotransmitter systems,
especially by glutamatergic inputs from PFC, hippocampus, amygdala and
other areas, which, together, are named “brain reward regions” (Russo &
Nestler, 2013). Drug-induced modifications in NAc glutamate neurotrans-
mission have been identified as an underlying factor driving drug-taking,
relapse, withdrawal and other drug-associated behaviours for several
drugs (Kalivas, LaLumiere, Knackstedt, & Shen, 2009).
The kynurenine metabolite that has received most attention due to
its neuromodulatory role is KYNA. The mechanism by which KYNA
can counteract the addictive effects of drugs of abuse seems to involve
the regulation of glutamatergic transmission through interactions with
several of its target receptors. Firstly, KYNA shows a great affinity to
NMDA receptors, where it functions as an antagonist by interacting at
the glycine binding site (Birch et al., 1988; Kessler et al., 1989; Stone &
Perkins, 1981). This relationship is well-documented, given that since
its discovery, hundreds of scientists have verified this antagonism

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N. Morales-Puerto, P. Giménez-Gómez, M. Pérez-Hernández et al. Pharmacology & Therapeutics 223 (2021) 107807

Fig. 3. Targets of the kynurenine pathway metabolites in the CNS. Several compounds derived from kynurenine metabolism exert effects on different receptors on the brain. KYNA
neuroprotective properties may come from its ability to antagonise both the NMDA and the AMPA glutamate receptor, as well as, potentially, the α7nAChR. On the contrary, QA
neurotoxicity is due to stimulation of both the NMDA and AMPA receptors. Moreover, KYNA is an agonist of astrocytic GPR35 and transcription factor AhR, which is also a target for
KYN and CA. XA participates on glutamatergic transmission in several stages: on the one hand, it prevents glutamate reuptake via inhibition of vesicular transporters; on the other
hand, alongside with CA, it can activate metabotropic glutamate receptors. Green arrows represent activation, red lines represent inhibition. 3-HK: 3-hydroxykynurenic acid; α7nAChR:
alpha-7 nicotinic acetylcholine receptor; AhR: aryl-hydrocarbon receptor; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BBB: blood-brain barrier; CA: cinnabarinic
acid; CNS: central nervous system; GPR35: G protein-coupled receptor 35; KYN: kynurenine; KYNA: kynurenic acid; mGluR: metabotropic glutamate receptor; NMDAR: N-methyl-D-aspartate
receptor; QA: quinolinic acid; TRP: tryptophan; vGLUT: vesicular glutamate transporter; XA: xanturenic acid.

(Moroni, Cozzi, Sili, & Mannaioni, 2012; Schwarcz et al., 2012a, 2012b;
Stone & Darlington, 2002). The relevance of the KYNA-NMDA receptor
interaction to the drug addiction field relies especially on the involve-
ment of NMDA receptors in two critical aspects. On the one hand, cogni-
tive processes, which are overall negatively affected by drug
consumption, can undergo alterations due to imbalances in the
kynurenine pathway (Akagbosu, Evans, Gulick, Suckow, & Bucci, 2012;
Chess, Simoni, Alling, & Bucci, 2007; Pocivavsek et al., 2012; Ramirez
Ortega et al., 2020). For instance, the increased concentrations of
KYNA found in the brains of schizophrenic patients (Erhardt, Oberg, &
Engberg, 2001; Linderholm et al., 2012; Nilsson et al., 2005), which
would cause a glutamatergic hypofunction via NMDA receptor antago-
nism, could be the explanation for the negative symptoms of schizo-
phrenia, in particular those involving cognitive impairment (Chess
et al., 2007; Shepard, Joy, Clerkin, & Schwarcz, 2003). On the other
hand, neural plasticity, a key factor in addictive behaviour, depends on
events of long-term potentiation or long-term depression involving
NMDA receptors on dopaminergic neurons which ultimately generate
modifications in the neural circuitry that lead to compulsive consump-
tion of substances of abuse (Lüscher & Malenka, 2011; Zweifel, Argilli,
Bonci, & Palmiter, 2008).
Additionally, despite its need of definitive validation, the role of
KYNA as a negative allosteric modulator of α7nAChRs is getting
attention in the field of drug addiction, since electrophysiological stud-
ies have demonstrated that physiologically relevant concentrations of
KYNA block the activity of this receptor in a non-competitive and
voltage-independent manner (Hilmas et al., 2001). Within the
mesolimbic pathway, α7nAChRs are mainly located at the terminals of
glutamatergic afferences that modulate the activity of medium-sized
spiny neurons of the NAc (Zappettini et al., 2014) and dopaminergic
neurons of the VTA (Jones & Wonnacott, 2004). The activation of these
receptors induces the release of glutamate that subsequently enhances
the release of DA in NAc from VTA dopaminergic neurons. Therefore,
negative modulation of KYNA on α7nAChR reduces mesolimbic activity.
Moreover, KYNA has been described to act as a ligand of the orphan
GPR35 receptor (Wang et al., 2006), whose activation may contribute to
the decrease in extracellular glutamate levels and, therefore, to a reduc-
tion in excitatory transmission (Albuquerque & Schwarcz, 2013). All
these evidences indicate that KYNA has a role modulating glutamatergic
neurotransmission and therefore potentially altering several aspects of
addictive processes.
In addition to acting at receptors involved in glutamatergic signal-
ling, KYNA, along with KYN, acts as an agonist of the AhR receptor
(DiNatale et al., 2010), a cytoplasmic receptor of pollutants or xenobi-
otics which impacts on neuronal proliferation, differentiation, and sur-
vival (Suzuki, Hidaka, Kumagai, & Yamamoto, 2020) and could

5
N. Morales-Puerto, P. Giménez-Gómez, M. Pérez-Hernández et al.
therefore also have an impact on the development of drug addiction.
AhR has been proposed as a cellular sensor of changes in the cellular mi-
lieu and as such its participates in several biological processes highly rel-
evant to tissue homeostasis, but it has also been implicated in the
development of a broad of pathological conditions (Bock, 2020). Addi-
tionally, gut microbiota produces a broad spectrum of metabolic prod-
ucts that interact with the host organism, among them TRP
metabolites (Rooks & Garrett, 2016), which can act as low-affinity
AhR ligands (Dvořák, Sokol, & Mani, 2020). Finally, dietary products
such as 3,3′-diindolylmethane, a natural product from the Brassica
genus with therapeutic potential, acts as a positive modulator of AhR
(Yin, Chen, Mao, Wang, & Chen, 2012). Taken together all these data in-
dicates the promiscuity of this receptor and the complexity of its study.
Although we have thoroughly reviewed the effects of KYNA, since it
is a neuromodulator with a large number of targets, we cannot forget
the role that QA might play in addiction due to its neurotoxic capacity,
nor should other metabolites be overlooked, such as xanthurenic acid
(XA), and cinnabarinic acid (CA) (Fig. 3) (Lowe et al., 2014). Similar to
KYNA, CA also activates the AhR receptor and thus may similarly mod-
ulate the development of drug addiction. In addition, it is a weak
orthosteric agonist of metabotropic glutamate receptor 4 (mGluR)
(Fazio et al., 2012), receptors that are located presynaptically and inhibit
neurotransmitter release (Nicoletti et al., 2011). Although physiological
brain levels of CA are below those required to activate these receptors,
levels become detectable under inflammatory conditions (Fazio et al.,
2012). Thus, under inflammatory conditions produced by several
drugs of abuse, CA may activate mGluR4 and restore the homeostasis
of extracellular glutamate levels which is altered following drug use
(Kalivas et al., 2009). Recently, LSP2-9166, a mGluR4/mGluR7 agonist,
has been shown to selectively reduce ethanol (EtOH) consumption, re-
inforcing efficacy of EtOH and reacquisition of EtOH self-administration
after abstinence (Lebourgeois et al., 2018) suggesting that modulation
of the metabolite might produce reductions in consumption of drugs.
