Getting High On Dopamine Neuroscientific Apects of Pleasure

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SexuS Journal www.sexusjournal.com │ Winter-2019 │Volume: 04 │Issue: 11 │Pages:883-906
◦◦◦ Sayin HÜ, Pleasure- High-on-Dopamine ◦◦◦ ISSN 2536-5185 (web) ISSN 2536-5169 (print)
Winter 2019, V:4; Issue: 11, March 31st, 2019
Neuro-Psychopharmacology ● Neuroanatomy
ISSN 2536-5185 (web) Neuroscience ● Pleasure ● Reward ● Addiction
ISSN 2536-5169 (print)
Original Review
Getting High on Dopamine: Pleasure

SAYIN HÜ SexuS Journal 4 (11): 883-906 MARCH Part-1
Getting High on Dopamine:

Neuroscientific Aspects of Pleasure
H. Ümit Sayin
Abstract:
Hedonism and pleasure are one of the main goals of human life. Pleasure can be accepted as a reward for
the brain, while the major reward neurotransmitters are dopamine, norepinephrine, oxytocin and gluta-
mate. Boost of dopamine in the “hedonic hot spots” creates euphoria, delight, pleasure, contentment and is
associated with happiness. The reward circuitry and pleasure centers in the brain involve the ventral teg-
mental area (VTA), nucleus accumbens (NA), substantia nigra (SN), ventral pallidum, insula, lateral thala-
mus, cingulate cortex, hippocampus, amygdala, medial prefrontal cortex and orbitofrontal cortex. Pleasure
is a learned enjoyable phenomenon and pursuing the pleasure principle is one of the crucial goals of human
life. However, to some extent of pleasure, due to the release of dopamine and glutamate and the activation
of D1-like excitatory dopamine receptors and NMDA receptors, may induce different forms of psychological
addiction. Sexual motivation, sexual drive and orgasm also use the same reward circuitry and similar neuro-
chemicals in the brain. The experience of “getting high on dopamine” has been one of the primary
longstanding goals for human beings, as well as for other higher primates and animals during the normal
course of evolution. Today, it is known that pleasure and sexual hedonism may even alter synaptic plastici-
ty, and may influence a variety of psychological responses and the personality of individuals, as Sigmund
Freud had pointed out a century ago.
KEY WORDS: pleasure center, hedonic hot spot, dopamine, glutamate, oxytocin, NMDA, reward circuit, hedonism,
orgasm, motivation, sexual drive
SexuS Journal ● Winter 2019 ● 4 (11): 883-906
Introduction
As established by Sigmund Freud,
pleasure and fulfilling libidinal instincts are
very important main goals of human life.
Freud established his structural psychology
school and psychoanalysis depending on
Corresponding Author: Ümit Sayin, M.D., PhD, www.humitsayin.com certain postulates; and he explained many of
Address: Institute of Forensic Sciences, İstanbul University, Cerrahpasa, the psychological disorders or disturbances
Aksaray, İstanbul ASEHERT-CİSEATED (www.ciseated.org)
humitsayin@gmail.com depending upon those niches. Some of them
Note: Figures and diagrams are drawn and created by Dr. Ümit Sayin us- were ( Freud, 1978, 1999; Cherry 2018):
ing Photoshop, Corel Draw and Powerpoint
Received November 12th 2018; Accepted December25th 2018;
 Pleasure principal, libido and id (Sayin, 2019-
Published March, 2019. b).
© Copyright 2019, H. Ümit Sayin  The structure of the psyche; id, ego, super-ego.
A Multidisciplinary Academic Journal Published Quarterly by CİSEATED-ASEHERT ● www.ciseated.org ● www.sexusjournal.com ● 883

 Life force (drive) versus Death instinct This is one of the reasons why
 Sexual development of the child and the people get addicted to cocaine, heroin,
phases of sexual development (oral, anal, amphetamines, nicotine, eating junk food,
phallic, latent and genital phases) gambling, watching TVs; each of these
 Sexual attraction mother (boys, Oedipus
activities have “contentment”, “liking”,
complex) or father (girls, Electra complex)
“craving inducing” side effects; in some,
 Childhood traumas and pleasurable experi-
ences like cocaine, MDMA (ecstasy) and meth-
amphetamine, the “happiness effect” is
Most of the psychoanalysis theory very abrupt and high, because of the re-
takes above as granted and universal lease of high concentrations of dopamine,
truths. Structural psychology and psycho- glutamate and norepinephrine at the
analysis, in the beginning, was succesfull pleasure and reward centers of the brain.
to some extent, until the advent of biologi- The other side of the medallion,
cal psychiatry (Sayin, 2019-a,b). However, however, is that people also get addicted
the biological and physiological basis for to “security”, “warmth”, “euphoria”, “happy
the the proposed abstractions of the psy- mood”; this psychological addiction at
che were not defined and established times may be worse than physiological
properly. Pleasure principal, as one of the addiction. Namely, people in their lives
most important postulates of structural often race for rewards: the reward of feel-
psychology, has been studied extensively ing good; reward of good taste and smell;
in terms of neurophysiological methods, reward of satisfying their ego; reward of
and it is concluded that Freud was right sexual pleasure and orgasm; reward of
about the pleasure principal, according to chocolate; reward of junk food; reward of
the latest findings of neuroscience. buying as they wish; reward of possessing;
Humans are hedonistic and pleasure reward of making money!
seeking higher primates. Contentment, In a racing wild capitalist society,
pleasure, liking, wanting, sexual interac- since everyone’s capabilities, IQs and EQs
tion, pleasure and orgasm, are all positive are not the same; many losers or genetical-
emotions that lead to the general term ly predisposed individuals will suffer
“happiness”; without any of them life for from depression, anxiety and insecurity,
humans would be meaningless and de- which are the consequences of living in
pressive. such a difficult world, because of not be-
Happiness is a combination of ing successful! So, these people tend to
many components. Brain structures are so activate their reward centers and circuitry
organized and specialized that there are chemically (e.g. cocaine, heroin, amphet-
certain pleasure centers, pleasure circuitry amines) or by habituation (e.g. excessive
and reward circuitry which work using eating, gambling, buying and possessing).
certain modulatory neurotransmitters, Dopaminergic system, which ex-
such as dopamine, oxytocin, glutamate, ists even in the bees for inducing pleasure
GABA and norepinephrine etc. Neurochem- to chase the smell of the flowers and col-
istry in the central nervous system uses lect flower essence (Jarriauult, 2018; Perk,
certain chemical, hormonal and neuro- 2005), is not constructed, by nature and
transmitter communication systems; evolution, to make the humans addicted
namely, if you mention pleasure, content- on purpose; its purpose is creating goals for
ment and orgasm, they all have a chemical continuing life and reproducing; because
equivalence and neurochemical homeo- without pleasure and hedonism life would
static state and a circuitry. be dull, boring and meaningless. Dopa-

