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\begin{document}

\title{Orphan peptide and G protein-coupled receptor signalling in alcohol use
disorder}



\author[1]{Roberta Anversa}%
\author[1]{Xavier Maddern}%
\author[1]{Andrew Lawrence}%
\author[1]{Leigh Walker}%
\affil[1]{The Florey Institute of Neuroscience and Mental Health}%


\vspace{-1em}



  
  \date{May 10, 2024}


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\textbf{Title:} Orphan peptide and G protein-coupled receptor signalling
in alcohol use disorder

Roberta Goncalves Anversa\textsuperscript{1,2}*, Xavier J
Maddern\textsuperscript{1,2}*, Andrew J Lawrence\textsuperscript{1,2}and
Leigh C Walker\textsuperscript{1,2}

*Contributed equally

\textsuperscript{1}Florey Institute of Neuroscience and Mental Health,
VIC 3052 Australia

\textsuperscript{2}Florey Department of Neuroscience and Mental Health,
University of Melbourne, VIC 3052 Australia

\textbf{Corresponding Author}

Leigh Walker, PhD

Florey Institute of Neuroscience and Mental Health

Melbourne Brain Centre, The University of Melbourne

30 Royal Parade, Parkville, 3052, Melbourne, VIC, Australia

Email: leigh.walker@florey.edu.au

Keywords:

Neuropeptide, GPCR, orphan, alcohol use disorder, CART, GPR6, GPR26,
GPR88, GPR135, GPR158

Word count:

Abstract: 144

Main text: 4877

Figures: 2

Tables: 1

References: 127



\textbf{Abstract}

Neuropeptides and G protein-coupled receptors (GPCRs) have long been,
and continue to be, one of the most popular target classes for drug
discovery in CNS disorders, including alcohol use disorder (AUD). Yet,
orphaned neuropeptide systems and receptors (oGPCR), that have no known
cognate receptor or ligand, remain understudied in drug discovery and
development. Orphan neuropeptides and oGPCRs are abundantly expressed
within the brain and represent an unprecedented opportunity to address
brain function and may hold potential as novel treatments for disease.
Here we describe the current literature regarding orphaned neuropeptides
and oGPCRs 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 AUD;
GPR6, GPR26, GPR88, GPR139, GPR158, and discuss their potential and
pitfalls as novel treatments and progress in identifying their cognate
receptors or ligands.



\textbf{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 \selectlanguage{greek}α, β \selectlanguage{english}and \selectlanguage{greek}γ \selectlanguage{english}that upon receptor
activation dissociate to \selectlanguage{greek}α \selectlanguage{english}and \selectlanguage{greek}βγ \selectlanguage{english}(Kolb et al., 2022). There are 16
distinct \selectlanguage{greek}α \selectlanguage{english}subunits that are categorised into four families based on
downstream signalling pathways: G\textsubscript{s} (increases adenylyl
cyclase and cAMP), G\textsubscript{i/o} (reduces adenylyl cyclase and
cAMP), G\textsubscript{q} (increase DAG and IP3) and
G\textsubscript{12/13} (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
\textasciitilde{}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 (J\selectlanguage{ngerman}ørgensen 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 \selectlanguage{greek}µ-\selectlanguage{english}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 \emph{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.

\textbf{3. Orphaned neuropeptides}

\textbf{3.1 Cocaine and amphetamine regulated transcript}

CART is a neuropeptide encoded by the \emph{CARTPT} gene, which,
consists of three exons and two introns (Dominguez, 2006; Douglass \&
Daoud, 1996). Alternative splicing of this transcript results in two
biologically active forms, CART\textsubscript{42-89} and
CART\textsubscript{49-89} in humans, corresponding to
CART\textsubscript{55-102} and CART\textsubscript{62-102} in rodents
(Kuhar et al., 2002). Despite decades of research on CART since its
initial isolation and sequencing in 1981 (Spiess et al., 1981), the
cognate receptor(s) for CART remains disputed, and CART remains an
orphaned ligand (Lau \& Herzog, 2014; Ong \& McNally, 2020). While CART
remains orphaned, it is suggested to signal via a
G\textsubscript{i/o}coupled GPCR, linked to phosphorylation of the ERK
pathway (Lakatos et al., 2005; Somalwar et al., 2018).

CART is densely expressed in reward-related circuits critically involved
in AUD, including the hypothalamus, nucleus accumbens, central amygdala
and Edinger-Westphal nucleus (Jaworski et al., 2008; Koylu et al., 1998;
Millan \& McNally, 2012; Walker et al., 2021), and has been heavily
implicated in a range of drug-related behaviours, including AUD (for
reviews see; Kuhar, 2016; Ong \& McNally, 2020; Vicentic \& Jones,
2007). Early studies identified an association between an intron 1
polymorphism of the CART gene and alcoholism in a Korean population
(Jung et al., 2004). While tools to probe the function of CART are
limited, several transgenic mouse lines have provided some insights.
Using two different transgenic CART KO mouse lines, CART KO mice show
reduced alcohol intake and preference in a two-bottle choice procedure
(Maddern et al., 2023; Salinas et al., 2014). Interestingly, sex
differences arise in restricted binge alcohol access, with male CART KO
mice showing increased but female CART KO mice decreased alcohol intake,
driven by bitter taste sensitivity in CART KO female mice, involving
CART signalling in the central nucleus of the amygdala (CeA; Maddern et
al., 2023). CART is also implicated in alcohol seeking behaviours.
Central infusions of CART peptide (CART\textsubscript{55-102}) reduced
context-induced reinstatement of alcohol seeking (King et al., 2010),
whilst neutralisation of CART signalling
(anti-CART\textsubscript{55-102}) in the CeA reduced stress-induced
reinstatement of alcohol seeking (Walker et al., 2021). This is likely
linked to the role of CeA CART in alcohol withdrawal-induced anxiety, as
CeA CART\textsubscript{55-102} neutralisation reduced social anxiety
induced by alcohol withdrawal (Dandekar et al., 2008). Further,
CART-containing neurons in the arcuate nucleus are activated following
re-exposure to stimuli previously associated with alcohol availability
(Dayas et al., 2008). Together, these data highlight a role of CART in
critical aspects of AUD from taste, consumption, alcohol-induced
withdrawal and relapse. Despite the vast literature implicating CART in
a range of alcohol-related behaviours the exact neurobiological
mechanism(s) mediating CART function remain unclear and are severely
hindered by the lack of known cognate receptor(s) (Ong \& McNally,
2020).