XA appears to interact indirectly with group II inhibitory mGluR2 and
mGluR3 possibly acting as an allosteric agonist. Activation of these re-
ceptors, as with mGluR4, could lead to a reduction of extrasynaptic
levels of glutamate and, thus, negatively regulate brain reward function
(Kenny, Boutrel, Gasparini, Koob, & Markou, 2005). In support of this,
activation of the receptors elevates intracranial self-stimulation thresh-
olds and decreases relapse to cocaine-seeking behaviour (Weiss &
Baptista, 2003). In addition, XA may also inhibit glutamatergic transmis-
sion by blocking transport of L-glutamate into synaptic vesicles thereby
ultimately reducing the synaptic release of L-glutamate (Bartlett,
Esslinger, Thompson, & Bridges, 1998) and restoring glutamate
homeostasis.
5. Alcohol
Alcohol, or EtOH, is the most widely consumed drug in the world. It
has been estimated that harmful use of alcohol produces 3 million
deaths every year, which represents 1 out of 20 of all deaths in the
world (5.3%). More than three quarters of these were among men.
These deaths occur relatively early in life; in the 20–39 years age
group 13.5% of the total deaths are alcohol attributable. Overall, the
harmful use of alcohol causes more than 5% of the global disease burden.
Its consumption is related to more than 200 diseases and injury condi-
tions. Moreover, the consequences are not only limited to the health
sphere: alcohol abuse brings economic and social losses to the society
at large (World Health Organization, 2019a). Pharmacological treat-
ments for alcohol use disorder can be sorted into several groups de-
pending on the strategy of action: aversive drugs, such as disulfiram;
anticraving drugs, including naltrexone and nalmefene (which is only
authorised for EtOH addiction in Europe); and other drugs of unknown
mechanism, such as acamprosate (Kranzler & Soyka, 2018; Mutschler,
Grosshans, Soyka, & Rösner, 2016). EtOH produces DA release by several
mechanisms. Firstly, EtOH directly binds to G protein-coupled inwardly
6
Pharmacology & Therapeutics 223 (2021) 107807
rectifying potassium channels located in VTA dopaminergic neurons,
producing an increase in VTA cell firing. Moreover, glutamatergic and
GABAergic synapses are also altered: EtOH acts reducing the activity
of γ-aminobutyric acid (GABA) interneurons and increasing the activity
of glutamate inputs on VTA dopaminergic neurons (Fig. 1) (Juarez &
Han, 2016).
5.1. Changes in kynurenine pathway associated with ethanol
administration
Exposure to EtOH has been repeatedly studied in the context of TRP
metabolism and, although most of the studies in humans focused on 5-
HT (LeMarquand, Pihl, & Benkelfat, 1994), preclinical studies in animals
have established that EtOH administration can modify TDO activity
leading to KYN accumulation (Badawy, 2002). These studies have also
been validated in humans, demonstrating that various doses of EtOH
produce an elevation in plasmatic KYN levels via liver TDO activation
(Badawy, 2002; Badawy, Doughrty, Marsh-Richard, & Steptoe, 2009).
This effect on the kynurenine pathway has been observed even after
prenatal alcohol exposure in human embryonic stem cell-derived neu-
ral lineages, providing evidence to support the study of the relationship
between foetal alcohol spectrum disorders and the kynurenine pathway
(Palmer et al., 2012).
The activation of the kynurenine pathway observed under experi-
mental conditions after alcohol exposure can also be found in the few
studies conducted in abstinent patients diagnosed with alcohol use dis-
order, reinforcing the idea that there is a relationship between EtOH
consumption and this metabolic pathway of TRP. In this sense, in a
study carried out with 169 patients, the results revealed no changes in
plasmatic TRP but KYN levels were augmented. The changes in KYN
levels were independent of the presence of depression; however an as-
sociation with duration of abstinence and alcohol use disorder severity
was found (Neupane, Lien, Martinez, Hestad, & Bramness, 2015). An-
other study examined TRP metabolism in alcohol-dependent patients
assessing short-term withdrawal (4 weeks abstinence) and long-term
withdrawal (12 weeks abstinence). In line with previous results, levels
of TRP remained unchanged, while an elevation of KYN was found in
week 4 which was even greater at week 12 (Gleissenthall et al., 2014).
In the same direction, preclinical studies show that EtOH withdrawal in-
creases IDO1 activity in the PFC of mice (Dos Santos, Junqueira Ayres, de
Sousa Pinto, Silveira, et al., 2021). Altogether, these evidences suggest a
possible role of the kynurenine pathway in the mediation of the in-
creased stress sensibility in post-withdrawal alcohol-dependent pa-
tients. This imbalance in TRP metabolism can last even after
protracted abstinence as revealed by a recent study in which plasmatic
concentration of KYN was increased while that of KYNA was decreased
(Vidal et al., 2020). Nonetheless, the relationship between the
kynurenine pathway and EtOH consumption may well be more com-
plex. Recent research has shown that KYNA can be found in the order
of micromolar concentrations in several commercial alcoholic bever-
ages including red wine (Turska et al., 2019), which may also contain
picolinic acid and QA (Yılmaz & Gökmen, 2020), suggesting that EtOH
consumption may affect the kynurenine pathway not only through its
alteration, but also by affecting substrate availability.
In animal models, our laboratory has studied the effect of voluntary
consumption of EtOH with the Drinking in the Dark paradigm (a para-
digm that has been established as a model of binge drinking) on TRP,
KYN and 5-HT levels in plasma and in limbic forebrain, a brain area, an-
terior to the optic chiasm excluding the olfactory bulbs, which contains
the reward system area (Wang, Liu, Harvey-White, Zimmer, & Kunos,
2003). Our results showed that there were no changes in TRP, KYN or
5-HT in either plasma or limbic forebrain, which suggests that this
model cannot modify TRP metabolism or the kynurenine pathway
(Giménez-Gómez et al., 2018). In order to further explore the role of
EtOH consumption in the kynurenine pathway, we used the Chronic In-
termittent paradigm, a model validated to produce changes in the
N. Morales-Puerto, P. Giménez-Gómez, M. Pérez-Hernández et al.
neuroimmune component of chronic EtOH abuse. Our data demonstrate
that this model can alter the kynurenine pathway producing an increase
in KYN both in plasma and brain. It is the first study showing that EtOH
consumption can modulate the kynurenine pathway in the brain of ro-
dents (Giménez-Gómez et al., 2019). In our study, EtOH consumption
produces an alteration in the permeability of the gut and the extravasa-
tion of LPS, a proinflammatory compound that induces the activation of
IDO1 (Wang et al., 2010) and consequently increases the levels of KYN
in brain. Taken together all this evidence indicates that the mechanisms
implicated in EtOH-induced alterations of kynurenine pathway are
complex, and at least three ways exist. The first is the direct contribution
of KYN metabolites from alcoholic beverages (Turska et al., 2019). The
second implicates the regulation of IDO1 by LPS, and this mechanism re-
quires more attention in the future since it is supported by the observa-
tion that EtOH consumption produces extravasation of LPS in both
humans and rodents (Giménez-Gómez et al., 2019; Orio, Alen, Pavón,
Serrano, & García-Bueno, 2019). Finally, EtOH produces an increase in
glucocorticoids (Lu & Richardson, 2014) and it is well-established that
glucocorticoids can activate TDO (Badawy, 2017).
5.2. Pharmacological modulation of kynurenine pathway and effects on
ethanol use
The first evidence of the relationship between the manipulation of
the kynurenine pathway and EtOH was obtained when studying the
link between the consumption of this drug and the hole reflex in ro-
dents. Intraperitoneal administration of KYNA, XA and picolinic acid at-
tenuated the alterations in the hole reflex produced by low dose EtOH
while the intracerebroventricular administration completely abolished
them (Table 1) (Lapin, Mizaev, Prakh'e, & Ryzhkov, 1991).
