1. GPCR signalling in alcohol use disorders
G protein-coupled receptors (GPCRs), also termed seven-transmembrane
(7TM) domain receptors, are the largest class of receptors in the
mammalian genome (Alexander et al., 2019). GPCRs are currently classed
into five main categories based on phylogenetic studies, forming the
GRAFS classification - Glutamate (Class C), Rhodopsin (Class A),
Adhesion, Frizzled/Taste2, and Secretin (Fredriksson et al., 2003).
These dynamic receptors undergo confirmational changes upon ligand
binding, and downstream modulation of transducer proteins. This includes
via heterotrimeric G proteins subunits α, β and γ that upon receptor
activation dissociate to α and βγ (Kolb et al., 2022). There are 16
distinct α subunits that are categorised into four families based on
downstream signalling pathways: Gs (increases adenylyl
cyclase and cAMP), Gi/o (reduces adenylyl cyclase and
cAMP), Gq (increase DAG and IP3) and
G12/13 (activates Rho) (Kolb et al., 2022). GPCRs have
long been of interest as pharmacological targets to treat
neuropsychiatric disorders and other diseases. As of 2017, there were
475 drugs that target GPCRs approved by the FDA, representing
~34% of all FDA approved drugs, acting on 108 unique
GPCR targets (Hauser et al., 2017; Hauser et al., 2018). These drugs
target only a fraction of known GPCRs, with dopamine, serotonin,
cannabinoid and opioid receptors being prominent targets for disorders
of the brain, including alcohol use disorder.
There are currently three FDA approved drugs for the treatment of
alcohol use disorders (AUD); Disulfiram, Acamprosate and Naltrexone.
Disulfiram acts to inhibit aldehyde dehydrogenase, causing adverse
reactions when consumed (Jørgensen et al., 2011). Acamprosate, has an
unknown mechanism of action, although does reduce craving in some
individuals with AUD (Spanagel et al., 2014; Witkiewitz et al., 2012).
Naltrexone acts to reduce alcohol craving and heavy drinking in some
individuals with alcohol use disorder predominantly through antagonism
of the µ-opioid receptor (Anton, 2008). Unfortunately, all these
treatments suffer from limitations, including inadequate efficacy,
adverse side effects and low compliance, rendering them somewhat
ineffective at a population level (Kranzler & Soyka, 2018; Walker &
Lawrence, 2018). Further, the last compound approved by the FDA for AUD
was Acamprosate, almost 20 years ago, highlighting the lack of effective
treatments progressing to approval (Witkiewitz et al., 2012). Currently
there are 412 trials listed on clinicaltrials.gov for
treatment/assessment of alcohol use. Of these, 73 assess drug
interventions and 44 (60%) target GPCR mechanisms including serotonin
receptors (14/44, 31%) cannabinoid receptors (8/44, 18%), oxytocin
receptors (6/44, 13%) and GLP1 receptor (4/44, 9%) (See Table 1 for
summary). A variety of other GPCR targets for AUD are in preclinical
development including, but not limited to, muscarinic receptors (Walker
et al., 2020; Walker et al., 2023), neurotensin receptors (Rodriguez et
al., 2023) and neurokinin receptors (Schank, 2020). These data highlight
the potential of GPCR signalling to treat alcohol use disorders, a topic
which is being widely explored. However, one avenue of GPCR signalling
that remains underexplored is the potential of orphan neuropeptides and
GPCRs (oGPCRs) as novel targets for disease, including AUD.
Orphan neuropeptides are endogenous peptides that do not have a known
receptor, while oGPCRs are receptors for which their endogenous ligand
is yet to be identified. Despite considerable efforts, more than 100
GPCRs remain orphaned, primarily within Rhodopsin (class A) and
Glutamate (class C) GPCR. The International Union of Basic and Clinical
Pharmacology Committee on Receptor Nomenclature and Drug Classification
(NC-IUPHAR) consider an oGPCR de-orphaned only when results are
reproducible and criteria for likelihood of in vivo pairing are
met (Alexander et al., 2019). Importantly, almost half of oGPCRs are
expressed in the brain (Ehrlich et al., 2018; Hauser et al., 2017) and
these represent an unprecedented opportunity to address brain function
and disease. Indeed, it is estimated that 56% of non-sensory GPCRs are
still unexplored clinically, which includes a substantial population
(27%) of orphan GPCRs (Hauser et al., 2017). There are 106 de-orphaned
GPCRs that currently have an FDA approved drug (31.6%), compared to
only 1 oGPCR (1.1%) (Figure 1A). Further, 57 (17.0%) of de-orphaned
GPCRs have a drug currently in clinical trial, compared to 2 (2.3%)
oGPCRs (Figure 1A). Specifically for CNS indications, 130 (27.1%) of
approved de-orphaned GPCR drugs are for CNS indications, but none target
oGPCRs (Figure 1B). Of the de-orphaned GPCRs currently in clinical
trial, 27 (35.5%) of these receptors are being targeted for CNS
indications, whilst there are no drugs targeting oGPCRs (Figure 1B).
Here we describe the current literature regarding orphaned neuropeptides
and GPCRs implicated in AUD. Specifically in this review we focus on the
orphaned neuropeptide cocaine and amphetamine regulated transcript
(CART), and several oGPCRs that have been directly implicated in alcohol
use disorder; GPR6, GPR26, GPR88, GPR139, GPR158, and discuss their
potential and pitfalls as novel treatments.