minergic happiness is a virtual reality trap, marize the anatomy and neuropharmacol-
with which nature hunts us. Such a chemi- ogy of pleasure and the role of dopamine
cal reward system has some disad- on it.
vantages, though, dependence and addic- Pleasure and Reward
tion may develop! Centers of the Brain
Psychology generally uses the term The brain areas that are activated
“reward” referring pleasure and liking. with good-positive emotions, pleasure,
During the last 30-40 years, neuroscience feelings-emotions, sexual pleasure, and
was able to investigate and unravel some orgasm have been investigated for years.
of the mechanisms of how pleasure, happy After many supporting findings it was
feelings, contentment, orgasm, orgasmic concluded that these areas include:
pleasure and peak experiences are gener- • orbitofrontal cortex
ated in the brain structures. Although neu- • cingulate cortex
roscientists are at the beginning phase of • medial prefrontal cortex
pleasure-happiness research, latest sophis- • insula
ticated techniques such as magnetic reso- • nucleus accumbens
nance (MR), positron emission tomogra- • ventral pallidum
• substantia nigra
phy (PET) and functional magnetic reso-
• ventral tegmental area
nance imaging (fMRI) enabled them to
• thalamus
learn a lot about the brain mechanisms of
These brain areas are often called
pleasure and happiness. Maybe, one day it
“hedonic hotspots”. The experiments and
will be possible to induce dopamine re-
observations claim that either the electrical
lease in the pleasure centers of the brain,
(using micro electrodes) or chemical stim-
by means of vibrations or electro-magnetic
ulation (amphetamines or cocaine) of these
like waves without using any invasive
brain structures can induce pleasure or
techniques or pharmacological methods.
positive emotions (Kringelbach, 2009; Ber-
Today it is even possible to detect
ridge, 2007, 2008, 2009, 2015; Koob, 1997,
the centers that are activated or inactivat-
2009, 2010; Volkow, 2007; Komisaruk,
ed during sexual pleasure and orgasm
2006; Wise, 2017; Jannini, 2018; Funahashi,
(Komisaruk, 2006; Wise, 2017; Jannini,
2011; Kim, 2015).
2018). New horizons have been discovered
A reward activates the reward-
in the area of sexual physiology by fMRI.
pleasure system or hedonic hotspots and
For instance, nearly half of hemiplegic
generates feelings of pleasure or positive
women continue to attain sexual pleasure
emotions (e.g., liking). At the same time, a
and orgasm, when their cervix is stimulat-
reward also activates motivational systems
ed, even though the sacral plexus that
either originating from the limbic system
conveys the orgasm center is totally none-
or the anatomical pleasure regions and
functional; an interesting finding that
produces incentive behavior (e.g., wanting).
Komisaruk et al. have shown. It was dis-
For example, when rats press a key and
covered that the Vagus nerve center was
receive electrical stimulation through an
activated during hemiplegic-orgasms,
electrode implanted in the hypothalamus,
providing information that vagus nerve
they try to press the key as continuously
innervates the cervix and uterus, thus car-
as they can to get more electrical stimula-
rying pleasure signals from cervix to the
tions, which is the well documented “brain
brain directly, bypassing the spinal cord
stimulation reward (BSR).”
(Komisaruk, 2004; 2003; 2005; 2006).
The electrical stimulation of some
In this review we will try to sum-

