Preface to the Review Series Neuropharmacology of addiction

Alcohol use disorder (AUD) is the third leading cause of preventable deaths in the United States (White et al., 2020), costing the US economy around $250 billion per annum (Sacks et al., 2015). Despite this, data from the 2022 National Survey on Drug Use and Health suggest that only 7.6% of people aged 12 and over with an AUD received treatment for this condition within the last year (SAMSHA, 2022). At present, there are only three drugs approved by the FDA specifically for the treatment of AUD, namely, disulfiram, naltrexone (both oral and long-acting injectable) and acamprosate; with nalmefene also being approved by the European Medicines Agency. While some clients find benefit from the available treatment options, none of them are universally effective and new, mechanism-based treatments are sorely needed.

In this context, Walker and colleagues review the growing evidence suggesting that muscarinic M₄ receptors may represent a novel therapeutic target for AUD (Walker et al., 2024). Indeed, evidence aligns from human post-mortem data showing a down-regulation of M₄ mRNA and protein in the putamen from people with AUD, with analogous findings in rodent dorsolateral striatum (Walker et al., 2020). Moreover, targeting M₄ receptors with a tool molecule positive allosteric modulator (PAM) reduced alcohol self-administration and seeking in rats (Walker et al., 2020; Walker et al., 2021), while M₄ knockout mice show elevated voluntary alcohol intake (de la Cour et al., 2015). Of note, several pharmaceutical companies are actively pursuing compounds that are either M₄ receptor agonists or PAMs for the indication of schizophrenia. One example is KarXT, a drug that has already reported positive Phase III results (Kaul et al., 2024) and is likely to be FDA approved as a novel treatment for schizophrenia. Such approval would open up the way for repurposing KarXT into the AUD space relatively rapidly—something that would certainly appear worth testing.

The striatum therefore appears to be one of the key loci where M₄ receptors are impacted by alcohol use. Another article in this issue canvasses a more general role of GPCRs in the modulation of striatal dopamine release and how this pertains to the mechanism(s) of action of psychoactive drugs (Littlepage-Saunders et al., 2024). Dopamine transmission within the basal ganglia is a common target for many drugs of abuse. The team from the Johnson lab review the evidence surrounding modulation of striatal dopamine release, including that mediated by drugs of abuse, by a range of GPCRs such as dopamine receptors, metabotropic glutamate receptors, cannabinoid, muscarinic and opioid receptors. They also explore the implications of co-release of dopamine with other transmitters, such as glutamate and GABA and how circuit-level manipulations will assist in our future understanding of the biological basis for normal and abnormal regulation of dopaminergic transmission, including its relevance for various pathological conditions.

Another GPCR touted as a potential therapeutic target for drug and alcohol abuse is the 5-HT_2C receptor; evidence in this regard is reviewed by Ubhayarathna et al. (2024). Indeed, lorcaserin (a 5-HT_2C agonist), which was withdrawn by the FDA, has shown promise in a proof-of concept study in humans with AUD (Campbell et al., 2021). The current review synthesises structural, molecular and behavioural data to argue that the 5-HT_2C receptor is worthy of further interrogation as a possible treatment target for drug and alcohol abuse. It is noteworthy that the 5-HT_2C receptor is one of the molecular targets for psychedelic drugs, including psilocybin which has been effective in clinical studies of addiction (van der Meer et al., 2023), while RNA editing and/or heteromerisation of the 5-HT_2C receptor may also represent other ways to engage this target (Ubhayarathna et al., 2024).

The final review in this issue concentrates on the hypothalamic orexin system and its implications in motivated behaviour, including reward-seeking (Mohammadkhani et al., 2024). Indeed, the orexin system has been established as a critical component in alcohol use and seeking for some time (Lawrence et al., 2006). The review by Mohammadkhani and colleagues provides a timely update on the role of the orexin system as a motivational activator and how dysregulation of this system may contribute to disorders characterised by either excessive motivation (such as drug and alcohol abuse) or diminished motivation (such as depression). From a translational perspective, a recent case report demonstrated a positive impact of treatment with the dual orexin receptor antagonist suvorexant in a person with AUD (Campbell et al., 2024).

Therefore, this special issue has highlighted a select group of GPCRs that are proactively being studied as potential therapeutic targets for drug and alcohol abuse. A number of these receptors are already targeted by drugs approved for other indications (e.g., suvorexant for insomnia). As such, preclinical research has the capacity to provide a critical rationale for repurposing and/or the off-label use of approved medications in the drug and alcohol space. Given the low level of treatment options currently available, such options are sorely wanting.

Key protein targets and ligands in this article are hyperlinked to corresponding entries in the IUPHAR/BPS Guide to PHARMACOLOGY http://www.guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2023/23 (Alexander et al., 2023).

A. J. Lawrence: Conceptualization (equal); writing—original draft (equal). C. J. Langmead: Conceptualization (equal).

AJL has no conflicts to declare. CJL is co-founder and scientific advisor, Pacalis Therapeutics Pty Ltd. with an interest in developing new therapeutics for substance use disorders.