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GABAB receptor modulation — to B or not to be B a
pro-cognitive medicine?
Jordi Serrats1, Mark Oliver Cunningham2 and
Ceri Hywel Davies3
Metabotropic GABAB receptors clearly modify cognitive
performance in preclinical animal models, yet translation to
treating human disease has been elusive. Compared to their
ionotropic GABAA receptor counterpart GABAB receptors not
only regulate postsynaptic excitability but also regulate diverse
synaptic inputs by presynaptically inhibiting neurotransmitter
release. As such, the choice of agonist, antagonist,
ve or +ve
modulator as well as CNS exposure level, timing of delivery and
longevity of action strongly influence the probability of unlocking
the procognitive potential of GABAB receptors in human
disease. Quantitative clinical analysis of target/mechanistic
engagement of GABAB receptors within cognitive circuits at the
level of distinct pre-synaptic and post-synaptic subpopulations
is required to determine the optimal pharmacological/dosing
profile for different cognitive disorders.
Addresses
1
CNS Drug Discovery Unit, Takeda Pharmaceuticals Limited, Takeda
California, 10275 Science Center Drive, San Diego, CA 92121, USA
2
Institute of Neuroscience, The Medical School, Framlington Place,
University of Newcastle upon Tyne, NE2 4HH, UK
3
CNS Drug Discovery Unit, Takeda Pharmacuticals Limited, Shonan
Research Center, Takeda Pharmaceutical Company Limited, 26-1,
Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
Corresponding author: Serrats, Jordi (jordi.serrats@takeda.com)
Current Opinion in Pharmacology 2017, 35:xx–yy
This review comes from a themed issue on Tribute to Norman
Bowery
Edited by David G Trist and Tom Blackburn
http://dx.doi.org/10.1016/j.coph.2017.09.012
1471-4892/ã 2017 Published by Elsevier Ltd.
Introduction
GABAB receptors are highly expressed throughout brain
regions implicated in learning and memory processes [1]
and their role in cognitive function has been explored for
over 30 years initially driven by the identification of the
first selective agonist baclofen and subsequently by the
development of selective antagonists, such as CGP35348.
These pharmacological agents together with genetic
knockout of different GABAB receptor subunits have
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generated a wealth of data regarding how GABAB recep-
tors can influence cognitive performance in rodents and
non-human primates although translation of these effects
to humans has proved elusive (reviewed in [2]). The
reason for this disconnect potentially resides in our, firstly,
incomplete understanding of which populations of GABAB
receptor on different neuronal subtypes need to be acti-
vated or inhibited under different disease states [3] and
secondly, inability to control the spatial and temporal
delivery of agonists, antagonists as well as positive or
negative modulators to the appropriate brain regions as
required. In respect to the first point GABAB receptors are
present on multiple types of inhibitory and excitatory
neurones at both pre-synaptic (autoreceptor and hetero-
receptor) and postsynaptic loci [4] as well as on microglia
and astroglia that support normal neuronal function [5,6].
The first selective antagonists that were developed in the
early 1990s were instrumental in defining physiological
activation of postsynaptic GABAB receptors as the mech-
anism for a slow inhibitory postsynaptic potential [7] and
then GABAB autoreceptors as a control mechanism that
modifies the strength of fast GABAA receptor-mediated
inhibition (and likely GABAB receptor mediated inhibi-
tion also) in an activity dependent manner [8–11] — an
observation that in its own right was notable in represent-
ing probably the first demonstration of physiological
activation of any autoreceptor in the brain [12]. Finally
physiological activation of heteroreceptors controlling the
release of fast and slow acting neurotransmitters such as
glutamate and acetylcholine [13,14] was demonstrated.
Attempts to pharmacologically separate these receptor
populations, however, using selective pharmacological
agents has proved difficult with agonists and antagonists
generally modifying the activity of all receptor popula-
tions at 10–30-folds differences in concentration most
likely resulting from differences in signal transduction
coupling and/or local GABA concentration (Figure 1).
This limited specificity of intervention is important
because each population of GABAB receptor has the
potential to dramatically change the pattern of network
activity and thereby positively or negatively impact cog-
nitive performance.