subcortical structures, such as the nucleus It is reported that a reward con-

accumbens (NA), the lateral hypothala- tains different functional components, i.e.,
mus, and the ventral tegmental area liking (pleasure/ palatability) and wanting
(VTA), have been proven to induce strong (appetite - incentive motivation), and that
motivational behaviors in animals. It liking is controlled by neurotransmitter
should always be kept in mind that “want- systems such as opioid systems. Ventral
ing” and “liking” are two different feelings. pallidum (VP), where wanting is in-
A heroin addict wants heroin, because volved, uses mesocortical and NA dopa-
he/she tries to prevent the abstinence syn- mine systems (Berridge, 1996). The ventral
drome; but he/she may not like the drug pallidum and the nucleus accumbens (NA)
(or hate it). The stimulation of VTA, NA or seem to participate in “liking” mechanisms
lateral hypothalamus has been proposed that induce pleasure. (Table-1)
to induce “wanting”. However, the stimu-
lation of orbitofrontal cortex, the medial Medial Prefrontal Cortex
prefrontal cortex and insula have been The anterior cingulate area is hy-
proposed to induce a “liking” behavior pothesized to take part in the self-
(Kringelbach & Berridge, 2009). All these knowledge and the subject’s subjective
areas have neuronal connections with the feelings. Cingulate’s contribution in the
other hedonic hot spots. self- knowledge of one’s own subjective
In rat experiments, BSR response feeling could be important for us to expe-
has also been observed, not only in the rience happy feelings. The medial pre-
hypothalamus, but also, in VTA, substan- frontal cortex with the anterior cingulate
tia nigra-which has abundant dopaminer- cortex is reported to be a crucial cortical
gic neurons-, cerebral cortex (orbital pre- structure for self-reflection, self-
frontal cortex), cingulate cortex and the perception, perception of the other people,
septum (Rolls, 1974, 2000). social cognition (Amodio & Frith, 2006).
Neuropharmacological studies
show that dopamine is the main neuro- Orbitofrontal Cortex
transmitter, which mediates pleasure reac- The orbitofrontal cortex contains
tion (Phillips et al., 1989; Spanagel & taste and olfactory areas (Ongur, 2000).
Weiss, 1999), while some dopamine ago- This olfactory area may mediate the re-
nists and antagonists (e.g. into lateral hy- ward factors of odor, and olfactory senso-
pothalamus or VTA) modulated the ry region responding to the smell of food
pleasure and BSR. It is shown that the me- only when the animal was hungry (Critch-
dial forebrain bundle includes massive ley, 1996). This area may also contribute to
dopamine fibers. Both the meso-cortical satiety. Also in human subjects, using
dopamine fibers and the nigrostriatal do- fMRI, these areas were found to be active
pamine fibers pass through the lateral during satiety (Kringelbach et al., 2003,
hypothalamus, so that the stimulation of 2009).
lateral hypothalamus seems to induce Anterior Insula
excessive release of dopamine. Many imaging studies of emotion
show activation of the anterior insula (AI)
Basal Ganglia in human subjects experiencing different
The nucleus accumbens (NA) and emotional feelings, e.g. sexual arousal,
the ventral pallidum have been consid- romantic love, anger, sadness, happiness,
ered to participate in the mechanisms of disgust, empathy etc. (Craig, 2009). (Fig-
liking that cause pleasure responses. 1, 2, 3).

Subcortical Structures Wanting Liking Brain Stimulation Re-

ward
Lateral hypothalamus ● ● ● ● ● ●
Septum ● ● ● ● ● ●
Ventral tegmental area ● ● ● ● ● ●
Substantia nigra ● ● ● ● ● ●
Ventral pallidum ● ● ● ● ● ● ● ● ●
Nucleus accumbens ● ● ● ● ● ● ● ● ●
Cortex Structures
Cingulate cortex ● ● ●
Medial orbitofrontal cortex ● ● ● ● ● ●
Anterior Insula ● ● ●
Table-1: Wanting, liking and BSR responses in different regions of the brain. Dots depict that there is wanting, liking
or brain stimulation reward response in that region . (Reference: Modified from Shintaro Funahashi, Brain Mechanisms of
Happiness, Psychologia 2011)
Receptor Locations Functions

Found in high concentration in mesolimbic, nigro- Voluntary movements, regulate growth and development,
D1 striatal and mesocortical areas , such as substantia regulations of feeding, affect, attentions, reward, pleas-
Excitatory nigra, olfactory bulb, nucleus accumbens, caudate, ure, sexual activity, orgasm, sleep, impulse control, emo-
↑↑ cAMP putamen, striatum. tions, instincts, reproductive behaviors, working memory,
Expressed in low level in cerebellum, hippocam- learning, control of rennin in kidney
pus, thalamus, hypothalamus, kidney
Expressed in high levels in as substantia nigra, Involved in working memory, reward-motivation functions
D2 olfactory bulb, caudate, putamen, ventral tegmen- regulate blood pressure, renal functions, gastrointestinal
Inhibitory tal area(VTA), nucleus accumbens Found in low motility, vasodilatations, regulate locomotion-presynaptic
↓↓ cAMP level in hypothalamus, septum, kidney, cortex, receptors inhibit locomotion and post synaptic receptors
heart, blood vessels, adrenal glands, gastrointesti- activate locomotion
nal tract, sympathetic ganglia
D3 Expressed only in CNS and it is not found out- Involved in endocrine function cognitions, emotions, regu-
D3 side the CNS. Found in olfactory bulb, nucleus lations of locomotor functions and modulates endocrine
Inhibitory accumbens functions
↓↓ cAMP
Substantia nigra, hippocampus, amygdala, thala-

D4 mus, hypothalamus, kidney, frontal cortex, heart, Regulations of renal functions, gastrointestinal motility,
Inhibitory blood vessels, adrenal glands, gastrointestinal vasodilatations, blood pressure, modulations of cognitive
↓↓ cAMP tract, sympathetic ganglia, globus pallidum, Low- functions
est receptor found in CNS than all dopamine re-
ceptors
Substantia nigra, hypothalamus, hippocampus, Involved in pain process, affective functions, emotions,
D5 dental gyrus, kidney, heart, blood vessels, adrenal endocrine functions of dopamine
Excitatory glands, gastrointestinal tract, sympathetic ganglia
↑↑ cAMP
Table-2 : The summary of the locations and functions of dopamine receptors.