Furthermore, KYN and KYNA may modulate mechanisms specifi-
cally related to EtOH addiction. Regarding KYN, our laboratory showed
recently that the exogenous administration of L-kynurenine can reduce
EtOH consumption in mice under the Drinking in the Dark paradigm
(Giménez-Gómez et al., 2018). Moreover, both metabolites act as strong
inhibitors of the mammalian liver mitochondrial low Km aldehyde de-
hydrogenase, a key enzyme in the metabolism of EtOH (Fogaça et al.,
2016a), both in vitro (Badawy & Morgan, 2007) and in vivo (Badawy,
Bano, & Steptoe, 2011). In this line, there are evidences that indicate
that KYNA, 3-hydroxykynurenine (3−HK) and 3-hydroxyanthranilic
acid administered by intraperitoneal injection to rodents block the ac-
tivity of aldehyde dehydrogenase and this inhibition could induce aver-
sion towards EtOH (Table 1). These results imply that it is possible to
manipulate the kynurenine pathway to reduce EtOH consumption via
an aversive mechanism (Badawy et al., 2011), similar to what occurs
with disulfiram (Hald, Jacobsen, & Larsen, 2009).
Recently, the use of Ro 61–8048, a selective KMO inhibitor, as a phar-
macological tool in order to produce a strong elevation in KYNA has
demonstrated effectiveness in manipulating EtOH consumption or the
reinstatement of EtOH. Cue-induced reinstatement can be abolished
by administration of Ro 61–8048 (Table 1) (Vengeliene, Cannella,
Takahashi, & Spanagel, 2016). In the same line, our group has demon-
strated that Ro 61–8048 can reduce EtOH consumption in the Drinking
in the Dark model. Ro 61–8048 prevented EtOH-induced DA release in
the NAc shell thanks to its ability to increase KYNA concentration in
brain, acting as a negative allosteric modulator of α7nAChRs. The use
of PNU120596, a selective positive allosteric modulator of α7nAChRs,
allowed us to verify the involvement of the named receptors, since its
administration prevented the effects of Ro 61–8048 (Table 1) (Fig. 4)
(Giménez-Gómez et al., 2018), an outcome consistent with those ob-
served in studies with other abuse substances by other groups
(Justinova et al., 2013; Secci et al., 2017; Vengeliene et al., 2016). The
exact mechanism by which an elevation in KYNA can reduce EtOH
self-administration and its reinstatement needs more investigation to
be clearly elucidated, but the most promising hypotheses appear to be
for the former, modulation of the α7nAChRs in glutamatergic
7
Pharmacology & Therapeutics 223 (2021) 107807
connexions to VTA, in order to reduce their firing and for the latter, fol-
lowing withdrawal, antagonism of NMDA receptors. These results to-
gether highlight the usefulness of manipulating the kynurenine
pathway as a pharmacological tool to modify EtOH consumption and
point to a possible modulator of alcohol drinking behaviour.
Finally, in the last year a relationship between the emotional deficits
caused by ethanol consumption and the kynurenine pathway has been
established. EtOH consumption produces mood (Boden & Fergusson,
2011) or anxiety alterations (Kliethermes, 2005). Our group has con-
firmed that the Chronic Intermittent paradigm of EtOH consumption
produces depressive symptomatology in mice via elevation of KYN
levels. Moreover, treatment with antibiotics counteracts these effects.
Our data reveal the involvement of the microbiota in the consequences
on mood of EtOH consumption via the alteration of kynurenine path-
way (Giménez-Gómez et al., 2019). In the same line, it was recently ev-
idenced that an IDO1 inhibitor can reduce emotional deficits caused by
EtOH addiction (Jiang et al., 2020). Taken together, these data indicate
that the kynurenine pathway plays a role in the development of mood
disorders due to EtOH consumption and open a new door for the treat-
ment of these alcohol-related pathologies.
6. Nicotine
According to World Health Organization, more than 1.1 billion peo-
ple over the age of 15 years smoked tobacco in 2016, which accounts for
more than a fifth of the global population. Tobacco use is a major risk
factor for cardiovascular and respiratory diseases, for over 20 different
types of cancer and for other pathologies. It is estimated that more
than 8 million people suffer a tobacco-related death yearly, most of
them taking place in low or middle income countries (World Health
Organization, 2019b).
Although most of the harm of tobacco smoking comes from the inha-
lation of smoke and other chemicals present in tobacco preparations,
the main addictive and psychoactive compound of tobacco is nicotine.
Nicotine is an agonist of nAChR, which is highly expressed in VTA dopa-
minergic neurons. Thus, nicotine can produce an increase in DA release
by their direct effect in VTA dopaminergic neurons. Complementary to
this effect, nicotine also acts on GABA interneurons and glutamatergic
afferents via the nAChR located in these neurons, with the final conse-
quence of an increase in DA release via desensitization of GABA neurons
and an increased glutamate potentiation (Fig. 1) (Juarez & Han, 2016).
Pharmacological treatments for smoking cessation include nicotine re-
placement therapy (patch, gums, …) (Wadgave & Nagesh, 2016),
bupropion (antidepressant) (Tran, Ho, & Varghese Gupta, 2019) and
varenicline (partial nicotinic agonist) (Jordan & Xi, 2018).
.
6.1. Changes in kynurenine pathway associated with nicotine
administration
In the early 2000's, several studies analysed the effect of nicotine ex-
posure on KYNA concentration in the brain of experimental animals.
Prolonged nicotine administration caused significant changes in KYNA
levels. These nicotine-induced changes occurred as period-of-expo-
sure-dependent fluctuations of KYNA concentration, where KYNA levels
decreased when the time of exposure was 4, 5 or 6 days, whereas longer
treatments (a 10- or 15-day treatment) caused an increment in KYNA.
The effect of nicotine on KYNA concentration was also dose-
dependent and non-region-specific, since similar effects were observed
in different brain areas, i.e. hippocampus, striatum and frontal cortex.
However, these changes were not accompanied by alterations on
KYNA serum levels nor KYN brain and serum levels (Hilmas et al.,
2001; Rassoulpour, Wu, Ferre, & Schwarcz, 2005). These results were
corroborated in in vitro experiments and, using several nAChR inhibi-
tors, ruled out the involvement of the direct activation of nAChR by nic-
otine administration in the KYNA increase. Moreover, they suggested an
N. Morales-Puerto, P. Giménez-Gómez, M. Pérez-Hernández et al.
Table 1
Modulation of the kynurenine pathway and effects associated with drug abuse. ALDH: aldehyde dehydrogenase; EtOH: ethanol; KMO: kynurenine 3-monooxygenase..
Compound Structure
Kynurenine
Kynurenic acid
3-Hydroxykynurenine
3-Hydroxyanthranilic acid
Picolinic acid
Xanthurenic acid
Ro 61–8048
enhancement in KAT I and KAT II activities as responsible for the change
in KYNA production, but the exact mechanism is unknown (Zielińska,
Kuc, Zgrajka, Turski, & Dekundy, 2009).
Not much has been studied regarding nicotine addiction and
kynurenine pathway alterations in humans. In 2006, it was determined
that serum IDO activity was lower in smokers than in non-smokers. This
effect was strong and immediate but of short duration, given that the ac-
tivities were similar in non-smokers and smokers that had not smoked
in the two days previous to the study (Pertovaara et al., 2006).