Recently, two orphaned GPCRs, GPR68 (Foster et al., 2019) and GPR160
(Yosten et al., 2020), have been proposed as putative CART receptors.
GPR68 is a ubiquitously expressed proton-sensitive receptor in brain
neurons (Wang et al., 2020), and is expressed in key regions where CART
terminals are located, including the striatum, amygdala and hippocampus.
Additionally, GPR68 holds many characteristics of a peptide-activated
GPCR (Foster et al., 2019). Indeed, CART(42-89)\textsubscript{9-28}, a
shorter variant of the CART protein, led to GPR68-dependent mass
redistribution responses, suggested to reflect numerous intracellular
events, including protein trafficking and receptor internalisation, with
both sub- and low-micromolar potencies (Foster et al., 2019).
CART(42-89)\textsubscript{9-28}, along with two other peptides
(Osteocrin\textsubscript{33-55} and Corticotropin), acted as positive
allosteric modulators of GPR68 (Hauser et al., 2020). However, this
research remains limited, and it is unclear whether CART peptides are
able to stimulate GPR68 in the brain (Funayama et al., 2023). Of note,
the primary signalling pathways for GPR68 appear to be
G\textsubscript{s} and G\textsubscript{q} (Mogi et al., 2005), whilst
CART is thought to be via G\textsubscript{i/o} coupled signal
transduction (Lakatos et al., 2005; Somalwar et al., 2018), suggesting
this is unlikely to be a cognate receptor for CART.

Another oGPCR, GPR160 has recently been posited as a cognate receptor
for CART, driven by observations that either a CART antibody or GPR160
antibody were able to attenuate CART\textsubscript{55-102} induced
nociceptive responses in mice (Yosten et al., 2020). Additionally,
CART\textsubscript{55-102} stimulated cFos mRNA (a marker of neuronal
activation) expression in KATOIII cells with endogenous expression of
GPR160, and exogenous CART\textsubscript{55-102} co-immunoprecipitated
with GPR160 antibody in KATOIII cell lysates (Yosten et al., 2020).
Furthermore, CART\textsubscript{55-102} stimulated ERK phosphorylation
in PC12 cells, the only known cell line with specific binding of CART
(Lin et al., 2011), which was attenuated via a GPR160 mRNA-targeted
small interfering RNA (siGPR160; Yosten et al., 2020). Subsequent work
found that injection of GPR160 antibody, prior to CART peptide
CART\textsubscript{55-102}, into the 4\textsuperscript{th} ventricle
prevented exogenous CART peptide-induced reductions in food and water
consumption in rats (Haddock et al., 2021). Although these studies
provided promising evidence of GPR160 being a putative receptor of CART,
they did not assess, or report, the specific binding and/or affinity of
CART peptide to GPR160 (Haddock et al., 2021; Yosten et al., 2020).
Importantly, a recent study found that the GPR160 antibody did not
displace binding of either CART\textsubscript{55-102} or
CART\textsubscript{62-102}, nor did it compete with the specific binding
site of the CART peptide in PC12 cells (Freitas-Lima et al., 2023).
Additionally, no GPR160 mRNA or protein was found in PC12 cells,
suggesting that CART binding in PC12 cells occurs via a different
receptor present in this cell line (Freitas-Lima et al., 2023).
Furthermore, saturation and competition binding assays in a THP1 cell
line with high endogenous GPR160 expression revealed no specific
binding, or competition, with CART peptide radioligands in THP1 cells,
strongly suggesting no presence of a CART receptor (Freitas-Lima et al.,
2023). Thus, the identity of a cognate CART receptor remains elusive and
further work is needed. Without these developments the full potential of
targeting the CART system as a treatment for many neuropsychiatric
disorders, including AUD, remains stalled.

\textbf{4. Orphaned GPCRs}

\textbf{4.1 GPR6}

GPR6 is a constitutively active Class C GPCR that couples to a
stimulatory G-protein (G\textsubscript{S}) leading to increased cAMP
levels at a similar amplitude of fully activated GPCRs (Tanaka et al.,
2007; Uhlenbrock et al., 2002) and enhanced neurite outgrowth \emph{in
vitro} (Tanaka et al., 2007). GPR6 mRNA is predominantly expressed in
neurons in the brain, particularly in the striatum (caudate, putamen,
nucleus accumbens, and olfactory tubercle) and to a lesser extent the
frontal cortex, retrosplenial cortex, hippocampus, amygdala, and
hypothalamus (Heiber et al., 1995; Marchese et al., 1994; Song et al.,
1994). Within the striatum GPR6 is localised on dopamine D2
receptor-expressing striatopallidal medium spiny neurons (MSNs; Heiman
et al., 2008; Lobo et al., 2007). Controversy about the endogenous
ligand for GPR6 still persist. Initial studies showed agonism of GPR6 by
sphingosine-1-phosphate (S1P) but these results were not replicated
(Ignatov et al., 2003; Yin et al., 2009), leaving GPR6 as an orphan
receptor (Alexander et al., 2017).

