Pharmacogenetic approaches to the treatment of alcohol addiction

Abstract

Addictive disorders are partly heritable, chronic, relapsing conditions that account for a tremendous disease burden. Currently available addiction pharmacotherapies are only moderately successful, continue to be viewed with considerable scepticism outside the scientific community and have not become widely adopted as treatments. More effective medical treatments are needed to transform addiction treatment and address currently unmet medical needs. Emerging evidence from alcoholism research suggests that no single advance can be expected to fundamentally change treatment outcomes. Rather, studies of opioid, corticotropin-releasing factor, GABA and serotonin systems suggest that incremental advances in treatment outcomes will result from an improved understanding of the genetic heterogeneity among patients with alcohol addiction, and the development of personalized treatments.

Figure 1. An alcohol–endogenous opioid–dopamine cascade is the target of naltrexone

Schematic of the alcohol–opioid–dopamine cascade that is thought to be the target of naltrexone, based on integration of circuitries originally proposed in REFS ,. Dopaminergic ventral tegmental area (VTA) neurons that project to the nucleus accumbens (NAc) are under tonic inhibition by GABAergic interneurons within the VTA. GABA release from these neurons is in turn under negative regulation by the mu-opioid receptor (MOR). When alcohol is ingested, endogenous opioids such as β-endorphins (β-EPs) are released, resulting in inhibition of GABA release in the VTA and removal of the inhibitory tone from the dopamine cells. This cascade ultimately results in increased dopamine release in the terminal areas in the NAc.

Figure 2. Efficacy of naltrexone is moderated by OPRM1 variation in rhesus macaques and humans

Results from studies indicating that carriers of the minor 77G (rhesus) or 118G (human) alleles of OPRM1 (which encodes the mu-opioid receptor (MOR)) are more sensitive to effects of naltrexone on alcohol preference and consumption than non-carriers. a | Set-up of an alcohol-preference test in monkeys. Each monkey is tagged by a microchip in its collar. Alcohol is made available for 1 hour daily, 5 days a week. During this time, monkeys can walk up, place their head into one of the several ‘bar’ booths, be identified through the chip being read, and choose between an aspartame-sweetened alcohol solution or a solution of aspartame alone. b | Suppression of alcohol preference by naltrexone as a function of OPRM1 genotype. In rhesus 77G carriers (CG), which have a greater baseline alcohol preference, naltrexone suppressed alcohol preference, whereas in rhesus subjects that are homozygous for the more common 77C allele (CC), naltrexone lacked effect. Data from REF. . c | Selective increase in ‘good clinical outcome’ after naltrexone treatment compared to placebo in individuals with alcohol addiction carrying the 118G allele (Asp40), and lack of efficacy in subjects who are homozygous for the more common 118A allele (Asn40). ‘Good clinical outcome’ is a dichotomous composite measure of clinical efficacy that includes abstinence or absence of heavy drinking and improvement with regard to negative consequences of drinking. Figure is modified, with permission, from REF. © (2009) American Medical Association.

Figure 3. Dopamine release in the ventral striatum in response to alcohol is restricted to OPRM1 118G carriers

The effect of alcohol on activation of the dopaminergic brain reward circuitry in carriers of the OPRM1 118G allele, as assessed using positron emission tomography (PET) and [¹¹C]-raclopride displacement. Alcohol given to male social drinkers under closely controlled conditions induced a robust dopamine release (detected as reduced binding potential of the radioligand) in minor 118G allele carriers (AG), whereas no measurable release was observed in subjects homozygous for the major 118A allele (AA). The units in the PET scan represent the change in binding potential (nCi ml^–1). AVS, anterior ventral striatum; PVS, posterior ventral striatum. Figure is modified, with permission, from REF. © (2011) Macmillan Publishers Ltd. All rights reserved.

Figure 4. Innate or acquired hyperactivity of extrahypothalamic CRF systems is associated with high alcohol preference

a | Schematic localization on a coronal section of the rat brain. The red box indicates the area that approximately corresponds to the subsequent in situ expression panels. b | Low expression of Crfr1 in a control rat (not genetically selected for high alcohol preference and without a history of alcohol exposure). c | Markedly upregulated Crfr1 expression (darkened areas) in the medial nucleus of the amygdala (MeA) and basolateral nucleus of the amygdala (BLA) of an unselected rat that was exposed for 7 weeks to intoxicating blood alcohol levels, 3 weeks after exposure to alcohol was terminated. d | Similarly upregulated Crfr1 expression in the BLA of a Marchigian-Sardinian alcohol-preferring (msP) rat, observed in the absence of any alcohol exposure. These findings show that increased expression of Crfr1 in the BLA can result from a ‘kindling’ process induced by exposure to cycles of alcohol intake and withdrawal, but it can also be an innate trait that is present in the absence of any alcohol exposure, such as in the msP rat line, which has been genetically selected for high alcohol preference. Part a reproduced, with permission, from REF. © (2005) Elsevier. Parts b and d reproduced, with permission, from REF. © (2006) National Academy of Sciences. Part c reproduced, with permission, from REF. © (2008) Elsevier.

Figure 5. CRF₁ antagonism suppresses stress-induced relapse-like behaviour in msP rats

In the stress-induced relapse model, animals are first trained to establish operant self-administration of alcohol. Once stable self-administration rates are achieved, this behaviour is extinguished by removing alcohol as reinforcer, after which lever-pressing rates decline to low levels over the course of about 2 weeks (Ext). Exposure to a stressor — a 10 minute footshock — reinstates response rates on the previously alcohol-reinforced lever, even though alcohol continues to be absent. Antalarmin, a corticotropin-releasing factor receptor 1 (CRF₁) antagonist, blocks stress-induced relapse-like behaviour in Marchigian-Sardinian alcohol-preferring (msP) rats at doses that are ineffective in rats that are not selected for high alcohol preference. This shows that the CRF₁ receptor is crucial for stress-induced relapse, and that the activity of the CRF system is higher in msP rats compared to non-preferring rats. Figure is reproduced, with permission, from REF. © (2006) National Academy of Sciences.