6.2. Pharmacological modulation of kynurenine pathway and effects on
nicotine use
KMO has been the target of several studies that aim to reduce nico-
tine consumption. Pharmacological inhibition of KMO diminishes the
reinforcing effects of nicotine in animal models. Ro 61–8048 succeeded
in reducing nicotine self-administration at different doses, as well as
relapse-like effects due to reexposure to nicotine. nAChR seemed to be
involved in the mechanism of action of Ro 61–8048. When using
Pharmacology & Therapeutics 223 (2021) 107807
Function Use related to drug abuse
Metabolite of the kynurenine pathway • Reduction of nicotine-evoked glutamatergic
signalling (Koshy Cherian et al., 2014)
• Reduction of EtOH consumption
(Giménez-Gómez et al., 2018)
Metabolite of the kynurenine pathway • Prevention of the effect of EtOH in the
hole reflex (Lapin et al., 1991)
• Blockade of the activity of ALDH
(aversion to EtOH) (Badawy et al., 2011)
Metabolite of the kynurenine pathway • Blockade of the activity of ALDH
(Aversion to EtOH) (Badawy et al., 2011)
Metabolite of the kynurenine pathway • Blockade of the activity of ALDH
(Aversion to EtOH) (Badawy et al., 2011)
Metabolite of the kynurenine pathway • Prevention of the effect of EtOH in the
hole reflex (Lapin et al., 1991)
Metabolite of the kynurenine pathway • Prevention of the effect of EtOH in the
hole reflex (Lapin et al., 1991)
KMO inhibitor • Prevention of cannabinoid abuse
(Justinova et al., 2013)
• Abolition of EtOH cue-induced reinstatement
(Vengeliene et al., 2016)
• Reduction of EtOH consumption
(Giménez-Gómez et al., 2018)
PNU120596 to modulate the activity of α7nAChRs, the effects of Ro
61–8048 on reinforcement and relapse were not observed, although
these findings did not agree across different animal species (Fig. 4)
(Secci et al., 2017). The mechanism through which an elevation in
KYNA levels can reduce nicotine self-administration involves gluta-
matergic connections from the cortex to VTA and NAc. When nicotine
produces an increase in glutamatergic firing in these connections,
KYNA may act as an allosteric negative modulator of the α7nAChR in
these glutamatergic neurons, therefore blocking the effect of nicotine
on the reward system. We should not, however, overlook the participa-
tion of NMDA receptor antagonism by KYNA in VTA dopaminergic neu-
rons, which would make these neurons unresponsive to the
glutamatergic firing induced by nicotine.
A recent study proposed modulation of KMO gene expression as a
therapeutic target for smoking initiation and dependence. Bioinformat-
ics analysis identified a non-coding RNA region which could be used as a
genetic tool to modulate KMO expression. This non-coding RNA region
encodes for two microRNA, has-miR-5096 and has-miR-1285-3p, both
of which bind to a regulatory region of the KMO mRNA. Downregulation
8
N. Morales-Puerto, P. Giménez-Gómez, M. Pérez-Hernández et al. Pharmacology & Therapeutics 223 (2021) 107807

Fig. 4. Mechanism of DA release inhibition by Ro 61–8048. The risk of addiction of a given drug of abuse depends on the release of DA in the NAc from projection neurons located in the VTA.
Several studies using different drugs, such as EtOH, nicotine, cannabis or cocaine, have aimed to elucidate the mechanism by which Ro 61–8048 is able to prevent or reduce some of the
drug-related behaviours (self-administration, relapse-like effects, …). The most popular explanation involves the inhibition of α7nAChR by KYNA. Ro 61–8048 binds in a non-competitive
manner to KMO enzyme, causing an allosteric change that blocks the metabolism of KYN towards 3-HK. In this situation, KYN is mainly converted by KATs to KYNA, increasing significantly
its concentration. The antagonism of α7nAChR by KYNA causes an interruption of glutamatergic signalling from cortex to VTA. As a result, dopaminergic neurons in VTA stop firing and DA
is not released in the NAc, thus ceasing the activation of the reward circuits induced by drug exposure. 3-HK: 3-hydroxykynurenine; α7nAChR: α7 nicotinic acetylcholine receptor; KAT:
kynurenine aminotransferase; KMO: kynurenine monooxygenase; KYN: kynurenine; KYNA: kynurenic acid; NAc: nucleus accumbens; VTA: ventral tegmental area.

of KMO via microRNA would result in an increase of KYNA levels, thus
promoting α7nAChR inhibition (Aziz, Abdel-Salam, Al-Obaide, Alobydi,
& Al-Humaish, 2018).
The link between nicotine and the kynurenine pathway, in particular
KYNA, is especially interesting in the context of schizophrenia. Schizo-
phrenia is a complex neuropsychiatric disorder with patients often
exhibiting a high degree of cognitive impairment whose underlying
cause is thought to involve glutamatergic dysfunction. Schizophrenic
patients also have elevated KYNA brain concentration compared
with control subjects (Erhardt et al., 2001; Linderholm et al., 2012)
and increased KYNA levels have been linked to cognitive deficits in
animal models (Akagbosu et al., 2012). Thus, it has been proposed
that the elevated KYNA concentration produces aberrant glutamater-
gic signalling. Interestingly, schizophrenic patients exhibit a high prev-
alence of nicotine abuse (Hughes, Hatsukami, Mitchell, & Dahlgren,
1986). A plausible explanation for nicotine use by schizophrenic pa-
tients might be that, given the antagonism of KYNA on α7nAChR, nic-
otine consumption would enhance the activity of these receptors in
glutamatergic neurons, thereby alleviating the glutamatergic dysfunc-
tion. Thus, KYNA and the pro-cognitive effects of nicotine can be pro-
posed as a link between these two pathologies. Decreasing KYNA
levels could be a therapeutic target in pathologies where an
upregulation of KYNA occurs and would be an alternative approach
to restoring NMDA receptor function in glutamatergic neurons. In sup-
port of this, a study with Wistar male rats showed that decreasing
KYNA levels via inhibition of KAT II enzyme with PF-04859989, a po-
tent KAT II inhibitor, restored KYN or nicotine administration-evoked
glutamate release events in the PFC. Although these experiments did
not aim to determine the targeted receptors for the observed effects,
the authors, based on previous work in which they observed that
nicotine-evoked glutamatergic transients were unaffected by knock-
out of this nAChR, argue that, while representing a believable explana-
tion, inhibition of α7nAChR may not be the main system involved in
the presented results, but rather interference of KYNA on the activity
of ionotropic glutamate receptors appears a more likely target
(Koshy Cherian et al., 2014; Parikh, Ji, Decker, & Sarter, 2010). This hy-
pothesis is consistent with evidence obtained a decade before, where
electrophysiological experiments on Sprague-Dawley rats demon-
strated that the inhibitory effect of increased KYNA levels on
nicotine-evoked VTA dopaminergic neuron increase in firing was
prevented by the partial agonist at the glycine site of the NMDA re-
ceptor, D-cycloserine (Erhardt, Schwieler, & Engberg, 2002).
Finally, a recent study has shown results that may speak in favour of
the synergy between the activity of these two receptors (Phenis et al.,

9
N. Morales-Puerto, P. Giménez-Gómez, M. Pérez-Hernández et al.
2020). Administration of an acute injection of KYN reduced the
performance of adult rats in a working memory task, while the
co-administration of positive allosteric modulators of nAChR succeeded
in maintaining normal levels of performance in this test while a NMDA
agonist did not. However, when exposed to NMDA antagonist 7-Chloro-
KYNA, deficits in the working memory task were also observed. Hence,
these results highlight the involvement of both nAChR and NMDA re-
ceptors in cognitive deficits induced by increases in KYNA levels.
7. Cannabis
In several countries, cannabis is the most abused illicit drug,
both among the general and young population. In 2016, 192 million
people used it at least once in the previous year. Perception of low
risk of harm in addition to easy access makes cannabis the most
common substance initiated in adolescent years. In fact, from the
aforementioned 192 million cannabis users, 13.8 million were
aged 15–16. Cannabis use is usually concomitant with and also
the gateway to other drugs of abuse (World Health Organization,
2019b).
Cannabis, also commonly known as marijuana, is obtained from the
Cannabis plant, endemic to Asia but nowadays cultivated worldwide.