GPR6 expression is most dense within the striatum, a brain region
important for reward behaviours, decision making and motor control (Lobo
et al., 2007). Two intermingled but distinct populations of MSNs,
differing in dopamine receptor subtype expression control behavioural
output from the striatum. Dopamine D\textsubscript{1}receptor-expressing
MSNs in the dorsal striatum project into and inhibit the substantia
nigra pars reticulata (SNr; direct, or striatonigral pathway), releasing
inhibition of thalamic activity and therefore prompting behaviour. In
contrast, D\textsubscript{2} receptor-expressing MSNs project to and
inhibit the external globus pallidus (indirect or striatopallidal
pathway), disinhibiting the subthalamic nucleus (STN) and exciting the
downstream SNr, which ultimately inhibits the thalamus and supresses
behaviour (Kreitzer \& Malenka, 2008). These pathways are postulated to
antagonise each other to allow a balanced striatal output (Albin et al.,
1989).

Dopamine is released in the dorsal striatum by neurons located in the
substantia nigra pars compacta (SNpc) and acts upon
D\textsubscript{1}dopamine receptors (which depolarise the cell in
response to dopamine) and D\textsubscript{2} dopamine receptors (which
hyperpolarise the cell in response to dopamine). Drugs of abuse acutely
increase dopamine release in the striatum, and thus have the dual effect
of exciting the direct pathway while simultaneously inhibiting the
indirect pathway (Kreitzer \& Malenka, 2008). GPR6 is specifically
expressed in striatopallidal, D\textsubscript{2} receptor-positive
neurons (Heiman et al., 2008; Lobo et al., 2007), and their deletion
leads to adaptive changes in both striatopallidal-specific genes
(\emph{Drd2} and\emph{Adora2a} ) and a striatonigral-specific gene
(\emph{Tac1;} Lobo et al., 2007). Further, GPR6 deficient mice have
increased in dopamine and metabolite levels in the striatum (Oeckl et
al., 2014) and enhanced instrumental responding for a sucrose reward,
without altered motor co-ordination (Lobo et al., 2007).

Genome-wide RNA sequencing has recently shown \emph{GPR6} is
downregulated in the dorsal striatum of individuals with alcohol use
disorder (Walker et al., 2020). In the prefrontal cortex (PFC) however,
sequencing revealed \emph{Gpr6} was upregulated in both food and
cocaine- ``addicted'' compared to ``non-addicted'' mice (Navandar et
al., 2021). However, the exact role of GPR6 in driving alcohol and
substance use is not known; whether dysregulation of GPR6 signalling is
causal or a consequence of substance use is not established and whether
targeting GPR6 may have potential to reduce alcohol and substance use
requires elucidation.

Recently several small molecule inverse agonists have been identified
and developed to interact with GPR6. Phylogenetically GPR6 is closely
related to the cannabinoid receptors, and cannabidiol (CBD), several
synthetic cannabinoids and endocannabinoid-like N-acylamides act as
inverse agonists at GPR6 (Laun et al., 2019; Laun \& Song, 2017; Shrader
\& Song, 2020). Preclinical studies have shown CBD may be effective to
reduce opioid, psychostimulant, nicotine and alcohol use (Nona et al.,
2019; Prud'homme et al., 2015). However, the mechanisms that CBD acts
through are widespread, and whether any actions are mediated via GPR6
would require further examination. A novel compound CVN424 has recently
been developed and shown to be a potent, orally active, and
brain-penetrant selective inverse agonist for GPR6, which is effective
in reducing Parkinson's-like symptoms in a rodent model (Brice et al.,
2021). This compound has successfully undergone Phase I safety trials
and is currently in Phase II trials (Margolin et al., 2022),
highlighting a potential future opportunity of repurposing for other
indications. However, given the opposing regulation of GPR6 in the
striatum and PFC in response to drugs of abuse, whether inverse agonism
would further exacerbate symptoms is a possibility that may limit
development in this regard.

\textbf{4.2 GPR26}

GPR26, first cloned in 2000, is a Class A (Rhodopsin) GPCR that couples
to G\textsubscript{s} and promotes constitutive activation of the
adenylyl cyclase (AC) pathway (Jones et al., 2007; Lee et al., 2001).
GPR26 is brain-specific, with enriched expression observed within the
cortex, amygdala, hippocampus, hypothalamus, thalamus and midbrain
ventral tegmental area (VTA)-SN (Ehrlich et al., 2018; Jones et al.,
2007; Lee et al., 2001; Zhang et al., 2011). Early studies hypothesized
GPR26 to be activated by nucleoside di- and tri-phosphates based on its
sequence homology with purinergic P2Y receptors; however, this was not
confirmed (Lee et al., 2001) and GPR26 remains orphaned.