Pathway Function
Nigrostriatal Dopaminergic Pathway Movement and sensory stimuli
Mesolimbic Dopaminergic Pathway Pleasure and reward seeking behaviors, addiction, emotion, perception
Mesocortical Dopaminergic Pathway Cognition, memory, attention, emotional behavior, and learning
Tuberoinfundubular Dopaminergic Pathway Control of the hypothalamic pituitary endocrine system, inhibition of prolactin
secretion
Figure-1: Dopaminergic pleasure-reward pathways or other dopaminergic pathways. A) Dopamine and serotonin
pathways B) Four main dopaminergic pathways. C) Pleasure-reward circuitry and pleasure centers in the limbic sys-
tem and cortex.

Figure-2: Hedonic hot spots or pleasure centers in the brain. A) Insula, one of the centers for liking behavior B)
Cingulate cortex (Anterior cingulate: self-knowledge, perception of the self; subjective emotions C) Orbitofrontal
cortex (taste, odor etc. associations) for liking behavior.

Figure-3: Pleasure reward center and circuit originating from VTA and projecting to ventral pallidum, nu-
cleus accumbens and prefrontal cortex. This circuitry mostly uses dopamine, glutamate neurons and GABA
interneurons. In the circuitry DA transmission takes place in the process of wanting and eventually liking-
pleasure as well; for food liking orexin, opioids are also used; Opioids induce pleasure reaction at NA and
VP, particularly in sexual pleasure Reference: Robinson, 2016; Berridge 2009; 2015; Koob, 2009, 2010) Modi-
fied from Robinson, 2016.

inhibitory neurotransmitter in the central

nervous system. DA receptors have sub-
types which are mainly two families D1-
like (D1, D5) and D2-like (D2, D3, D4)
groups. Activation of D1- group receptors
increases cyclic adenosine 3, 5,-
monophosphate (cAMP) through stimula-
tion of adenylyl cyclase via Gs stimulatory
G-proteins.
But activation of D2-group re-
Figure-4: Main neurotransmitters which play ceptors decreases cAMP through Gi (inhib-
important roles in the pleasure-reward genera- itory) pathway. The other receptor sub-
tion. types belong to the D2-like subfamily (D2,
D3, and D4) and they are Gi protein-
coupled receptors that inhibit adenylyl
cyclase and activate K+ channels (Missale,
1998; Vallone, 2000).
The cAMP is formed from the ATP
through an enzyme adenylyl cyclase (AC)
and it is metabolized by the enzyme phos-
phodiesterase (PDE) which exists in the
cytoplasm.
Drugs or agents (such as caffeine) that
block phosphodiesterase (PDE) activity,
also block the inhibition. In the central
nervous system, the inhibition of inhibition
also results in excitation.
When the cAMP concentrations
rise, cAMP-dependant protein kinase
(PKA), phosphorylates receptors and
channels, and activates important tran-
scription factors like cyclic adenosine mono-
phosphate response-element binding protein
(CREB) (Tervilliger, 1991; Carlezon, 2005).
Figure-5: Dopamine’s effect on D1-like or D2-
cAMP is a second messenger responsible
like receptors. By the activation of G-proteins a
cascade of reactions starts. Dopamine is an for the cellular effects of multiple hor-
excitatory neurotransmitter at D-1 and D-5 mones and neurotransmitters via activa-
dopamine receptors; however, dopamine is an tion of its main effector, protein kinase A
inhibitory neurotransmitter at D-2, D-3, D4 (PKA).
dopaminergic receptors
Endogenous DA levels and DA re-
lease increase in the Nucleus Accumbens
(NA), Ventral Tegmental Area (VTA) and
Dopamine and Pleasure & Reward
Orbitofrontal Cortex (ORB-C) and thala-
Dopamine (DA) is an excitatory or

mus (THL) when the CNS stimulant drugs tem. Reward system of DA in the brain
are used such as nicotine, cocaine, MDMA, includes the VTA and NA, where a se-
amphetamine and methamphetamine quence of reactions occurs based on the
(Lefoll, 2005) and also these stimulant sub- drug stimuli and behavior, i.e., drug seek-
stances are associated with the reward ing consumption. Below figure depicts the
system in those areas by means of increas- mechanism of action of cocaine and meth-
ing the release of dopamine extremely, amphetamine (Fig-6).
compared to the usual-daily reward sys-
Figure-6: The Mechanism of Action of Methamphetamine and Cocaine.