In this review we will provide an overview of the liter-
ature that supports GABAB receptor mediated regulation
of cellular processes relevant to learning and memory as
well as summarize what we know about their effects on
preclinical models of learning and memory and their link
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COPHAR-1656; NO. OF PAGES 8
2 Tribute to Norman Bowery
Figure 1
Physiology
pB
pB
pB hB pB
(a) Schematic representation of the location of three GABAB receptor populations in a brain microcircuit of three glutamatergic excitatory neurons
(green) a single monoaminergic neuron (orange) and a single GABAergic inhibitory interneurone. (b) Current concentration responsiveness of
GABAB receptor populations to agonist and antagonists.
to human disease. In reviewing this literature we will
highlight how experimental design and use of agonists
and antagonists selects different mosaic patterns of acti-
vation and inhibition of postsynaptic, autoreceptor and
heteroreceptor populations and how this can have a strong
bearing on the electrophysiological or behavioural func-
tional outcomes achieved.
Synchronized neuronal network activity
Synchronous neuronal network activity is believed to play
a critical role in learning and memory processes [15,16]. In
this respect, sharp wave ripple complexes, theta (4–
10 Hz) and gamma (30–80 Hz) frequency activity, which
are all heavily reliant on GABAergic synaptic inputs, have
been shown to be important for higher order processing
[17] and are disrupted in diseases where cognitive
impairment is observed (e.g. schizophrenia).
The temporal nature of network oscillations is too rapid
for GABAB receptors to play a role in initiating activity
directly. However, the enduring effects (seconds) of
activation of GABAB receptors are likely to be capable
of modulating spike transfer [18] and key features of the
various network rhythms outlined above. Evidence to
support this notion is relatively (and somewhat surpris-
ingly) scant but a small number of in vitro and in vivo
studies have examined the impact of pharmacological
manipulation of GABAB receptors.
Sharp wave ripple (SPW-R) complexes have been pro-
posed to facilitate the off-line memory consolidation of
previous spatial information encoded during hippocampal
theta and gamma activity [19]. These discrete events can
be observed in rodent brain slices spontaneously or fol-
lowing the use of protocols that can induce long-term
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coph.2017.09.012
Pharmacology
hB pB hB aB
antagonist
hB
aB hB pB
agonist
aB pB
10-100x
Current Opinion in Pharmacology
potentiation in vitro [20]. Intracellular recordings have
indicated that GABAergic function is critical for the
generation of SPW-R activity [21]. Using rat hippocampal
slices, Hollangel et al. [22], demonstrated that SPW-R
activity was transiently suppressed by bath application of
the GABAB receptor agonist baclofen. This suppression
was prevented by the GABAB receptor antagonist
CGP55845 but the antagonist alone had no effect on
the incidence of SPW-R events, suggesting very little
if any endogenous activation of GABAB receptors during
this pattern of activity. Using paired pulse stimulation and
calcium-sensitive electrodes the authors suggested that
the effect of baclofen on SPW-R activity is mediated via
inhibition of presynaptic calcium dependent neurotrans-
mitter release. Given the abrupt transitions between
SPW-R and theta/gamma activity that occur in vivo it
is possible that the appearance of SPW-R events is
likewise regulated by modulation of neurotransmitter
release probability.
The critical role of GABAergic interneurons in synchro-
nizing pyramidal cells and promotion of oscillatory activ-
ity via phasic inhibition, has focused attention on the
GABAA receptor rather than the GABAB receptor. In fact,
it had been assumed that the contribution of GABAB
receptors is negligible. However, using tetanic stimula-
tion to evoke transient gamma oscillations in rat hippo-
campal slices, Whittington et al. [23], demonstrated that
the duration of this induced interneuronal generated
gamma (ING) oscillation required GABAB receptor-
mediated inhibitory post-synaptic potentials (IPSPs).
