4.4 GPR88
GPR88 is a brain specific Gi/o coupled GPCR that is
densely expressed in GABAergic MSNs in the striatum (Massart et al.,
2009; Mizushima et al., 2000). Lower expression of GPR88 has also been
reported in the olfactory tubercle, cortex, thalamus, and inferior
olivary nucleus of Gpr88 -Cre mice and Sprague-Dawley rats (Ghate
et al., 2007; Quintana et al., 2012; Van Waes et al., 2011). Within the
striatum, GPR88 is expressed in both dopamine D1- and
D2-receptor expressing MSNs and it is primarily
localised in dendritic spines containing vesicular glutamate transporter
1 (vGluT1), but not 2 (vGluT2) or tyrosine hydroxylase (TH; Massart et
al., 2009; Quintana et al., 2012). The involvement of GPR88 in distinct
behaviours appears to be cell-type specific. GPR88 in
D2R-MSNs is implicated in shaping social and defensive
behaviours; and to sustain inhibition of basal ganglia coordination of
locomotion and motor coordination. In contrast, GPR88 activation in
D1R-MSNs in the striatum promotes novelty habituation
and motor learning (Meirsman et al., 2019).
The striatum is also a critical brain region involved with
decision-making, reward-seeking, and addiction (Kalivas & Volkow, 2005;
Massart et al., 2009). Depletion of GPR88 increases MSNs excitability
via glutamatergic and autoreceptor RGS4-dependent GABA signalling
(Quintana et al., 2012). With the development of Gpr88 KO mice,
Meirsman and collaborators showed a role for GPR88 expressed in
Adenosine receptor (A2AR/D2)-expressing
striatal neurons in increasing trait anxiety-like behaviours without
affecting other associated behaviours such as conflict anxiety and fear
(Meirsman, Le Merrer, et al., 2016; Meirsman, Robe, et al., 2016). Given
the well-defined role for the striatum in AUD and the emerging research
on striatal GPR88 contribution to behaviours such as poor motor
coordination, impaired cue-based learning and hyperactivity in both
rodents (Logue et al., 2009; Maroteaux et al., 2018; Quintana et al.,
2012) and humans (Alkufri et al., 2016), it comes with no surprise that
GPR88 activity in this brain region might be important for the
development and maintenance of addiction-like behaviours associated with
alcohol use.
Gpr88 KO mice show increased voluntary alcohol intake and
motivation to acquire alcohol, but not other palatable rewards (Ben
Hamida et al., 2018). Additionally, alcohol-induced dopamine release in
the nucleus accumbens was reduced, suggesting decreased reward-driven
alcohol consumption and/or consumption of alcohol driven by habitual
behaviour in Gpr88 KO mice (Ben Hamida et al., 2018). In
addition, previous research has shown that Gpr88 KO mice have
lower basal extracellular dopamine in the striatum, but
amphetamine-induced dopamine release was normal, suggesting a role for
this receptor in dopamine signalling regulation in the striatum (Logue
et al., 2009). Altogether, these data suggest that targeting this
receptor could have therapeutic effect to treat alcohol use disorder.
Preclinical studies targeting GPR88 have shown efficacy of the agonist
RTI-13951-33, derived from the 2-PCCA ((1R ,
2R )-2-pyridin-2-yl-cyclopropane carboxylic acid ((2S ,
3S )-2-amino-3-methyl-pentyl)-(4′-propylbiphenyl-4-yl)-amide)
scaffold, in reducing alcohol self-administration and intake in rats, in
a dose-dependent manner, without impairing locomotion (Jin et al.,
2018). This agonist is potent, brain penetrant, and selective to the
GPR88 receptor. In contrast, a study found that in GPR88 KO mice,
intraperitoneal injection of this agonist decreased locomotor activity,
as well as reduced voluntary alcohol drinking, suggesting a GPR88
independent mechanism of action (Ben Hamida et al., 2022). Similar
results have been previously reported where the GPR88 agonist 2-PCCA
dose-dependently decreased locomotor activity in rats (Li et al., 2013).
These distinct behavioural outcomes can be attributed to the differences
between administering a GPR88 receptor agonist in a naïve animal vs
using a transgenic Gpr88 KO mouse, which can be complicated by
compensatory mechanisms during development. Nonetheless, further
pharmacological characterisation of RTI-13951-33 is needed to elucidate
its mechanism and therapeutic potential. These data do however support a
theoretical rationale for further assessment of GPR88 targeted
treatments for AUD.