Figure-7: A) Dopaminergic receptor-intracellular cascades interaction. Dopamine receptors two differ-

ent functions: excitation and inhibition. Activation of D-1 like receptors start a cascade of events that results
in the activation of some genes, like CREB, and may induce synaptic plasticity. B) A Dopaminergic synapse
KEGG Diagram with the gene expressions and moleculer biology of the chemical reactions.

pleasure and climax states, such as oxy-

These drugs stimulate mainly every tocin, norepinephrine, prolactin and en-
part of the brain, but particularly VTA, dogenous opiates (see the following arti-
prefrontal cortex and NA as well as cle, part-2).
some other subcortical structures of the It is assumed that cross molecular
limbic system. Extracellular DA release signaling of dopaminergic and com-
induces action potential firing at D1 do- bined molecular signaling of dopamin-
paminergic receptors and in some peo- ergic and glutamatergic systems, partic-
ple they may initiate craving (Schultz, ularly through dopamine (D-1) and glu-
2006). In CNS stimulant addicts this tamate receptors (NMDA and AMPA)
craving is correlated with the concentra- play critical roles in the cellular tran-
tion of DA released (Volkow, 2007; scriptional chains which affect the syn-
Franken, 2005). Craving is an electro- aptic plasticity and learning, by means of
chemical learned behavior hypothesized reorganizing the neural networks initial-
to be the new adaptation formation of ly, which eventually results in the altera-
the mesolimbic dopaminergic system tion of emotions and behavior, as well as
(Berridge, 1993). In animal and human psychological responses of the individu-
studies self-administration of DA in- al ( Hyman, 2001; Kelley, 2002; Berke,
creasing substances, creates some posi- 2000).
tive-like clinical effects, such as pleasure, The mesocortical dopaminergic
euphoria, increased libido, and en- system which includes the VTA, extends
hanced sexual pleasure, cessation of anx- its fibers into the prefrontal, cingulate and
iety, hedonism, and loss of the depres- perirhinal cortex; which is generally re-
sive mood. ferred to as mesocorticolimbic system. In
Cellular mechanisms in addiction the human brain, there are relatively few
also involve glutamatergic receptors and neurons in the SNc (substantia nigra, pars
glutamate (GLU). In pleasure and he- compacta) and VTA (less than 400,000 in
donism mechanisms AMPA, NMDA and the SNc and roughly 5,000 in the VTA
metabotropic glutamate receptors also (Bjorklund, 2007; Weidong, 2009). Despite
play important roles. As well known, that the number of neurons is small, the
NMDA receptors are responsible for the projections from individual neurons are
short term learning mechanisms and very extensive and hence modulate vari-
long term potentiation (LTP), a form of ous brain functions, including pleasure,
electrophysiological learning and condi- emotions and mood. The midbrain dopa-
tioning. These two receptor systems and minergic neuron is estimated to have total
the neurotransmitters DA and GLU are axonal (including collaterals) length of 74
widely distributed in the brain, particu- cm (Bjorklund, 2007) whereas synaptic
larly prefrontal cortex, limbic system, connections are equally as extensive, with
basal ganglia (NA, VTA, Putamen etc.) 500,000 terminals or synapses common for
which play important roles in emotions, an individual neuron (Bjorklund, 2007).
motivation, learning, memory, sexual Most of the pleasure responses are gener-
behavior and orgasm. Most of the pleas- ated by those 5000 dopaminergic neurons
urable acts, sexual activity or orgasmic and nearly 25 x 108 synapses.
climaxes are associated with dopamine Genes that are responsible for the
release in many parts of the brain. Actu- generation and phosphorylation of
ally many other neurotransmitters or CREB work mostly through NMDA
hormones are released during high and/or Dopamine D-1 receptors. Drugs

which antagonize the NMDA and/or adrenergic systems work together, while
Dopamine D-1 activation also inhibit the glutamatergic NMDA receptors mediate
formation of CREB (Steiner, 2000; Kelley, acute electrophysiological short term
2002; Das, 1997) (See Figs 6-7). memory, referred as LTP; dopaminergic
Some of these drugs that block and adrenergic, as well as acetyl-
these processes (e.g. NMDA receptors) cholinergic, systems mediate the long
can also be useful to treat addiction (ab- term memory in limbic structures (e. g.
stinence syndrome in animals). For in- VTA, amygdala and hippocampus) and
stance we found that an NMDA antago- the neo-cortex (particularly pre-frontal
nist, MK-801 (dizocilpine) or CPG-39551 cortex) (Berridge, 2007, 2008, 2009, 2015;
blocks the abstinence syndrome in mor- Kim, 2015; Pfaus, 2009, 2012; Koob 1997).
phine addicted rats (Koyuncuoglu, 1992, During the course of early development,
1994; Sayin, 2016a-b, 2017, 2018). Also a severe traumas (e.g. epileptic seizures)
shamanic psychoactive and hallucino- can induce long term alterations in the
genic plant, ibogaine, is proven and ap- synaptic plasticity, electrophysiology of
proved by NIDA to block the craving hippocampus, learning and anxiety, as
and addiction to many substances we have shown recently (Sayin, 2004,
(Sayin, 2016, 2017-b, 2018, 2019-a,b; 2015, 2017-a, 2019-a,b)
Ruck, 2018). Ibogaine is also an NMDA
antagonist. Thus, NMDA receptors have Dopamine and Noradrenalin
crucial roles in learning pleasure and Noradrenalin (NA, norepineph-
retrieving the knowledge about it, in- rine) has more stimulant activity to in-
cluding the development of addiction. crease dopamine and it regulates the
VTA is dopaminergic center and dopamine transmission in the mesocor-
dopaminergic neuron generation area, ticolimbic circuit. Cell bodies of the nor-
mesocortical dopaminergic pathway adrenalin projected at the nucleus ac-
starts here with many dopaminergic cumbens (NA) and ventral tegmental
neurons originating. Nucleus Accum- area (VTA) from brain stem A1 and A2
bens (NA) is the center for motivation and areas as well as locus ceruleus (LC)
goal directed behavior. Dopamine as an (Jones, 1977). Noradrenalin acts
action potential producing molecule in through the excitatory mechanisms and
the brain is very crucial for memory in- these projections directly stimulate the
duction; dopaminergic activity and do- dopaminergic neurons, inducing firing
paminergic synaptic plasticity & learn- and releasing dopamine; thus, indirectly
ing helps the animals (or humans) to noradrenergic neurons projecting to the
remember both positive and negative ex- prefrontal cortex (PFC) influence the
periences. dopamine neurotransmission in the nu-
Traumas probably have a deeper cleus accumbens (Swanson, 1975).
influence in the limbic system and cor-
tex, while positive-hedonic experiences Dopamine and Serotonin
are never forgotten either. This branded 5-HT (Serotonin) also plays, most
memory gives the animals the motiva- probably, an inhibitory role in the brain
tion to repeat the pleasurable experienc- reward system. Neurotransmission is
es (e.g. pressing the lever to deliver electric mediated by the 5-HT receptors, until
shocks through an electrode implanted in the now 15 different 5-HT receptor subtypes
lateral hypothalamus). are identified. Among these 5-HT-1B is
Dopaminergic, glutamatergic and involved in reward system, 5-HT-1B