Following on from this study, kainate evoked gamma
oscillations (which constitute a pyramidal-interneurone
generated gamma (PING)) were interrogated with
GABAB receptor agonists and antagonists and in stratum
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GABAB receptor modulation — to B or not to be B a pro-cognitive medicine? Serrats, Cunningham and Davies 3
pyramidale of CA3, the amplitude of gamma oscillations
was shown to be augmented by CGP55845. Moreover, the
application of the GABAB receptor agonist baclofen abol-
ished gamma oscillations which could then be recovered
by subsequent application of CGP55845. In addition,
stimulus induced suppression of gamma oscillations
was largely inhibited by antagonism of GABAB receptors.
A notable observation regarding this effect was that the
time course of stimulus induced suppression of gamma
oscillations was strikingly similar to the duration of
GABAB receptor mediated slow IPSP. By altering the
frequency of paired pulse stimulation the authors
reported an activity-dependent run-down of the gamma
activity suppression. Interestingly, this activity-depen-
dent exhaustion of inhibition revealed a stimulus-depen-
dent temporal entrainment of the gamma activity. Fur-
thermore, the degree of repetitive synaptic input required
to cause this entrainment was dramatically reduced by
GABAB receptor antagonism. These findings suggest that
GABAB receptor antagonists can facilitate the induction
of gamma frequency activity by repetitive stimulation
possibly by alleviating the inhibitory influence of post-
synaptic GABAB receptor activation.
Theta frequency oscillations are also relevant to mnemo-
mic processes in both hippocampal and cortical networks
and have been shown to be critical for acquisition, recol-
lection and spatial orientation as well as susceptible to
regulation by GABAB receptor antagonists. In this
respect, whilst inhibitory input from subcortical struc-
tures strongly regulates theta oscillations, local circuitry
within the hippocampus and cortex can support the
generation of this activity [24]. Since the contribution
of inhibitory basket cells, in terms of spiking, during the
theta cycle is profound it is not surprising that these
rhythms are also subject to modulation by GABAB recep-
tors. In organotypic hippocampal slices, muscarinic recep-
tor activation was found to promote GABA spillover that
activated postsynaptic GABAB receptors and promoted
theta frequency rhythmic inhibitory post-synaptic cur-
rents (IPSCs) [25]. The frequency of these rhythmic
IPSCs was increased by GABAB receptor antagonism.
Notably in acute rat hippocampal slices in which a theta
oscillation was evoked by carbachol the power of the
oscillation was increased following GABAB receptor block
[26]. A similar observation has also been made in rodent
motor cortex brain slices where GABAB receptor blockade
led to an increase in carbachol/kainate evoked theta and
gamma frequency oscillations [27]. However, in the
rodent primary auditory cortex, CGP35348, did not affect
gamma oscillations in the supra-granular and infragranular
layers evoked by brief applications of glutamate and actu-
ally reduced the plasticity induced augmentation of the
infragranular glutamate evoked gamma oscillation [28].
The in vitro effects of GABAB receptor modulation on
synchronized network activity have led to the investigation
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of the role of GABAB receptors in modulating in vivo brain
activity. In the hippocampus GABAB receptors promote
conversion of theta and gamma activity to sharp wave
ripples and potentially the transition from memory acqui-
sition to consolidation [29]. In this respect it is also worth
noting that CGP35348 enhances learning and memory
induced by theta rhythm activity in vivo [30]. How differ-
ent GABAB receptor populations including those that
influence the cholinergic system contribute to these effects
is still unclear.
Synaptic plasticity
The published literature regarding the influence of
GABAB receptors on synaptic plasticity is complex and
points to this receptor class possessing the ability to both
positively and negatively influence the induction of LTP
under different experimental conditions [31,32].
GABAB autoreceptors facilitate the induction of LTP
During priming-pulse stimulation (a single stimulus
(priming-pulse) followed 200 ms later by a burst of four
stimuli delivered at 100 Hz (primed-burst)) that reflects
physiologically relevant frequencies and periods of neuro-
nal activity GABAB receptor activation is essential for LTP
as demonstrated by the ability of GABAB receptor antago-
nists to block its induction in the hippocampal CA1 region.
The GABAB receptors located on excitatory glutamater-
gic terminals — heteroreceptors — are unlikely to
account for this effect since were these to be activated
physiologically the induction of LTP would be expected
to be restricted because the NMDA receptor-mediated
component of synaptic transmission would be impaired
and the effect of a GABAB receptor antagonist would be
to enhance, rather than block, LTP.
