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

Abstract

While most individuals with access to alcohol drink it recreationally, some vulnerable individuals eventually lose control over their intake and progressively develop compulsive alcohol drinking and decreased interest in alternative sources of reinforcement, two key features of addiction. The neural and molecular mechanisms underlying this vulnerability to switch from controlled to compulsive alcohol intake have not been fully elucidated. It has 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 GABAB receptor agonist baclofen, which decreases GABA release, specifically reduces 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 with quinine or when an alternative ingestive reinforcer, saccharin, was available. In these rats, which were characterized 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 may represent an endophenotype of vulnerability to develop a compulsive drinking of alcohol that is shown here to be mitigated by baclofen.

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

“…25 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, whereas compulsive drinking has been linked (in mice) to altered function in a medial prefrontal cortex-dorsal periaqueductal grey 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.…”

“…12,13 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.…”

The Novel Positive Allosteric Modulator of the GABAB Receptor, KK-92A, Suppresses Alcohol Self-Administration and Cue-Induced Reinstatement of Alcohol Seeking in Rats

“…An additional, possible mechanism of action is based on the recent observation that alcohol-dependent rats had reduced amygdalar levels of the GABA transporter GAT3 and, subsequently, high concentrations of extracellular GABA (Augier et al, 2018). It has been proposed that activation of amygdalar presynaptic GABA B receptors by baclofen-and GABA B PAMs, we add-would inhibit GABA release, reducing extracellular GABA levels, restoring the enhanced tonic inhibition of amygdala and, in the end, decreasing alcohol drinking (Spanagel, 2018;Marti-Prats et al, 2021).…”

The development of compulsive coping behaviors depends on the engagement of dorsolateral striatum dopamine-dependent mechanisms

“…SIP training was carried out as previously described (32, 66, 67) in twelve operant chambers located within ventilated sound-attenuating cubicles (Med associates, St. Albans, USA) and made of aluminium and transparent acrylic plastic with a stainless-steel grid floor (24 cm x 25.4 cm x 26.7 cm). Chambers were equipped with a house light (3-W), a food tray (magazine) installed at the centre of the front wall, and a bottle from which a stainless-steel sipper tube delivered water or alcohol into a receptacle placed in a magazine on the wall opposite the food magazine.…”