receptors are strongly expressed in me- tems are widespread in many parts of
so-cortico-limbic system (Bruinvels, the brain, particularly cortex, limbic sys-
1993). Release of 5-HT is regulated by tem, basal ganglia and the reward cir-
the auto receptors present in the nerve cuitry. It is thought that activation of D-1
endings (Hjorth, 1991) and hetero re- and NMDA receptors is crucial for the
ceptors located on dopaminergic, glu- intracellular DNA transcriptional and
tamatergic, GABAergic or cholinergic translational cascades, resulting in adap-
neurons (Morikawa, 2000). Serotonin tive alterations in gene expression and
and dopamine work at opposite direc- hence synaptic plasticity and reorganiza-
tions in the formation of pleasure and tion of neuronal networks. Finally, the
reward. mood, psychology and behavior are af-
There are important psycho- fected or modified (Berke, 2000; Hyman,
pharmacological interactions that exist 2001; Kelley, 2002; Koob, 1997) .
between serotoninergic and dopaminer- Synaptic proteins are synthesized by
gic neurons. Serotonin seems to exert a means of the gene expression and the
tonic inhibitory effect on dopaminergic gene is expressed after phosphorylated
neurons at various sites, particularly at CREB binds to different response ele-
the limbic pleasure zones. Some sero- ments in different genes (Fig-5, Fig-7).
tonergic ﬁbers innervate dopaminergic CREB has been hypothesized to exert
neurons in the ventral midbrain. These important roles in learning and memory
dopaminergic neurons project their long in the corticostriatal and mesolimbic
axons forward into the striatum, limbic, projection areas (Silva, 1998). This whole
and cortical areas (Jacobs, 1992). Seroto- process is dependent on the activation of
nin input to these areas may be inhibit- NMDA and/or Dopamine D-1 activity.
ing dopaminergic neuronal ﬁring The drugs that inhibit NMDA or D-1
(Komisaruk, 2006). activity, also inhibit the formation of
Serotonin can also inhibit dopa- CREB (Das, 1997; Konradi, 1996; Liste,
mine release at presynaptic serotonin 1997; Steiner, 2000; Stewart, 2001; Wang,
receptors on dopaminergic neurons 1994).
(Alex et al., 2005). This inhibitory action
by presynaptic inhibition has been well Dopamine and GABA
studied in the basal ganglia, and it is the GABA is an inhibitory neuro-
basis of a “serotonin-dopamine counter- transmitter. When GABA binds to
interaction conceptualization”. The balance GABAA receptors, the GABA receptor
of the serotonin-dopamine “balance- channel becomes permeable to Cl- ions
hemostasis see-saw” may work both ways; and hyperpolarizes the cell, taking the
if the balance is in favor serotonin, resting membrane potential to around -
pleasure is diminished. If the balance is 80 to -90 mV from -60-70 mV of normal
in favor of dopamine, pleasure, euphoria resting membrane potential; it becomes
and contentment is enhanced (Komisa- more difficult for a neuron to fire an ac-
ruk, 2006) (See Fig-9). tion potential. GABA is released, most of
the time, from short interconnecting in-
Dopamine and Glutamate terneurons which lie in between the oth-
Cellular mechanisms in pleasure, er neurons making many inhibitory syn-
reward and finally addiction involve apses. Unlike dopaminergic neurons
dopaminergic and glutamatergic sys- with long axons originating from VTA,
tems. These two neurotransmitter sys-

projecting to prefrontal cortex; interneu- cognitive processes are very complex in