In contrast, there is a better case for GABAB receptors
located at GABAergic synapses to be the population as
the primary promotional population for the induction of
LTP by priming stimulation. In this respect, fast GABAA
receptor-mediated inhibition (IPSPA — which is regu-
lated by GABAB autoreceptors in an activity dependent
manner) is widely believed to restrict LTP because:
(i) the induction of associative and non-associative LTP
is greatly enhanced when IPSPA is blocked by picro-
toxin [33–36]. Thus, only 4 pulses delivered at 100 Hz
(i.e. stimulation equivalent to the primed burst of a
priming-pulse tetanus) does not induce LTP in control
medium whilst substantial LTP is readily induced in
slices treated with GABAA receptor antagonist.
(ii) the optimal interval between priming-pulse and
primed-burst for the induction of LTP by priming-
pulse stimulation corresponds to the frequency at
which maximal GABAB autoreceptor-mediated
depression of IPSPA occurs.
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4 Tribute to Norman Bowery
Furthermore, the observations that 100 mM CGP
35348 which practically abolished IPSPB without affect-
ing the depression of synaptic inhibition, during the
priming-pulse tetanus, had little effect on the induction
of LTP. whereas 1 mM CGP 35348, which prevented the
depression of IPSPA during the tetanus, prevented LTP
being induced support the concept that GABAB autorecep-
tor-mediated depression of IPSPA strongly promotes
NMDA receptor-dependent LTP. Indeed, as might be
expected if this is the case, when GABAA receptor-mediated
synaptic inhibition is blocked by picrotoxin, CGP 35348 is
no longer effective at blocking the induction of LTP.
Put another way, during periods of high frequency affer-
ent input, synaptically released GABA activates GABAB
autoreceptors to inhibit subsequent GABA release. The
consequent reduction in the level of hyperpolarisation
associated with the biphasic IPSPA/B, that follows activa-
tion of the glutamatergic EPSPs, increases the extent to
which both AMPA and NMDA receptor-mediated EPSPs
summate and increases the probability of inducing LTP.
However, summation of AMPA-receptor-mediated
EPSPs (EPSPAs) is not likely to be absolutely essential
since LTP can still be induced when AMPA receptors are
blocked pharmacologically using CNQX. Thus, EPSPAs
will add to the postsynaptic depolarization and further
promote the activation of EPSPN to a level that is supra-
threshold for LTP induction.
IPSPB restricts the induction of LTP
The strong inhibitory influence of IPSPA on the induction
of LTP presupposes that IPSPB also opposes this process,
Indeed, the hyperpolarization associated with IPSPB does
restrict the expression of EPSPN. Not surprisingly, there-
fore, under conditions where IPSPA is abolished, or where
intense tetanic stimulation is delivered that reduces the
hyperpolarizing (and resistance shunt) strength of IPSPA,
selective blockade of postsynaptic GABAB receptor-
mediated events facilitates NMDA receptor activity
and the induction of LTP. However, in the case of
intense tetanic stimulation in the presence of GABAB
receptor antagonist concentrations that block IPSPB alter-
native mechanisms may facilitate the induction of LTP.
For example, activation of depolarizing GABAA receptor-
mediated synaptic potentials (IPSPD) may enhance the
expression of EPSPN through depolarization of the post-
synaptic membrane. This latter scenario may be more
physiologically relevant during development when the
IPSPB is developing and the chloride equilibrium poten-
tial in neurones is not fully matured and more susceptible
to imbalance. In contrast in the adult state the influence
of postsynaptic GABAB receptors on synaptic plasticity
may be more relevant during pathophysiological states
when GABAA receptor-mediated inhibition is diminished
in which case the IPSPB could have a greater influence on
EPSPN [37].