GPR26 mRNA and protein are found in several brain regions critical in
regulating reward processing including the amygdala and midbrain VTA-SN
(Jones et al., 2007). While little research has directly explored the
role of GPR26 in alcohol or substance use disorders, using a novel GPR26
KO mouse line, Zhang and colleagues (Zhang et al., 2011) showed male
GPR26 KO mice consumed more alcohol than WT controls in a two-bottle
free-choice paradigm. However, this was only observed at a low
concentration of alcohol (7\% v/v), and at higher concentrations (9\%
and 12\% v/v), alcohol-drinking behaviours were similar to WT (Zhang et
al., 2011). This same study linked GPR26 to anxiety and depression, two
disorders that are often co-morbid with alcohol and other substance use
disorders (Boden \& Fergusson, 2011; Sinha, 2012; Walker, 2021). GPR26
deficient mice showed heightened levels of anxiety-like behaviour in the
elevated plus maze and open field test, and increased depression-like
behaviours in the Porsolt swim and tail suspension test (Zhang et al.,
2011). However, the links between aberrant anxiety- and depressive-like
behaviour and alcohol consumption were not explored. GPR26 KO mice also
displayed reduced CREB phosphorylation in the CeA compared to WT
counterparts (Zhang et al., 2011), a process that has been linked to
heightened anxiety and alcohol consumption (Pandey et al., 2005).
However, little future exploration has arisen from these studies, and no
novel targeting methods have arisen to further explore the links between
GPR26, anxiety, depression and alcohol intake.

\textbf{4.4 GPR88}

GPR88 is a brain specific G\textsubscript{i/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 \emph{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 D\textsubscript{1}- and
D\textsubscript{2}-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
D\textsubscript{2}R-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
D\textsubscript{1}R-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 \emph{Gpr88} KO mice,
Meirsman and collaborators showed a role for GPR88 expressed in
Adenosine receptor (A\textsubscript{2}AR/\textsubscript{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.

\emph{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 \emph{Gpr88} KO mice (Ben Hamida et al., 2018). In
addition, previous research has shown that \emph{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 ((1\emph{R} , 2\emph{R}
)-2-pyridin-2-yl-cyclopropane carboxylic acid ((2\emph{S} , 3\emph{S}
)-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 na\selectlanguage{ngerman}ïve animal vs
using a transgenic \emph{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.

\textbf{4.5 GPR139}

GPR139 is a class A peptide receptor first discovered in 2002 and
discretely expressed within the human and rodent brain (Takeda et al.,
2002). The highest expression of GPR139 mRNA is observed in the dorsal
medial habenula, with lesser expression in the VTA, dorsal striatum,
nucleus accumbens, lateral septum, hypothalamus and medial mammillary
nucleus (Liu et al., 2015; Matsuo et al., 2005; Susens et al., 2006;
Wang et al., 2015). Previous research, using a GPR139 plasmid
transfected into CHO-K1 cells, suggested that GPR139 signalling is
dependent on a receptor coupling to an inhibitory G-protein and
phospholipase C enzyme action, as well as imerization for proper
function (Susens et al., 2006). Further, similar to GPR88 signalling,
GPR139 interacts with both \selectlanguage{greek}µ-\selectlanguage{english}opioid and dopamine D2 receptors in the
brain (Rabiner et al., 2022), also suggesting a role for GPR139 in
complex CNS processes. Further research into the interaction between
GPR139 and the opioid system found that this receptor activation led to
anti-opioid activity in \emph{C. elegans} . This was conserved in
rodents, where deletion of GPR139 in mice potentiated opioid-induced
inhibition of neuronal firing (Wang, Lee, Shih, et al., 2019). These
data were further corroborated by electrophysiological data from GPR139
KO mice medial habenula neurons, where GPR139 receptor signalling was
suggested to prevent \selectlanguage{greek}µ-\selectlanguage{english}opioid receptor-mediated neuronal inhibition via
G\textsubscript{q/11} coupling (Stoveken et al., 2020). Further, GPR139
and D2 mRNA are co-expressed in several other brain regions implicated
in AUD, including the caudate putamen, lateral septum, lateral habenula,
VTA and arcuate nucleus of rats, mice, and humans (Wang, Lee, Kuei, et
al., 2019), but their interactions have not been explored in regard to
alcohol or substance use in these regions.

GPR139 binding is suggested to not be restricted to one endogenous
ligand, and recent research has implicated adrenocorticotropic hormone
and melanocyte-stimulating hormone \selectlanguage{greek}α \selectlanguage{english}and \selectlanguage{greek}β \selectlanguage{english}subunits as agonists at this
receptor (Nohr et al., 2017). In addition, physiological concentrations
of L-tryptophan and L-phenylalanine can activate this receptor (Liu et
al., 2015; Shoblock et al., 2019). Nonetheless, GPR139 remains an orphan
receptor to date.

Within the medial habenula, GPR139-positive neurons, which also
co-express \selectlanguage{greek}µ-\selectlanguage{english}opioid receptor, send indirect downstream projections to
the interpeduncular nucleus, where GPR139 receptors are also present
(Boulos et al., 2017; Liu et al., 2015). These two brain regions form an
important relay centre between limbic systems and midbrain and
hindbrain, having roles in addiction, anxiety and emotional processing
(Batalla et al., 2017; Bianco \& Wilson, 2009; Ehrlich et al., 2018;
Fowler \& Kenny, 2012). Indeed, signalling between the medial habenula
and the interpeduncular nucleus has been associated with alcohol,
nicotine, opiate, and stimulant dependence (McLaughlin et al., 2017).
Nonetheless, research in alcohol-dependent rats suggested that
compulsive-like drinking and decreased withdrawal-induced hyperalgesia
was not mediated by the medial habenula-interpeduncular nucleus circuit,
but by the activity of GPR139 itself within the medial habenula
(Kononoff et al., 2018).