Tetrahydrocannabinol (THC) is the main psychoactive compound in
cannabis and is a partial agonist of the cannabinoid receptor 1 (CB1),
which mediates its psychoactive effects (Fogaça et al., 2016a). Cannabis
acts producing an increase in DA release in NAc by at least two mecha-
nisms. The first one involves an increase in DA neural firing by decreas-
ing GABAergic inhibition of dopaminergic neurons, a mechanism in
which the CB1 receptors are implicated (Oleson & Cheer, 2012). Second-
ary to that, cannabinoids such as THC produce the activation of excit-
atory glutamatergic pyramidal neurons that project from PFC to the
VTA and NAc (Fig. 1) (Pistis, Muntoni, Pillolla, & Gessa, 2002; Pistis,
Porcu, Melis, Diana, & Gessa, 2001).
7.1. Changes in kynurenine pathway associated with cannabis or THC
administration
Cannabis active metabolites influence several steps of TRP metabo-
lism. In 1972, it was demonstrated that cannabis extract, as well as
pure THC, could increase the activity of two hepatic enzymes of rat,
one of them being TDO (Poddar & Ghosh, 1972). Later in 1974, the
same research group pointed out that cannabidiol (CBD, non-
psychoactive cannabis compound) did not increase TDO activity per
se, but in combination with THC potentiated the effect of the latter
(Poddar, Bhattacharyya, & Ghosh, 1974).
THC and CBD might exert a biphasic stimulation of TRP degradation
towards KYN by IDO in immune cells (Jenny, Santer, Pirich, Schennach,
& Fuchs, 2009; Jenny, Schröcksnadel, Überall, & Fuchs, 2010). At
nanomolar concentrations of both THC and CBD, activation of CB1- and
CB2-receptor increased IDO activity in peripheral blood mononuclear
cells. On the other hand, micromolar concentrations of these cannabi-
noids down-regulated TRP metabolism, with the effect of CBD being
greater. This effect suggests an implication of cannabinoids in the regu-
lation of 5-HT levels, due to the increment of circulating TRP (Jenny
et al., 2010).
Regarding the nervous system, di Giacomo et al. (2020a) studied the
effect of CBD and cannabigerol on the hypothalamic cell line Hypo-E22
under oxidative stress due to exposure to H2O2. They found that both
CBD and cannabigerol presented neuroprotective effects regarded as a
reduction of the ratio 3-HK/KYNA, suggesting a blockade of the neuro-
toxic branch of the kynurenine pathway. The same authors later dem-
onstrated that cultured PFC tissue treated with CBD, after an
excitotoxic depolarizing stimulus, was protected against neurotoxicity
due to increased 3-HK levels, at the same time as the decrease in
KYNA levels was reverted, while cannabigerol did not prevent these ef-
fects (di Giacomo et al., 2020b).
10
Pharmacology & Therapeutics 223 (2021) 107807
On the effects of THC on the CNS, experiments with Wistar rats
showed that KYNA levels in the PFC of adult offspring of dams treated
with THC during the last week of pregnancy were elevated, and an
increase in KAT I mRNA levels was also found. The same work de-
monstrated that administration of KYN during adulthood after prenatal
exposure to THC exacerbated the increase in KYNA concentration in the
PFC compared with control animals. The observed changes occurred
specifically in the adult animal, given that fetal and maternal plasma
levels of KYNA and KAT I and KAT II mRNA remained unaltered after
prenatal administration of THC (Beggiato, Ieraci, Tomasini, Schwarcz,
& Ferraro, 2020).
7.2. Pharmacological modulation of kynurenine pathway and effects on
cannabis or THC use
Pharmacological modulation of brain KYNA levels by using KMO
inhibitors may become an effective treatment for marijuana depen-
dence. A study in Sprague-Dawley rats showed that systemic admin-
istration of Ro 61–8048 caused an elevation of KYNA levels in VTA
and NAc, resulting in a blockade of THC-induced DA release in
these brain regions. In behavioral experiments with rats and mon-
keys, self-administration of the synthetic cannabinoid WIN
55,212–2 decreased significantly after Ro 61–8048 treatment. A sim-
ilar effect was observed in the rewarding effects of THC. Ro 61–8048
administration also avoided relapse to THC use after re-exposure to
THC or WIN 55,212–2. The actions of Ro 61–8048 were achieved
through negative modulation of α7nAChR via increase of KYNA
levels, given that the administration of PNU120596 prevented this
effect (Table 1) (Fig. 4) (Justinova et al., 2013). As we described
above, THC can increase the release of DA via an increase in the firing
of glutamatergic neurons that project to both VTA and NAc. In this
sense, KYNA can block the activity of these glutamatergic neurons
via its effect on α7nAChR and finally produce a decrease in DA re-
lease in NAc. Likewise, similar to the case of nicotine, KYNA could
also be acting through inhibition of NMDA receptors on dopaminer-
gic neurons, blocking its firing.
Glutamate plays a central role in the mechanism by which Ro
61–8048 exerts its effects on marijuana cessation. In experiments with
primary astrocyte cultures of rat cerebral cortex, the addition of either
rimonabant (CB1 receptor antagonist) or nanomolar concentrations of
KYNA to the culture medium managed to prevent THC-induced in-
creases in extracellular glutamate levels. Furthermore, in in vivo studies
with rats, Ro 61–8048 also inhibited THC-induced glutamate release in
the rat reward-related brain areas, namely VTA, NAc and medial PFC,
thus preventing signalling among these brain regions (Secci et al.,
2019).
8. Amphetamine and its derivatives
The group of amphetamines comprises a series of compounds,
including amphetamine itself and substituted amphetamines,
such as methamphetamine and MDMA, among others. This chem-
ically diverse group of drugs acts directly in the CNS and has as pri-
mary targets the transporters of monoamine neurotransmitters,
i.e. DA and 5-HT (Sitte & Freissmuth, 2015). According to the
World Health Organization Report, major markets for metham-
phetamine continue to grow and it is currently the second greatest
drug threat in the US, after heroin. Another harmful feature of
the amphetamines is its dynamic market: each year, hundreds of
new synthetic amphetamine-like substances are synthesised and
added to the traffic (World Health Organization, 2019b). Interest-
ingly, some compounds of this group, such as MDMA or amphet-
amine have been, or even still are, used to treat some disorders,
such as attention deficit and hyperactivity disorder or narcolepsy
(Heal, Smith, Gosden, & Nutt, 2013). In fact, MDMA has recently
been proposed as a new pharmacotherapy for refractory post-
N. Morales-Puerto, P. Giménez-Gómez, M. Pérez-Hernández et al.
traumatic stress disorder (Mithoefer, Grob, & Brewerton, 2016).
Amphetamines alter DA release by two main mechanisms: the
first one involves the binding to the dopamine transporter, pro-
ducing an inhibition of DA reuptake and increasing the extracellu-
lar concentration of DA in NAc; the second one is exclusive of
the amphetamines, where DA release is achieved through dopa-
mine transporter-mediated reverse transport (Fig. 1) (Dela Peña,
Gevorkiana, & Shi, 2015).
8.1. Changes in kynurenine pathway associated with administration of am-
phetamine and its derivatives
D-amphetamine is one of the drugs that has been widely used to
study the kynurenine pathway functions in the brain. Acute administra-
tion of D-amphetamine induces a significant dose-dependent short-
term decrease of KYNA concentration in the striatum of rat brain. This
effect is noticeable not only in adult rat brain, but also during the post-
natal period (Poeggeler, Rassoulpour, Guidetti, Wu, & Schwarcz, 1998;
Rassoulpour, Wu, Poeggeler, & Schwarcz, 1998). The same authors ob-
served that the D-amphetamine-induced reduction in KYNA levels
was prevented in postnatal and adult rat striatum by using the D2 re-
ceptor antagonist haloperidol, suggesting a potential role of D-
amphetamine-induced striatal DA changes in the regulation of KYNA
concentration (Poeggeler et al., 1998). Moreover, this decrease in
KYNA concentration also occurred in other brain regions such as cortex,
hippocampus and cerebellum. However, no changes in other
kynurenine pathway metabolites such as KYN, 3-HK nor QA concentra-
tions were detected in striatum after D-amphetamine injection
(Rassoulpour et al., 1998).