rons are moderately short and tiny neu- humans, they get more pleasure than
rons. When interneurons are stimulated animals in sexual encounters and the
by glutamate (GLU), they release GABA components of the emotional, psycho-
at the presynaptic inhibitory terminals logical and sexual aspects are more
and induce post synaptic cell becoming complicated. Desire and motivation orig-
more hyperpolarized; thus it is more inate from certain “hedonic hot zones”
difficult for the postsynaptic cell to fire which are also under the control of some
action potentials (Kandel, 2013). neurotransmitter balance. In the Fig-9-
Phenobarbital, benzodiazepines 10, a summary of hot spots and the neu-
and alprazolam (XanaX), ethyl alcohol rotransmitters involved is depicted
exert their effects through GABAergic (Kim, 2015).
system and GABAA receptors. GABAA The similar areas involved in the
receptors are widely distributed in the pleasure-reward mechanisms, also take
limbic system and pleasure-reward are- part in the generation of sexual desire
as, such as amygdala, hippocampus, and motivation, however high cortical
globus pallidum, substantia nigra, VTA centers are integrated much. Neuro-
and NA. They modulate the overall exci- transmitters dopamine and glutamate
tation of the other neurons. It should be are the major neurotransmitters. Also
kept in mind that, inhibition of inhibi- prolactin (hormone), oxytocin (hormone
tion always results in excitation; namely, and neurotransmitter), norepinephrine
if some GABAergic interneurons are (neurotransmitter), prolactin (hormone),
inhibited, their target post-synaptic neu- vasopressin (hormone), acetylcholine
rons are excited, there is always an in- (neurotransmitter), serotonin (5-HT, neu-
hibitory tone on the neurons in the rotransmitter) GABA (inhibitory neuro-
pleasure circuitry, if this inhibitory tone transmitter), testosterone (hormone), en-
is released, excitation occurs. For in- dogenous opioids (beta-endorphine, subunit
stance GABAergic inhibition of D1-like of hormone), orexin (hormone) may take
dopamine receptor neurons, which are important modulating roles in the de-
excitatory, results in inhibition; however, velopment of motivation, sexual de-
GABAergic inhibition of D-2 like dopa- sire/pleasure and satisfaction (Komisa-
mine receptor neurons, which are inhibi- ruk, 2006; Meston, 2000; Kim, 2015).
tory, results in excitation at the last post- The initial formation of motivation
synaptic level. and desire starts when the sexually
stimulating sensory input is carried to
Sexual Desire, Reward medial pre-optic area (Kim, 2015), which
and Motivation gets information from hippocampal
Sexual drive is a built-in compo- formation and amygdala nuclei via
nent of reproductive behavior which is plenty of neural projections. This is
crucial for the sustenance of human be- achieved through the cingulate neurons
ings. Sexual desire and drive are also an that receive afferents from the associa-
important part of the survival instinct. tion cortices and form neocortico-
Sexual desire also shapes the emotions, temporo-hippocampal projections. From
love and sexual satisfaction, making the hippocampus, the hippocampo-
love, orgasm, self-fulfillment and human hypothalamic projections reach the lat-
relations. Since the higher cortical and eral septum and the amygdalo- hypotha-
lamic projections reach the bed nucleus of

the stria terminalis where they pass ferred in one synapse (Fig-10).
through synaptic transmission. The To compare with today’s modern
signals then reach their final destination, computers which use 64 bit system, one
the medial preoptic area. The medial pre- byte will be accepted as 64 bits. In the
optic area also integrates information VTA-NA-prefrontal cortex pathway, if a
from the ventromedial nucleus of the hypo- dopaminergic neuron makes 500 000
thalamus, suprachiasmatic nucleus, in- connections with other dendrites of neu-
fundibular nucleus, ventral premam- rons; this makes 5 x 104 connections of
millary nucleus. This circuitry is also 5000 dopaminergic neurons or 25 x 108
named as the telodience-phalic repro- synapses. To calculate the information
ductive complex (Kim, 2015; Pfaus, 2010, carrying capacity, ((25 x 108 synapses) x
2012). 50 bits)/64 bytes of dopaminergic pleas-
Since so many different brain re- ure information can be transferred in one
gions and neurotransmitters take part in second, which is 19.53 x 108 bytes per
the formation of sexual desire and re- second, or nearly 2 gigabytes/s of pleas-
sponse (Kim, 2015): ure information, when all VTA dopa-
minergic neurons are active. This much
Biophysical Aspects of pleasure information may carry lots of
Dopamine Discharge data about the details of the pleasure
The human brain and human psyche objects and the environment plus the
have a very complicated structure. There information coming from inside of the
are 1013 neurons in the human brain. The brain and mind, or the subconscious.
duration of an action potential is 0.8 milli- Thus we can calculate and comprehend
seconds, however most neurons can fire that the neurons, and hence the brain,
an action potential in every 0.5 millisec- have a much more information capacity
onds. The dopamine production and than one can imagine.
pleasure center VTA comprises dopamin-
ergic neurons (55-65 %), GABAergic neu-
rons (30 %) and glutamatergic neurons (5
%) (Hnasko, 2012, Steffensen, 1998)
Above it is mentioned that 5000 dopamin-
ergic neurons originate from VTA, deliv-
ering pleasure impulses into prefrontal
cortex, nucleus accumbens, olfactory
structures, caudate-putamen etc. The
midbrain dopaminergic neuron is esti-
mated to have total axonal (including col-
laterals) length of 74 cm (Bjorklund, 2007).
The synaptic connections of a single do-
paminergic neuron can be as much as 500
000 at the terminal synapses (Bjorklund,
2007). If we assume that the VTA dopa-
minergic neurons fire at a rate of 100 per
second and let’s accept that 2 actions po-
tential will correspond to 1 bit of infor-
mation (0 or 1; yes or no); then in one sec-
ond 50 bits of information may be trans-