Organic ligands that target GPR139 and present drug-like properties have
been developed in recent years. JNJ-63533054 is a small molecule agonist
that is orally bioavailable and can cross the blood-brain barrier
(Shoblock et al., 2019). A preclinical study reported that JNJ-63533054
reduced escalation of alcohol self-administration in alcohol-dependent
male rats, in a dose-dependent manner, when administered systemically
(Kononoff et al., 2018). Similarly, Wang et al., (2019) showed that
JNJ-63533054 suppressed morphine intake in morphine-dependent mice.
These data demonstrate the role of GPR139 in negatively regulating
opioid and alcohol intake and highlight the potential of
pharmacologically targeting this receptor. Analogous to JNJ-63533054,
TAK-041 (also known as NBI-1065846) is a novel potent GPR139 with a
favourable pharmacokinetic profile (Reichard et al., 2021). This
compound has been reported to increase sociability in mice with social
interaction deficits (Reichard et al., 2021) and to increase effort to
obtain food in mice that were moderately food deprived (Munster et al.,
2022) via GPR139 signalling. Indeed, a potential role for GPR139 in
motivational processes has been previously described. Dao and
collaborators reported that GPR139 KO mice display profound impairment
in gustatory reward acquisition in an operant task that was rescued by
TAK-041 delivered orally (Munster et al., 2022). TAK-041 was shown to be
safe and well tolerated in healthy volunteers and patients with
schizophrenia following Phase I clinical trials (Yin et al., 2022) and
has undergone Phase II clinical trials investigating its effects on
motivational anhedonia in patients with stable schizophrenia (trial ID
NCT03319953) and to determine this ligand effect on amphetamine-induced
dopamine release in the brain (ID NCT02959892). Currently, a Phase II
trial is assessing the efficacy of TAK-041 in improving symptoms of
anhedonia in patients with major depressive disorder, highlighting the
pharmacological potential of this molecule.

\textbf{4.6 GPR158}

GPR158 is a class C oGPCR, discovered in 2005 through genome assembly
and GPCR gene predictions (Bjarnadottir et al., 2005). It is one of the
most abundant oGPCRs in the brain, expressed throughout the CNS,
including the prefrontal cortex, hippocampus, striatum and cortex (Chang
et al., 2023). Interestingly, GPR158 does not signal through traditional
class C GPCR mechanisms, instead it localises regulator of G protein
signalling 7 (RGS7), G\selectlanguage{greek}\textsubscript{β}\selectlanguage{english}5 and allosterically promotes
GTPase activity of G\selectlanguage{greek}α\selectlanguage{english}i/o (Hajj et al., 2019). This ultimately reduces
the activity of adenylate cyclase and influences downstream signalling
pathways and subsequent behaviour (Hajj et al., 2019; Orlandi et al.,
2015; Song et al., 2019). Previously, osteocalcin (OCN) and heparan
sulphate proteoglycans (HSPGs) were proposed ligands for GPR158
(Khrimian et al., 2017). Further, a recent study suggests that glycine
acts as an endogenous ligand at GPR158, inhibiting formation of the
RGS7--G\selectlanguage{greek}β\selectlanguage{english}5 complex and adenosine 3',5'-monophosphate to regulate neuronal
excitability, suggesting this GPCR may have been adopted as a
metabotropic glycine receptor (Laboute et al., 2023), however, further
validation is required. The crystal structure of GPR158 both alone and
bound to RSG7 and G\selectlanguage{greek}\textsubscript{β}\selectlanguage{english}5 have recently been solved by two
groups (Jeong et al., 2021; Patil et al., 2022), which may accelerate
drug discovery and development GPR158 ligands.

GPR158 has been implicated in depressive disorders. In
humans,\emph{GPR158} mRNA is upregulated in the PFC of individuals with
major depressive disorder, which is conserved in rodent models of
stress-induced depressive behaviour and can be rescued through genetic
manipulation of GPR158 (Sutton et al., 2018). Interestingly, our recent
genome-wide RNAseq analysis showed reduced \emph{GPR158} expression
within the striatum of individuals with AUD (Walker et al., 2020),
suggesting region-specific actions and regulation of GPR158 may occur.
Given the link between stress, depression and alcohol use (Boden \&
Fergusson, 2011; Gilpin et al., 2015; Sinha, 2012; Walker, 2021), GPR158
may also be effective for the treatment of alcohol and substance use
disorders. GPR158 has recently been shown to mediate sensitivity to the
sedative effects of ethanol (Wei et al., 2023). Thus, GPR158 null mice
had a deficit in recovery from a sedative dose of alcohol (3.5 mg/kg)
without altering alcohol metabolism or basal differences in locomotor
activity, or basal anxiety-like behaviour (Wei et al., 2023). Further
using a GPR158 floxed mouse, they showed that this effect was in part
driven by GPR158 expression on both glutamatergic and GABAergic
populations in the brain (Wei et al., 2023). However, studies to date
have not reported the effect of either knockout mice, or selective drug
targets, in reducing alcohol or drug consumption, self-administration or
relapse.