Regarding the periphery, acute D-amphetamine treatment does not
seem to induce any short-term changes in KYN or KYNA in rat liver
(Rassoulpour et al., 1998). Yet, a recent study in mice showed that re-
peated administration of D-amphetamine over an 11-day period in-
duced a decrease in alpha-aminoadipic acid, a substrate for KAT-II that
can dictate the availability of KAT-II for the transamination of KYN to
KYNA (Schwarcz et al., 2012a, 2012b), and consequently produces a de-
crease in KYN plasma levels (Vanaveski et al., 2018). Moreover, it has
been described that amphetamine is a competitive concentration-
dependent inhibitor of the activity of KAT and kynurenine hydrolase
liver enzymes (Moussa, El-Ezaby, & Farid, 1978). However, the apparent
inconsistency of some of the results presented in these reports may be
explained by the use of different D-amphetamine concentrations, the
disparate drug administration protocols (from acute to chronic admin-
istration) or the intrinsic differences between rat and mouse
kynurenine pathway activity (Murakami & Saito, 2013).
Little is known about the effect of amphetamine derivatives on the
kynurenine pathway. Concerning MDMA, a randomized controlled
study of healthy subjects showed no changes on KYN and TRP plasma
concentration after a single dose during the first 24 h after exposure
(Boxler, Liechti, Schmid, Kraemer, & Steuer, 2017). However, studies
in rat carried out by our group showed that a neurotoxic dose of
MDMA induced a short-term increase of TRP in hippocampus while
KYN was elevated both in hippocampus and plasma, an effect mediated
by activation of the liver enzyme TDO (Abuin et al., submitted for
publication).
8.2. Pharmacological modulation of kynurenine pathway and effects on
amphetamine and its derivatives use
Several approaches have been used to determine the role of
kynurenine pathway on D-amphetamine effects in CNS, employing
mainly pharmacological and genetic tools. It has been shown that the
administration of Ro 61–8048 prevents the D-amphetamine-induced
reduction in KYNA concentration and the increase of NMDA-induced
neuronal vulnerability in striatal tissue of postnatal rats. These effects
were independent of the striatal DA release induced by the drug,
11
Pharmacology & Therapeutics 223 (2021) 107807
identifying a relationship between the endogenous KYNA levels in the
striatum and NMDA receptor-mediated excitotoxic events (Poeggeler
et al., 2007).
In another report, the authors demonstrated that subchronic pre-
treatment with KYN, which induced an increase in KYNA levels, poten-
tiated the D-amphetamine-induced DA release in the rat NAc and
reduced its inhibitory effect on firing rate and burst firing activity of
VTA dopaminergic neurons (Olsson et al., 2009). This pharmacological
approach was also tested in mouse to study the relationship between
KYNA concentration and the locomotor response induced by D-
amphetamine, showing that subchronic pretreatment with KYN pro-
duced a potentiation of D-amphetamine-induced locomotor activity,
consistent with the results mentioned above (Olsson, Larsson, &
Erhardt, 2012). In line with these observations, Kmo−/− mouse model
injected with D-amphetamine showed a potentiation of the horizontal
activity induced by the drug (Erhardt et al., 2017). However, these ef-
fects were not observed after acute KYN pretreatment, suggesting that
subchronic elevated KYNA levels exposure may induce some adaptive
mechanisms such as changes in axonal transport or α7nAChR expres-
sion (Olsson et al., 2009, 2012). All together, these works highlight the
potential implications of the regulation of KYNA concentration on D-
amphetamine-induced dopaminergic effects in striatum but to this
day, there is no evidence of the effect of pharmacological modulation
of the kynurenine pathway on amphetamine consumption.
Regarding MDMA, we recently demonstrated in rats that enzymatic
TDO activity in the liver is increased three hours after MDMA adminis-
tration, resulting in elevated concentrations of plasma KYN and, since
KYN can cross the BBB, the increase observed in periphery was also
found in several brain regions, such as hippocampus. In addition, we
also observed increased concentrations of hippocampal TRP and a ten-
dency to increase in plasma. We speculate with the possibility that
MDMA increases the availability of free plasma TRP, which can subse-
quently cross the BBB, which could explain the increase observed in
rat brain. MDMA acts inhibiting tryptophan hydroxylase (O'Shea et al.,
2006), producing a decrease in 5-HT and an increase in TRP, the sub-
strate for TDO, an enzyme whose activity can be regulated by the pres-
ence of substrate (Bender, 1983) producing finally an increase in KYN
levels.
We further demonstrated that TDO inhibitor 680C91 potentiates the
long-term serotonergic neurotoxicity induced by a neurotoxic dose of
MDMA while, on the contrary, L-kynurenine administered together
with probenecid attenuates the brain damage induced by MDMA
(Abuin et al., submitted for publication).
This study also revealed that modulating AhR activity by using
antagonists (i.e. CH-223191) or positive modulators, such as 3, 3′-
diindolylmethane, leads to a potentiation or attenuation of MDMA-
induced toxicity, respectively. Taking into account that KYN and KYNA
are agonists of AhR (Opitz et al., 2011), these results suggest a role of
KYN and presumably KYNA in the mechanism of action underlying
MDMA-induced toxicity. Thus, an increase in KYN levels or the adminis-
tration of 3, 3′-diindolylmethane would produce the translocation of
AhR to the nucleus counteracting the MDMA-induced toxicity, but
more research is needed in order to characterise the exact role of AhR
in the MDMA-induced toxicity.
Considering the moderate rise in the recreational use of these drugs
and the renewed interest of some of these drugs as a therapeutic strat-
egy to treat different neurological disorders, the pharmacological mod-
ulation of kynurenine pathway may be an interesting approach to
prevent harmful events derived of the administration of D-
amphetamine and its derivatives.
9. Cocaine
Cocaine is a highly addictive illegal drug which comes from the coca
plant, known for thousands of years (Biondich & Joslin, 2016). Purified
cocaine, which was first isolated more than 100 years ago, has been
N. Morales-Puerto, P. Giménez-Gómez, M. Pérez-Hernández et al.
traditionally used in the treatment for a variety of diseases and as anaes-
thetic to block local pain. Although it was banned when its harmful ef-
fects and addictive power were acknowledged in the beginning of the
1900's, cocaine became popular in the 80's for recreational purposes
among young people in Europe, North America and the producer coun-
tries of South America. After a progressive fall at the beginning of the
21st century, global cocaine manufacture reached its highest level in
history in 2016, with parallel evidence that cocaine use rose from
2013 to 2016. The routes of administration are flexible: consumers
can use it nasally, orally, intravenously or by inhalation. It is because
of this that cocaine addiction is a major health issue, not only for the
psychological and medical problems, but also, among other aspects,
for the spread of infectious diseases, such as AIDS or hepatitis (World
Health Organization, 2019b).
Cocaine produces its effects in the CNS by preventing DA reup-
take via transporter block, thus prolonging neurotransmitter pres-
ence in the synapsis of the NAc and amplifying the stimulus in the
mesolimbic reward areas (Fogaça et al., 2016b). Furthermore, it
also acts producing desensibilization of the D2-autorreceptor
resulting in increased levels of DA in NAc. Finally cocaine can in-
crease glutamate transmission and decrease GABAergic transmis-
sion (Fig. 1) (Juarez & Han, 2016).