Figure-8: Interaction of GABAergic interneurons with other neurons. In the upper panel, N2 is inhibited, there is
an inhibitory post synaptic potential (IPSP); it is difficult for N2 to fire an action potential. In the mid-panel when, N1 and
hence I (interneuron) do not fire, there is no GABAergic inhibition; but only the excitatory input of N3; N2 has an EPSP, and
finally fires an action potential. In the lower panel, N1, N3 and I fire together; either the EPSP induced by N3 is canceled by
the IPSP induced by interneuron (I) and firing of N1; or there is smaller IPSP, depending upon the impact of excitatory or
inhibitory inputs.

Figure-9: The neural correlates for the sensory inputs and learned behavior affecting sexual desire. The brain
learns to reinforce behavior that brings about reward. Notice how well the brain is organized to maximally exploit avail-
able sensory information, namely, tactile, olfactory, visual, vestibular and auditory. Three common regions, the piriform
cortex, medial preoptic area, and ventral tegmental area, are activated in male and female rats by conditioned olfactory
stimuli. Opioid actions in the ventral tegmental area potentiate mesolimbic dopamine activation, whereas opioid
action in the medial preoptic area inhibits sexual arousal and desire. Red are excitatory for sexual motivation whereas
blue are inhibitory. Opioids can be excitatory in the ventral tegmental area, inhibitory in the medial preoptic area, or
either in the ventromedial nucleus of the hypothalamus. Dopamine, gonadotropin releasing hormone, melanocyte
stimulating hormone, noradrenaline, and oxytocin are excitatory whereas serotonin, opioids, and the endocanna-
binoids are inhibitory. Key: CS - conditioned stimulus; UCS - unconditioned stimulus; ACC - anterior cingulate cortex; AH
– anterior hypothalamus; ArcN - arcuate nucleus of the hypothalamus; CPu - caudate putamen (striatum); LS - lateral
septum; MeApd - posterior-dorsal nucleus of the medial amygdala; mPOA - medial preoptic area; NAcc - nucleus accum-
bens; Pir Ctx - piriform cortex; PVN - paraventricular nucleus of the hypothalamus; Tu - olfactory tubercle; VMH - ventro-
medial nucleus of the hypothalamus; VP - ventral pallidum; VTA - ventral tegmental area; Modified from Georgiadis et
al.,2012; also see Pfaus et al., 2012, page 49; Pfaus et al., 2010 (illustration modified by David Mottet). Taken and modified
from, Kim WK, Schenck CH, Grant JE, Yoon G, Dosa PI, Odlaug BL, Shreiber, LRN, Hurwitz TD, Pfaus JG. Neurobiology of
Sexual Desire. SexuS Journal; 2015; 1 (1): 044-076.)

Figure-10:Dopaminergic, glutamatergic and GABAergic circuitries in the limbic system, thalamic and cortical areas
Figure-11: The balance between neurotransmitters and how they influence pleasure, libido, arousal and
orgasm. (Reference: Sayin, 2019; Sayin HÜ. Neuroanatomy and neurochemistry of sexual desire, pleasure, love and orgasm. Part-2,
SexuS Journal Winter 2019; 4:11 )

the question could be: if female orgasms do

Getting High on Dopamine induce addiction, is it malicious and det-
As we have cited the role of dopa- rimental for female psychology, taken so
mine, glutamate and D1 & NMDA recep- many health benefits of orgasmic experi-
tors in the formation of reward and pleas- ence? However, we know that, sexual ac-
ure mechanisms, it is very important to tivity and orgasm are anti-depressant,
keep in mind that a couple of hedonic cen- healing, renovating, anxiolytic, analgesic,
ters and two neurotransmitters cannot and a natural method to get high on do-
explain such complex cortical cognitive pamine; and also on oxytocin!
functions. However, most cited references Acknowledgements: We thank Prof.
in this article, have a consensus about the Carl Ruck and Prof. Carlos Schenck for read-
major role of dopamine and meso-limbic- ing the manuscript and giving valuable
cortical dopaminergic projections, which, comments. This review article is support-
lately, also became very important to ex- ed by BAP (İstanbul University-
plain the mechanisms of drug addiction, Cerrahpaşa), and CİSEATED-ASEHERT
or any other addiction of habituation, such funds.
as gambling.
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••• Sayin HÜ, Pleasure-High-on-Dopamine ••• A Multidisciplinary Academic

Article · June 2019

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Getting High on Dopamine: Pleasure

Getting High on Dopamine:

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subcortical structures, such as the nucleus It is reported that a reward con-

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Subcortical Structures Wanting Liking Brain Stimulation Re-

Receptor Locations Functions

Substantia nigra, hippocampus, amygdala, thala-

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inhibitory neurotransmitter in the central

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Figure-6: The Mechanism of Action of Methamphetamine and Cocaine.

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Figure-7: A) Dopaminergic receptor-intracellular cascades interaction. Dopamine receptors two differ-

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pleasure and climax states, such as oxy-

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projecting to prefrontal cortex; interneu- cognitive processes are very complex in

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the question could be: if female orgasms do

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