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To summarize, although postsynaptic GABAB receptors
appear to facilitate, whilst GABAB autoreceptors prevent
the induction of LTP, the net influence of these two
GABAB receptor populations on the induction of LTP
will strongly depend upon the relative activation of each
population. For example, (
)-baclofen might be
expected to either facilitate the induction of LTP by
depressing synaptic inhibition or restrict the induction of
LTP by depressing excitatory synaptic transmission and
hyperpolarizing the postsynaptic neurones. In addition
the effect of a GABAB receptor agonist or antagonist on
the induction of LTP is likely to depend upon the type of
conditioning stimulation used for LTP induction. For
example, relatively long periods of high frequency stim-
ulation (e.g. traditional tetani) suppress synaptic inhibi-
tion by shifting ECl
and EK+ [38]. Thus, GABAB auto-
receptors have little influence on the LTP induction
process whereas, postsynaptic GABAB receptors oppose
this form of LTP as each stimulus of the tetanus is
delivered during the time-course of the IPSPB. The
reverse scenario exists when LTP is induced by prim-
ing-pulse stimulation. In this case, the GABAB autore-
ceptor-mediated depression of IPSPA has a greater influ-
ence than IPSPB.
To further complicate the situation in an extended neu-
ronal network context we should also consider the effects
of GABAB receptors on synaptic plasticity in interneur-
ones. In this respect, the aforementioned discussion
relates to plasticity of excitatory synapses innervating
excitatory neurones. However GABAB receptors also
influence synaptic plasticity at excitatory synapses that
drive GABAergic inhibitory neurones and have been
implicated in long-term depression and potentiation of
inhibitory synaptic inputs. Furthermore, they have been
shown to have differential effects at distinct synapses
formed by different subpopulations of GABAergic inter-
neuron [39,40]; a level of complexity that further com-
plicates hypothesis generation in respect to how GABAB
receptor manipulation can be harnessed to produce pro-
cognitive benefit.
Behavioural learning and memory models
Given the complexity of the modulatory influence of
GABAB receptors on neuronal network activity and syn-
aptic plasticity it comes as no surprise that the literature
related to the in vivo cognitive effects of GABAB receptor
ligands is also complex [41]. Since most published stud-
ies have not reported either compound brain exposures or
GABAB receptor occupancy data it is not possible to
provide a detailed mechanistic analysis of which receptor
populations are engaged or not engaged in producing
specific effects. As such, here we simply focus on provid-
ing an overview of the data available regarding the
different effects produced by distinct GABAB receptor
agonists and antagonists in several models of learning and
memory.
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GABAB receptor modulation — to B or not to be B a pro-cognitive medicine? Serrats, Cunningham and Davies 5
As noted before, the GABAB receptor is highly expressed
throughout brain areas that are important for learning and
memory such as the hippocampus and cortex. Thus, the
expectation is that normal GABAB receptor function is a
necessary prerequisite for normal activity in a variety of
cognition models. In addition, we need to keep in mind
that interactions of the GABAB receptor and its down-
stream signalling pathways are becoming better under-
stood [42], and it is possible that different ligands have
divergent functional effects depending on the internal
pathways they activate, that is, their signal bias can sway
their functional impact.
Passive avoidance
In the passive avoidance model, the latency to step into
an area that has been linked to an aversive stimulus (i.e.
foot shock) is recorded. Performance is impaired when
the latency is lower than in the vehicle treated group, or
enhanced if the latency is higher. Knockout animals
lacking GABAB1a or GABAB1b receptor subunits do not
show any impairment [43]. However, mice that do not
express either GABAB1 or GABAB2 receptor subunits
have impaired performance [44]. Furthermore, perfor-
mance in this particular task appears to depend on the
levels of GABAB2 receptor subunit in the hippocampus.
Interestingly, in pharmacological studies, in the majority
of mouse studies, baclofen impairs performance whereas
administration of GABAB receptor antagonists after the
training phase of the task improve performance [45].
These data, when taken together, suggest that GABAB
receptor activation impairs consolidation of memories
whereas GABA B receptor antagonism improves
performance.