9.1. Changes in kynurenine pathway associated with cocaine
administration
Little is known about the consequences of cocaine consumption
on the kynurenine pathway. The first study in the literature using
18 cocaine-dependent individuals and 10 drug-free controls
established that there is a relationship between chronic exposure
to cocaine and alteration in TRP metabolism. Despite this study fo-
cusing on 5-HT metabolism, it also described a reduction in
anthranilic acid without alteration in KYN or 3-HK levels (Patkar
et al., 2009). A recent study from our lab using 110 cocaine users
and 65 controls examined for the first time the kynurenine pathway
including metabolites such as QA and KYNA in plasma. As previously
described, there were no changes in TRP or KYN levels, nor in QA, but
we found a decrease in KYNA levels (Araos et al., 2019). Both results
together indicate that alterations in kynurenine pathway metabo-
lites can occur without finding changes in KYN or TRP. Cocaine pro-
duces a decrease in KYNA without affecting the rest of the
kynurenine pathway, which suggests a modulation by cocaine of
KAT-II but which requires further study.
9.2. Pharmacological modulation of kynurenine pathway and effects on
cocaine use
Once again, redirecting the kynurenine pathway towards KYNA for-
mation by manipulation of KMO enzyme has proven to be a useful phar-
macological tool to block cocaine effects. In male Wistar rats, cocaine
relapse-like behaviour was avoided when KMO was inhibited. As with
alcohol, reestablishment of cue-induced cocaine-seeking conduct was
prevented by intraperitoneal administration of Ro 61–8048 (Table 1)
(Vengeliene et al., 2016). There is evidence in literature of increased glu-
tamatergic transmission during cocaine withdrawal. The effect of KYNA
on NMDA receptors may alleviate withdrawal symptoms due to a
decrease in glutamate activity and effectively prevent withdrawal.
Nonetheless, in contrast to the abolishment of THC and nicotine self-
administration by Ro 61–8048 treatment, KMO inhibition did not affect
cocaine self-administration (Table 1) (Justinova et al., 2013; Secci et al.,
2017). As in the experiments described above with other drugs, KMO
inhibition by Ro 61–8048 treatment shifted the metabolism of the
kynurenine pathway leading to a significant increase in plasma KYNA
concentration, with the expected consequences of either NMDA recep-
tor or α7nAChR inhibition. However, a possible explanation for the lack
of effect of Ro 61–8048 on cocaine self-administration is that cocaine-
12
Pharmacology & Therapeutics 223 (2021) 107807
induced DA increases in the NAc are mediated via the inhibition of the
dopamine transporter on which KYNA or other kynurenine pathway
metabolites have no effects (Fig. 1).
10. Opioids: a special case
Opiates are defined as the derivatives of opium alkaloids, the most
relevant being morphine, codeine and heroin. The term opioid com-
prises compounds of natural, semisynthetic, synthetic and endogenous
origin that act like morphine, interact with opioid receptors either as ag-
onists or antagonists and the effects of which are completely
antagonised by naloxone (Dinis-Oliveira, 2019).
Opioids are effective analgesics in the treatment of pain. However, in
addition to the side effects of these drugs, one of the most serious ad-
verse consequences is potential opioid abuse and addiction after re-
peated use (Compton, Jones, & Baldwin, 2016). The opioid crisis
continues increasing, in part due to the illicit intake of fentanyl and its
potent analogues, which has resulted in a greater propensity to over-
dose (Spencer, Warner, Bastian, Trinidad, & Hedegaard, 2019).
Opioids are a major concern in many countries because of the severe
health consequences associated with their use. In 2017, the use of opi-
oids accounted for 66% of the deaths attributed to drug use disorders.
Approximately 53.4 million people used opioids (both illegal and
prescription opioids for non-medical purposes) in 2017, which corre-
sponds to 1.1% of the global population aged 15–64 (World Health
Organization, 2019b). The mechanism by which opioid consumption
produces reward involves activation of opioid receptors in both VTA
and NAc. Opioids bind to μ-opioid receptors and decrease GABAergic
cell firing. This decrease disinhibits VTA dopaminergic neurons, increas-
ing DA release in NAc. Moreover, opioid consumption can also enhance
glutamatergic signalling in VTA dopaminergic neurons (Fig. 1) (Juarez &
Han, 2016).
10.1. Kynurenine pathway and opioids
To our knowledge, no research on the effect of opioids on the
kynurenine pathway has been conducted, but a few studies have looked
at the effects of some opioids on TRP levels. These studies indicate that
morphine addiction may be associated with uptake of TRP from the
blood to the brain (Larson & Takemori, 1977; Zaitsu et al., 2014). More-
over, a single injection of heroin produces an increase of TRP urine
levels. Therefore, changes in the levels of these peripheral metabolites
may be considered as possible biomarkers of heroin consumption and
withdrawal (Zheng et al., 2013).
Regarding the possibilities of pharmacological modulation of the
kynurenine pathway as an approach to opioid treatment, the evi-
dence suggests that activation of the NMDA receptor, of which
KYNA is antagonist, could be involved in the development of mor-
phine dependence (Trujillo & Akil, 1991) and in the development
of analgesic tolerance (Marek, Ben-Eliyahu, Vaccarino, & Liebeskind,
1991). In this sense, KYNA could act reducing the symptoms that
lead to relapse by blocking NMDA receptors. Moreover, a possible
modulation of opioid dependence by KYNA could take place at the
level of the opioid receptors themselves. Although it appears that
KYNA has no affinity for any of the opioid receptors, i.e. μ, κ and δ
(Zador et al., 2014), KYNA administration altered opioid receptor
signalling by modifying the activity of G proteins coupled to these
receptors by a mechanism that involves the NMDA receptor, since
antagonism of the NMDA receptor with MK-801 prevented the
KYNA-induced effect (Samavati et al., 2017).
All this evidence suggests that, although there is not much literature
on the relationship between the kynurenine pathway and opioid addic-
tion, there may be an opportunity for treatment of this drug use by
harnessing the effect that the kynurenine pathway exerts on the modu-
lation of pain.
N. Morales-Puerto, P. Giménez-Gómez, M. Pérez-Hernández et al.
10.2. Pain modulation: a link between the kynurenine pathway and opioids
The pharmacological manipulation of the kynurenine pathway, en-
hancing the activity of KYNA, has been proposed as a possible target in
the regulation of neuronal hyperexcitability and glutamatergic neuro-
transmission that are involved in pain generation, and the antinociceptive
actions of KYNA may be achieved through two of its target receptors. The
administration of KYN and probenecid inhibits the NMDA receptor in an-
imal models of trigeminal activation and sensitization (Knyihár-Csillik
et al., 2007), increases KYNA levels in cerebrospinal fluid and prevents
allodynia in a neuropathic pain model (Pineda-Farias et al., 2013). These
results are consistent with those from studies using direct blockade of
NMDA receptors. For instance, sub-anaesthetic doses of ketamine, a
NMDA antagonist, were found to moderately decrease acute pain and
hyperalgesia in a recent meta-analysis study of human patients
(Thompson et al., 2019) and to reduce the aversive response to noxious
stimuli in rodent chronic pain models by supressing NMDA hyperactivity
(Zhou et al., 2018).
On the other hand, KMO inhibition decreases neuropathic pain in-
tensity after chronic constriction injury to the sciatic nerve and potenti-
ates the analgesic properties of morphine (Rojewska, Piotrowska,
Makuch, Przewlocka, & Mika, 2016). More recently, these authors stud-
ied the role of GPR35 in nociceptive transmission and showed that in-
trathecal administration of zaprinast, a GPR35 agonist, and KYNA
reduces thermal and tactile hypersensitivity after chronic constriction
injury and enhances the effectiveness of morphine and buprenorphine
(Resta et al., 2016; Rojewska, Ciapała, & Mika, 2019; Rojewska,
Ciapała, Piotrowska, Makuch, & Mika, 2018).
