Baclofen decreases compulsive alcohol drinking in rats characterised by reduced levels of GAT-3 in the central amygdala

Abstract

<jats:title>Abstract</jats:title><jats:p>While most individuals with access to alcohol drink it recreationally, about 5 % lose control over their intake and progressively develop an alcohol use disorder (AUD), characterised by compulsive alcohol drinking accompanied by decreased interest in alternative sources of reinforcement. The neural and molecular mechanisms underlying the vulnerability to switch from controlled to compulsive alcohol intake have not been fully characterized, so limiting the development of new treatments for AUD. It has recently been shown that rats having reduced levels of expression of the gamma-aminobutyric acid (GABA) transporter, GAT-3, in the amygdala tend to persist in seeking and drinking alcohol even when adulterated with quinine, suggesting that pharmacological interventions aimed at restoring GABA homeostasis in these individuals may provide a targeted treatment to limit compulsive alcohol drinking. Here, we tested the hypothesis that the GABA<jats:sub>B</jats:sub> receptor agonist baclofen, which decreases GABA release, specifically decreases compulsive alcohol drinking in vulnerable individuals. In a large cohort of Sprague-Dawley rats allowed to drink alcohol under an intermittent two-bottle choice procedure, a cluster of individuals was identified that persisted in drinking alcohol despite adulteration or the availability of an alternative ingestive reinforcer, saccharin. In these rats, that were characterised by decreased GAT-3 mRNA levels in the central amygdala, acute baclofen administration (1.5 mg/kg, intraperitoneal) resulted in a decrease in compulsive drinking. These results indicate that low GAT-3 mRNA levels in the central amygdala represent an endophenotype of AUD and that the associated compulsive alcohol drinking characteristic is sensitive to baclofen.</jats:p>

Environment‐dependent behavioral traits and experiential factors shape addiction vulnerability

“…However, a picture is progressively emerging that identifies a potential candidate circuitry that involves the insula, the amygdala, and the striatum within which activation of the endogenous stress systems (Koob, 2015) may facilitate the transition to compulsive drug taking. Thus, the transition from controlled drug use to compulsivity, the vulnerability to which has been shown to be associated with alterations in the dopamine system in the ventral striatum (Everitt et al, 2008), GABAergic system in the central amygdala (Augier et al, 2018;Marti-Prats et al, 2020), and impaired top-down control by the prefrontal cortex (Chen et al, 2013), depends on amygdalo-striatal circuit interactions (Murray et al, 2015) resulting in the rigid instantiation of control over behavior by the dorsolateral striatum-dependent habit system (Belin et al, 2013;Giuliano et al, 2019). The self-administration of drugs in a negative emotional state may facilitate these transitions through the additional engagement of the insular cortex, which mediates addiction-relevant negative urgency (Dal Mas & Wittmann, 2017;Um et al, 2020), heightened impulsivity and the associated vulnerability to develop compulsivity (Belin-Rauscent et al, 2016).…”

“…We further investigated whether the facilitatory effect of EE on the development of compulsive cocaine intake also extended to alcohol. In a third experiment, the tendency of rats housed in EE versus SE (n = 12 each) to develop quinine-resistant (Wolffgramm & Heyne, 1995;Augier et al, 2018;Siciliano et al, 2019;Marti-Prats et al, 2020), compulsive, alcohol intake was assessed after several months of intermittent access to alcohol in a two-bottle choice procedure (Carnicella et al, 2014;Wise, 1973). EE rats did not differ from SE rats in their alcohol intake over 47 daily sessions of intermittent or unpredictable access to a choice between alcohol and water (Fig.…”

Environment-dependent behavioral traits and experiential factors shape addiction vulnerability

“…We further investigated whether the facilitatory effect of EE on the development of compulsive cocaine intake also extended to alcohol. In a third experiment, the tendency of rats housed in EE vs SE (n = 12 each) to develop quinine-resistant (45)(46)(47)(48), compulsive, alcohol intake was assessed after several months of intermittent access to alcohol in a two bottle-choice procedure (49,50). EE rats did not differ from SE rats in their alcohol intake over 47 daily sessions of intermittent or unpredictable access to a choice between alcohol and water ( Fig.…”

Individual differences in the engagement of habitual control over alcohol seeking predicts the development of compulsive alcohol seeking and drinking

“…The neural mechanisms and circuit basis of these complex changes in alcohol seeking and consumption have yet to be fully determined. In rats, preference for alcohol and the future development of compulsive alcohol seeking 28 and drinking 24 have been linked to individual differences in the expression of the GABA transporter GAT3 in the amygdala, while compulsive drinking has been linked (in mice) to altered function in a medial prefrontal cortex-dorsal periaqueductal gray circuit involved in punishment avoidance or resilience 38 . However, the observation that only compulsive P rats develop quinine-resistant, compulsive alcohol drinking suggests that the neural mechanisms underlying the universal tendency of P rats to drink high volumes of alcohol do not necessarily lead to the development of aversion-resistant compulsive drinking, even though P rats tend to drink more quinine-adulterated alcohol than the Wistar rats from which they were originally derived 61 .…”

“…We investigated the action-outcome (A-O) versus stimulus-response (S-R) associative structure underlying alcohol seeking, at different time points during a long history of alcohol use, in alcohol-preferring (P) rats [21][22][23] . We also assessed the development of compulsive (quinine-resistant) [24][25][26][27][28] alcohol drinking.…”