Active avoidance
In this model system, animals are given a stimulus (con-
ditioned stimulus) to warn them to avoid an area where
they will receive a foot shock. As such, this model tests
whether animals can make an action to avoid a negative
situation. Numerous GABAB receptor antagonists [46] all
improved performance in active avoidance tasks. How-
ever, baclofen displayed variable effectiveness [47]. As
such, whereas antagonism of GABAB receptors clearly
improves performance the reverse is not necessarily the
case for agonists
Morris water maze (MWM)
In the MWM, animals use spatial navigation cues to
locate a hidden platform. In this task, animals rely on
hippocampal function to learn where the hidden platform
is located (acquisition) and additional brain regions (e.g.
medial frontal cortex and striatum) to remember that
particular location (consolidation). GABAB receptor agon-
ism during the training phase is consistently detrimental
in this particular task [48]. In the only study where the
role of a GABAB receptor antagonist was studied for its
effect on the consolidation phase CGP35348 infusion into
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the hippocampal CA1 region [49], had no effect on
consolidation or recall but did improve task acquisition.
These data indicate that too much GABAB receptor
activation impairs performance in the MWM, however
GABAB receptor antagonism can improve spatial learning
[50]. Furthermore, there is some evidence to suggest
region-specific effects of GABAB receptor agonists and
antagonists since intra hippocampal or entorhinal admin-
istration has different effects to systemic delivery which
will modify GABAB receptor function right across the
CNS [48].
Working memory tasks
GABAB receptor agonists and antagonists have been
tested in several working memory tasks including the
T-maze or Y-maze as well as delayed matching-to-posi-
tion task. GABAB1 receptor subunit knockouts are
impaired in the Y maze task. Pharmacological studies
have delivered more complex results whilst still implicat-
ing this receptor system in working memory. In this
respect, performance in the T-maze seems to depend
on activity levels in the hippocampus, septum, prefrontal
cortex, thalamus and striatal areas. Thus, GABAB receptor
agonist infusion into the septum, basal forebrain, or
thalamus all impaired working memory performance
[50] whereas systemically administered baclofen
improved performance in delayed matching-to-position
tasks. In contrast, GABAB receptor antagonists produced
limited or no effects in working memory tasks when
dosed systemically [51] whereas, local infusion of saclofen
(a weak GABAB receptor antagonist into the dentate
gyrus produced some degree of improvement in working
memory performance [52].
Novel object recognition
The novel object recognition model tests the ability of an
animal to differentiate between a known object and a
novel one. If the animal remembers the object it will not
spend too much time with it, and will spend more time
with the novel object. If the animal does not remember
the object it has already explored it will spend equal time
with both objects. Long-term memory is usually tested
24 hours after the acquisition phase. Systemic dosing of
GABAB receptor agonists disrupt both acquisition and
consolidation of this task [53]. Furthermore, enhance-
ment of GABAB receptor function by genetic manipula-
tion also resulted in impairments in cognitive perfor-
mance as shown by Terunuma et al. [54] In contrast,
systemic administration of GABAB receptor antagonists,
does not affect either acquisition or consolidation.
Social recognition
Social recognition evaluates the time that an animal
spends with a familiar animal versus a new animal.
Typically, a rodent will spend more time with a new
animal due to its natural inclination to explore novel
partners. Systemic administration of CGP36742, a
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6 Tribute to Norman Bowery
GABAB receptor antagonist improves performance in
this test, suggesting that blocking GABAB receptors
could be of therapeutic benefit in disorders where social
memory is lacking or decreased, for example, autism or
schizophrenia [55].
Disease
Given the potential of GABAB receptor modulation to
deliver a pro-cognitive phenotype there has been consid-
erable interest in examining whether GABAB receptor
ligands can deliver clinical benefit in diseases where
cognitive impairment is observed. In this context the
balance of evidence from behavioural studies has sug-
gested that antagonism is a more favourable approach for
producing cognitive benefit than agonism and has stimu-
lated some interest in collecting additional evidence to
support this rationale in humans. In this respect a post-
mortem GABAB receptor expression study has suggested
an increase in GABAB1 receptor expression in the hippo-
campus in area CA2/3 that correlates with the extent of
neurofibrillary tangle pathology [56] although this rela-
tionship was not observed in area CA1 where there was a
decrease, not an increase, in expression [57,58]. Alterna-
tive splicing and GIRK expression also suggest possible
changes in GABAB receptor signalling in Azheimer’s
Disease [58,59] that have prompted the development
of clinical TMS protocols to identify specific changes in
GABAB receptor function in living patients. These latter
studies may yet stimulate a resurgence in the interest of
using GABAB receptor ligands for treating human cogni-
tive dysfunction which so far has not gathered a lot of
momentum in part because of the difficulty in developing
safe and well tolerated CNS penetrant ligands and in part
because of relatively weak clinical data. In this respect,
the most publicized procognitive clinical trial is that of
SGS742 (formerly known as CGP 36742) which was
progressed to Phase II in an attempt to treat mild cogni-
tive impairment [60]. This molecule is a relatively weak
GABAB receptor antagonist (blocks IPSPB at approx
100 mM and autoreceptors at approx 1 mM) and was
administered orally at 600 mg three times a day for eight
weeks in a double-blind trial in 75 patients aged 59–85.