\textbf{5. Concluding remarks}

Alcohol use disorders remains a major socioeconomic burden, and
treatment novel options remain elusive. Several orphaned neuropeptides
and oGPCRs are expressed throughout key reward circuitry (Figure 2) and
may provide novel targets and treatments for AUD; however, limitations
remain. Despite considerable efforts in the field of GPCR
de-orphanisation, more than 100 receptors remain orphaned, and these
receptors are also disproportionally understudied (Alexander et al.,
2023; Roth \& Kroeze, 2015). The challenges with orphaned peptides and
receptors persist, including technical - limited availability of
sensitive screening assays or ability to test appropriate ligands and
biological - a possible lack of endogenous ligand or receptor. In some
instances, these may have become evolutionarily redundant, or receptors
may only signal through ligand independent mechanisms (e.g. constitutive
activity or dimerisation) (Fricker \& Devi, 2018; Tao \& Conn, 2014).
With the development of integrated computational, structural, functional
and experimental approaches, elucidating orphan peptide and orphan
receptor interactions through screening putative receptors/ ligands in
silico are promising areas of future research (Foster et al., 2019).
Further, advancements in cryo-EM have enhanced exploration into membrane
bound GPCRs in both active and inactive state confirmations and
artificial intelligence approaches, such as machine learning are
increasing efficiency in drug design and development (Casad\selectlanguage{ngerman}ó \&
Casadó-Anguera, 2023), including several GPCR targeting compounds that
have progressed to phase I/II clinical trials (e.g. EXS21546, a
selective A\textsubscript{2A}~receptor antagonist for renal cell
carcinoma - clinicaltrials.gov ID: NCT04727138 \& NCT05920408). We have
outlined several targets that should be further explored as potential
treatment options for AUD; however, limitations in small molecule
compounds and mechanistic understanding are currently halting
development. Leveraging emerging technologies will both enhance our
fundamental understanding of orphaned peptides and receptors and provide
a more rapid and precise method to identify pharmacotherapies to provide
more treatment options for AUD.

\textbf{Acknowledgements}

LCW is supported by a National Medical Research Council (NHMRC) grant
(2002830) and Emerging Leader Fellowship (2008344). AJL is supported by
an NHMRC synergy grant (2009851). XJM is supported by an Australian
Research Training Program Scholarship. Figures were made using
Biorender.com

\textbf{Conflict of Interest}

All authors report no conflicts of interest.



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\textbf{Figure Legends:}

\textbf{Figure 1: FDA approved compounds and compounds in clinical trial
targeting GPCRs. (A)} 106 (31.64\%) de-orphaned GPCRs currently have an
FDA approved compound to target them, compared to only 1 (1.14\%) oGPCR
(left). Further, there are currently 57 (17.01\%) de-orphaned GPCRs that
have a drug in ongoing clinical trials, compared to only 2 (2.27\%)
drugs targeting oGPCR (right). \textbf{(B)} Of the total number of FDA
approved drugs targeting de-orphaned GPCRs, 130 (27.08\%) are for CNS
indications, whilst there are no approved drugs targeting oGPCRs for CNS
indications. Further, 27 (35.53\%) of the de-orphaned GPCRs currently
being targeted in ongoing clinical trials are for CNS indications,
whilst no oGPCRs are currently being targeted in ongoing clinical trials
for CNS indications.

\textbf{Figure 2: Orphan neuropeptide and receptor expression in key
brain regions implicated in alcohol use disorder,} colour-coded
according to the three key phases of the addiction cycle
(binge/intoxication, withdrawal/negative affect,
preoccupation/anticipation). Amyg., amygdala; CART, cocaine- and
amphetamine-regulated transcript; Hab., habenula; Hipp., hippocampus;
Hypo., hypothalamus; PFC, prefrontal cortex; VTA, ventral tegmental
area.