All in all, modulation of the kynurenine pathway may be effective in
the treatment of pain. Elevations in KYNA via direct infusion of KYN,
KYNA or inhibiting KMO seems the most appropriate strategy. Its effects
on NMDA receptors and as an endogenous agonist of GPR35, a receptor
whose activation could cause analgesia (Cosi et al., 2011) provide a new
opportunity to possibly substitute opioids for compounds that modulate
pain through the kynurenine pathway route, thus reducing their poten-
tial risk of addiction.
11. Future prospects and new trends
Throughout this review we have unravelled the relationship be-
tween the kynurenine pathway and drug consumption. Scientific litera-
ture indicates that there is an association between the kynurenine
pathway and EtOH, nicotine, cannabis, amphetamines and cocaine.
But even in these cases the characterisation of the kynurenine pathway
has not been exhaustive. Most studies available on the literature only
characterised the effect of the drug on KYN as a part of the TRP metab-
olism. Only a few studies have focused on KYNA or QA, and there are no
evidences in the literature about the effect that drug use can have on
other metabolites such as anthranilic acid, CA, XA or picolinic acid. Con-
sidering that some of these metabolites have neuroactive properties
(Fazio et al., 2015) it is necessary to study the role that drug consump-
tion may have on these compounds. In this way, progress could be
made towards a full understanding of the state of the kynurenine path-
way in relation to drug use. Moreover, the mechanisms by which drugs
of abuse alter the kynurenine pathway are known only for a few drugs,
and so further research is necessary to improve our knowledge in this
point.
Similarly, there is also no evidence of the effect that drug use has on
altering the targets of the kynurenine pathway. In the field of drug
abuse, the alleged role of KYNA in the modulation of α7nAChR is un-
doubtedly one of the most promising strategies for the future and has
already been shown to be effective in reducing the consumption of var-
ious drugs via the modulation of DA release. However, GABA interneu-
rons also play a key role in the regulation of DA release (Bouarab,
Thompson, & Polter, 2019). There is evidence in the literature that
local VTA GABA neurons synapse onto VTA DA neurons and provide a
13
Pharmacology & Therapeutics 223 (2021) 107807
significant source of inhibitory control (Airavaara et al., 2016; Polter,
Barcomb, Tsuda, & Kauer, 2018; Simmons, Petko, & Paladini, 2017;
Smith, Vento, Chao, Good, & Jhou, 2019). Since there are NMDA recep-
tors located in these GABA interneurons (Fig. 3) (Nugent, Penick, &
Kauer, 2007) and given its role as NMDA receptors antagonist it is pos-
sible that KYNA can modulate GABA interneurons, opening the door to a
new promising strategy to modulate DA release.
The rest of the receptors through which the metabolites of the
kynurenine pathway can exert their effect, however, should not be
neglected. In the future, the role that modulation of the kynurenine
pathway may play, after the consumption of substances, on other re-
ceptors, such as GPR35, should be characterised. This is so since there
is evidence that this receptor can play a relevant role in analgesia
(Larigot, Juricek, Dairou, & Coumoul, 2018; Nourbakhsh, Atabaki, &
Roohbakhsh, 2018). Moreover, regarding AhR, this receptor impacts
on neuronal proliferation, differentiation, and survival (Suzuki et al.,
2020), key components of the development of addiction to several
drugs (Koob & Volkow, 2016). In this sense, the manipulation of this re-
ceptor or their ligands opens a new opportunity in order to protect
against neurotoxicity caused by drug abuse and drug addiction.
Even more relevant could be the case of mGluR 2/3 and their possi-
ble modulation by XA. There is evidence implying that this receptor
family may be involved in pathologies such as anxiety, depression or
chronic stress-related disorders (Peterlik, Flor, & P., & Uschold-
Schmidt, N., 2015). Moreover, the modulation of these receptors has an-
tipsychotic and anti-stress effects (Swanson & Schoepp, 2003). Many of
these pathologies occur in the presence of drug use and, conversely,
they can be caused by drug use or abuse. Further, the kynurenine path-
way is also related to these pathologies (Platten et al., 2019). In this way,
the kynurenine pathway could play a relevant role in the neuropsychi-
atric disorders caused by drug use. This would constitute a new avenue
to address the relationship between the kynurenine pathway and sub-
stance use, focusing on the consequences of consumption.
In the future, not only will it be important to characterise the effect
of the receptors on which the kynurenine pathway acts. During recent
years, the microbiota-gut-brain axis has been established as a mecha-
nism that can play a relevant role in various mental illness (Zhu et al.,
2017). It is well known that microbiota can regulate TRP availability
for KYN metabolism, with downstream effects on CNS function
(Kennedy, Cryan, Dinan, & Clarke, 2017). These evidences oblige us to
pay special attention in the coming years to the effect of drugs of
abuse on the kynurenine pathway, but also on the intestinal microbiota.
This opens a totally new opportunity to explain, through these mecha-
nisms, key aspects related to drugs of abuse such as the transition
from voluntary consumption to addiction or consumption-associated
pathologies. Another strategy would entail the study of the effect of
early life administration of KYN in order to determine the importance
of this critical window in the addiction processes. It is known that ad-
ministration of KYN in early life produces an elevation in KYN levels in
adulthood (Alexander et al., 2013) and affects contextual memory
(Pocivavsek et al., 2014). Evaluating how a pretreatment with KYN or
other compounds of the kynurenine pathway could affect the consump-
tion of drugs or other parameters related to addiction in the long term
could constitute an interesting approach in the future.
Finally, the most studied pharmacological compound has been Ro
61–8048. This compound must be tested on the rest of substances
with the aim to elucidate whether it is an effective tool to reduce the
consumption of those substances in which glutamate, through the
α7nAChR receptors, plays an essential role or if, in addition, we are
faced with a proposal for general treatment for addictions. This com-
pound should especially be assessed in the case of opioids: it is likely
that modulating pain through this compound can become an alternative
treatment to opioids, thus preventing its consumption and subsequent
abuse. Nonetheless, even when most of the experimental evidence on
the functioning of Ro 61–8048 has been obtained in relation to its mod-
ulation of α7nAChR receptors, specifically in the case of EtOH, nicotine
N. Morales-Puerto, P. Giménez-Gómez, M. Pérez-Hernández et al.
and cannabis, we should not forget that there is a possibility that
another mechanism may be involved: the prevention of drug self-
administration observed after Ro 61–8048 treatment may be a conse-
quence of the blockade of NMDA receptors located on VTA dopaminer-
gic neurons due to the increment in KYNA concentration. Future
research could benefit from elucidating all targets implicated in Ro
61–8048 mechanism of action.
Moreover, it is necessary to approach other therapeutic strategies.
There is little evidence of the role that IDO1 inhibition can play in rela-
tion to drug abuse. There are several clinical trials involving IDO1 inhib-
itors studying the role of the kynurenine pathway in pathologies such as
cancer (Platten et al., 2019). The good results of this approach should
lead addiction research to evaluate these inhibitors in order to charac-
terise the role of IDO1 in aspects such as alteration of the immune sys-
tem produced by the consumption of drugs or aspects related to their
toxicity. All these perspectives together, on the one hand the correct
characterisation of the kynurenine pathway and, on the other hand,
the use of all the available pharmacological tools, may in the future
allow a full understanding of the relationship that exists between the
kynurenine pathway and substance abuse. A relationship that we now
only begin to intuit.
Declaration of Competing Interest
The authors declare that there are no conflicts of interest.
Acknowledgements
This study was supported by Ministerio de Ciencia e Innovación
(Grants SAF2013-40592, SAF2016-78864-R and PID2019-105847RB-
I00), Ministerio de Sanidad, Consumo y Bienestar Social [Plan Nacional
sobre Drogas (PNSD) Grants 2014I015, 2017I017 and 2019I025],
Instituto de Salud Carlos III Redes Temáticas de Investigación
Cooperativa en Salud-Red de Trastornos Adictivos (ISCII RETICS-RTA)
Grants RD12/0028/0002 and RD16/0017/0021, and Universidad
Complutense de Madrid Grant 910258.
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