No ‘predicted’ GABAB receptor mediated side effects, or
unexpected serious adverse events, were observed which
could either indicate low levels of receptor occupancy or
minimal resting GABAB receptor tone. However, despite
this SGS742 significantly improved working memory and
attention suggesting that during cognitive tasks GABAB
receptors are activated and their antagonism can promote
cognitive performance; an observation which could be
viewed as lining up favourably with (i) an expected brain
exposure that would hit postsynaptic GABAB receptors
more than presynaptic receptors and (ii) the pro-cognitive
effects of GABAB receptor antagonists preclinically
(albeit that these were weak in working memory tasks).
In this context it is notable that, whilst this initial clinical
study provided encouraging signals of efficacy SGS742
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failed to progress to Phase III testing and currently there
are no other GABAB receptor antagonists in clinical
development for cognitive diseases either as symptomatic
or disease modifying agents even though GABAB recep-
tors have recently been implicated in hippocampal neu-
rogenesis [61].
Going back to a neurophysiological substrate of CNS
disease, that is, disruptions in brain neuronal network
activity, it is clear that abnormal circuit rhythms are
heavily implicated in psychiatric/neurodevelopmental
disease states which exhibit cognitive impairment. For
example, patients with Fragile-X syndrome (FXS) exhibit
cortical hyperexcitability, greater gamma oscillation power
and spatial distribution that is correlated with social and
sensory processing deficiencies. Notably, the Fmr1 knock-
out mouse model displays changes in GABAB receptor
function and baclofen normalised auditory evoked gamma
oscillations and deficits in working memory, anxiety beha-
viours but not impairments in social interactions [62].
However, as described for MCI above, in the clinical
studies performed to date GABAB receptor ligands such
as arbaclofen have not delivered a strong efficacy profile.
Summary
In conclusion the GABAB receptor represents a poten-
tially powerful receptor system through which to nega-
tively of positively regulate cognitive performance.
Unleashing this potential has been elusive because of
the sophisticated nature by which this receptor system
operates to modulate synaptic integration within neuronal
circuits and the inability thus far to pharmacologically
intervene selectively, and with the desired directionality,
at different populations of postsynaptic receptor, auto-
receptor and heteroreceptor. Whilst different dose levels
potentially provides the opportunity to modify different
receptor populations with some degree of specificity (low
agonist concentrations specifically reduce GABA —
mediated inhibition without effects on postsynaptic
membrane potential or heteroreceptor activation and
low antagonist concentrations prevent the slow IPSP
preferentially ahead of affecting presynaptic GABAB
receptors the more recent development of allosteric mod-
ulators that manipulate the function of this receptor
subtype in a signal biased way [63] may provide a
new direction for therapeutic intervention that in the
future may ultimately be complemented or replaced by
specific activity dependent subpopulation modulation. In
this context there is still ample opportunity to continue to
evaluate the therapeutic opportunity that GABAB recep-
tors can provide to cognitively impaired patients. By
comparison to other procognitive approaches clinical
GABAB receptor modulation for cognitive dysfunction
is certainly still in its infancy!!
Conflicts of interest statement
Nothing declared.
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COPHAR-1656; NO. OF PAGES 8
GABAB receptor modulation — to B or not to be B a pro-cognitive medicine? Serrats, Cunningham and Davies 7
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