\textbf{Tables:}

\textbf{Table 1. Compounds currently in clinical trial for alcohol use
disorder}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\textbf{NCT Number} & \textbf{Compund} & \textbf{GPCR action} &
\textbf{GPCR Class} & \textbf{~Receptor class} & \textbf{Study
Title}\tabularnewline
\midrule
\endhead
NCT03764098 & Guanfacine & Yes & Class A & Adrenoceptors & Mechanistic
Evaluation of Guanfacine on Drinking Behavior in Women and Men With
Alcohol Use Disorders\tabularnewline
NCT04827056 & Dexmedetomidine & Yes & Class A & Adrenoceptors & Effect
of Sublingual Formulation of Dexmedetomidine HCl (BXCL501) - Alcohol
Interaction Study\tabularnewline
NCT04135846 & Doxazosin & Yes & Class A & Adrenoceptors & Alpha-1
Blockade for Alcohol Use Disorder (AUD)\tabularnewline
NCT03137082 & Guanfacine & Yes & Class A & Adrenoceptors & Guanfacine to
Reduce Relapse Risk in Women With Alcohol Use Disorder
(AUD)\tabularnewline
NCT04793685 & Prazosin & Yes & Class A & Adrenoceptors & Prazosin for
Alcohol Use Disorder With Withdrawal Symptoms\tabularnewline
NCT05317546 & Cannabidiol & Yes & Class A & Canabiniod & Cannabidiol in
Youth Alcohol Use Disorder\tabularnewline
NCT04873453 & Cannabidiol & Yes & Class A & Canabiniod & CBD for the
Treatment of Alcohol Use Disorder\tabularnewline
NCT05613608 & Cannabidiol & Yes & Class A & Canabiniod & Alcohol Use
Disorder and Cannabidiol\tabularnewline
NCT05159830 & Cannabidiol & Yes & Class A & Canabiniod & Cannabidiol for
Reducing Drinking in Alcohol Use Disorder\tabularnewline
NCT05387148 & Cannabidiol & Yes & Class A & Canabiniod & The Efficacy
and Neurobehavioural Mechanism of Cannabidiol (CBD) for Alcohol
Dependence\tabularnewline
NCT05860699 & Cannabidiol & Yes & Class A & Canabiniod & Cannabidiol as
an add-on Treatment During Inpatient Alcohol Cessation in Patients With
Severe Alcohol Use Disorder: a Phase ii Trial\tabularnewline
NCT04603781 & Cannabidiol & Yes & Class A & Canabiniod & CBD Oil for
Reducing Emotional Impact of COVID-19\tabularnewline
NCT05781009 & Pregnenolone & Yes & Class A & Canabiniod & Pregnenolone
for the Treatment of Alcohol Use Disorder\tabularnewline
NCT02461927 & Naltrexone (+ Ketamine) & Yes & Class A & Opioid &
Ketamine for the Rapid Treatment of Major Depressive Disorder and
Alcohol Use Disorder\tabularnewline
NCT05919017 & Naltrexone & Yes & Class A & Opioid & Exploring the PK of
Different Doses of Naltrexone in Patients With AUD\tabularnewline
NCT05028062 & Naltrexone & Yes & Class A & Opioid & Naltrexone in AUD
Reward Drinkers\tabularnewline
NCT05656534 & Suvorexant & Yes & Class A & Orexin & Orexin Receptor
Antagonists as Modulators of Threat Sensitivity in Individuals With
Alcohol Use Disorder\tabularnewline
NCT05312008 & Oxytocin & Yes & Class A & Oxytocin & Does Oxytocin Alter
Tolerance to or Motivation for Alcohol\tabularnewline
NCT03878316 & Oxytocin & Yes & Class A & Oxytocin & Intranasal Oxytocin
for the Treatment of Alcohol Use Disorder\tabularnewline
NCT04071119 & Oxytocin & Yes & Class A & Oxytocin & Alcohol and
Cigarette Craving During Oxytocin Treatment\tabularnewline
NCT04523922 & Oxytocin & Yes & Class A & Oxytocin & Oxytocin to Enhance
Integrated Treatment for AUD and PTSD\tabularnewline
NCT03846505 & Oxytocin & Yes & Class A & Oxytocin & Oxytocin to Enhance
Alcohol Behavioral Couple Therapy (ABCT)\tabularnewline
NCT05093296 & Oxytocin & Yes & Class A & Oxytocin & Oxytocin and
Naltrexone: Investigation of Combined Effects on Stress- and Alcohol
Cue-induced Craving in Alcohol Use Disorder\tabularnewline
NCT05674929 & BPL-003 & Yes & Class A & Serotonin & An Open-Label,
Single Dose Study in Patients With Alcohol Use Disorder\tabularnewline
NCT05913752 & CMND-100 & Yes & Class A & Serotonin & A First in Human
Study of CMND-100 in Healthy and Alcohol Use Disorder (AUD)
Subjects\tabularnewline
NCT05474989 & LSD & Yes & Class A & Serotonin & LSD Treatment for
Persons With Alcohol Use Disorder\tabularnewline
NCT05943665 & MDMA & Yes & Class A & Serotonin & MDMA for AUD/PTSD
Comorbidity\tabularnewline
NCT05709353 & MDMA & Yes & Class A & Serotonin & MDMA-assisted Prolonged
Exposure Therapy for Comorbid Alcohol Use Disorder and Post-traumatic
Stress Disorder\tabularnewline
NCT05416229 & Psilocybin & Yes & Class A & Serotonin &
Psilocybin-assisted Therapy for Treatment of Alcohol Use
Disorder\tabularnewline
NCT04410913 & Psilocybin & Yes & Class A & Serotonin & Pilot Trial of
Visual Healing\selectlanguage{ngerman}Â® in Psilocybin-assisted Therapy for Alcohol Use
Disorder\tabularnewline
NCT05646303 & Psilocybin & Yes & Class A & Serotonin &
Psilocybin-Assisted Psychotherapy in Adults With Alcohol Use Disorder
(AUD)\tabularnewline
NCT04141501 & Psilocybin & Yes & Class A & Serotonin & Clinical and
Mechanistic Effects of Psilocybin in Alcohol Addicted
Patients\tabularnewline
NCT04718792 & Psilocybin & Yes & Class A & Serotonin & Psilocybin for
Treatment of Alcohol Use Disorder: a Feasibility Study\tabularnewline
NCT04620759 & Psilocybin & Yes & Class A & Serotonin & Psilocybin
Treatment of Major Depressive Disorder With Co-occurring Alcohol Use
Disorder\tabularnewline
NCT05421065 & Psilocybin & Yes & Class A & Serotonin &
Psilocybin-Assisted vs Ketamine-Assisted Psychotherapy for Alcohol Use
Disorder\tabularnewline
NCT04066192 & Brexpiprazole & Yes & Class A & Serotonin \& Dopamine &
Brexpiprazole in Alcohol Use Disorder\tabularnewline
NCT03526354 & Brexpiprazole & Yes & Class A & Serotonin \& Dopamine &
Brexpiprazole Study\tabularnewline
NCT05520775 & Semaglutide & Yes & Class B1 & Glucagon & Semaglutide for
Alcohol Use Disorder\tabularnewline
NCT05892432 & Semaglutide & Yes & Class B1 & Glucagon & Clinical Trial
of Rybelsus (Semaglutide) Among Adults With Alcohol Use Disorder
(AUD)\tabularnewline
NCT05891587 & Semaglutide & Yes & Class B1 & Glucagon & Semaglutide
Therapy for Alcohol Reduction - Tulsa\tabularnewline
NCT05895643 & Semaglutide & Yes & Class B1 & Glucagon & Does Semaglutide
Reduce Alcohol Intake in Patients With Alcohol Use Disorder and Comorbid
Obesity?\tabularnewline
NCT04679142 & Baclofen & Yes & Class C & GABA & Baclocur
Post-Authorisation Safety Study in Real-life Settings in
France\tabularnewline
NCT04831684 & GET73 & Yes & Class C & Glutamate & Novel mGluR5 Modulator
Effects on Alcohol Drinking and MRI Outcomes\tabularnewline
NCT04218357 & Probenecid & Yes & Class T & Taste & Probenecid as
Medication for Alcohol Use Disorder\tabularnewline
NCT05870111 & Citicoline & No & & & Citicoline in Youth Alcohol Use
Disorder\tabularnewline
NCT03896516 & GLWL-01 & No & & & Manipulating Ghrelin Signaling Via GOAT
Inhibition in Alcohol Use Disorder\tabularnewline
NCT05830708 & Lactobacillus sp. Probiotic & No & & & The Efficacy of
Probiotics for the Treatment of Alcohol Use Disorder Among Adult
Males\tabularnewline
NCT05178069 & Lactobacillus Rhamnosus GG & No & & & LGG Supplementation
in Patients With AUD and ALD\tabularnewline
NCT05807139 & Spironolactone & No & & & Spironolactone in Alcohol Use
Disorder (SAUD)\tabularnewline
NCT05134857 & Zonisamide & No & & & The Zonisamide and Reinforcement for
Reducing Alcohol Use (ZARRA) Study\tabularnewline
NCT04015869 & Allopregnanolone & No & & & Effect of Allopregnanolone on
Stress-induced Craving\tabularnewline
NCT05223829 & Brexanolone & No & & & Utility of Brexanolone to Target
Stress-induced Alcohol Use Among Men and Women With Posttraumatic Stress
Disorder\tabularnewline
NCT04084860 & CI-581a & No & & & The Role of Brief Potent Glutamatergic
Modulation in Addressing Problem Drinking\tabularnewline
NCT05042102 & Donepezil & No & & & Donepezil and Cognitive Training for
Alcohol Use Disorder (AUD)\tabularnewline
NCT04098302 & Dutasteride & No & & & Dutasteride Treatment for Reducing
Heavy Drinking in AUD: Predictors of Efficacy\tabularnewline
NCT04527185 & Endotoxin & No & & & Effect of Endotoxin on Alcohol
Consumption\tabularnewline
NCT05414240 & Ibudilast & No & & & Ibudilast for Treating Alcohol Use
Disorder\tabularnewline
NCT05661669 & Ketamine & No & & & Ketamine for the Treatment for Alcohol
Use Disorder in the ED\tabularnewline
NCT04616781 & Ketone Ester & No & & & Ketone Ester Intervention in
Alcohol Use Disorder\tabularnewline
NCT02989662 & Mifepristone & No & & & INIA Stress and Chronic Alcohol
Interactions: Glucocorticoid Antagonists in Heavy
Drinkers\tabularnewline
NCT03707951 & N-acetylcysteine & No & & & N-Acetylcysteine for
Adolescent Alcohol Use Disorder\tabularnewline
NCT05408247 & N-acetylcysteine & No & & & A Randomised Controlled Trial
of N-acetylcysteine for the Management of Alcohol Use
Disorder\tabularnewline
NCT05899660 & Omega-3 & No & & & Impact of Omega 3 in Alcohol Use
Disorder\tabularnewline
NCT03864146 & Pioglitazone & No & & & Pioglitazone for the Treatment of
Alcohol Use Disorder\tabularnewline
NCT05107765 & Pioglitazone & No & & & Effects of Pioglitazone on Stress
Reactivity and Alcohol Craving\tabularnewline
NCT04322305 & Pregabalin & No & & & Pregabalin Trial for the Treatment
of Alcohol Use Disorder\tabularnewline
NCT02884908 & Pregabalin & No & & & Pharmacogenetic Treatment With
Anti-Glutaminergic Agents for Comorbid PTSD \& AUD\tabularnewline
NCT04331288 & PT150 & No & & & Effects of Ethanol on the
Pharmacokinetics of PT-150 (Formerly ORG34517) (PT150 PK
Study)\tabularnewline
NCT04232800 & Riboflavin & No & & & Riboflavin for Glutamate Reduction
in Alcohol Withdrawal\tabularnewline
NCT05902754 & Sulforaphane & No & & & Broccoli Extract Supplementation
in Older Adults With Alcohol Use Disorder\tabularnewline
NCT03904498 & Tolcapone & No & & & COMT Inhibition Among Individuals
With Comorbid AUD/ADHD\tabularnewline
NCT03176953 & Topiramate & No & & & Topiramate and Prolonged
Exposure\tabularnewline
NCT04770493 & Lamotrigine & No & & & Enhancing the Effects of Alcohol
Treatment With Lamotrigine\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
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