Cocaine effects on mouse incentive-learning and human addiction are linked to α2 subunit-containing GABA _A receptors

Abstract

Because GABA A receptors containing α2 subunits are highly represented in areas of the brain, such as nucleus accumbens (NAcc), frontal cortex, and amygdala, regions intimately involved in signaling motivation and reward, we hypothesized that manipulations of this receptor subtype would influence processing of rewards. Voltageclamp recordings from NAcc medium spiny neurons of mice with α2 gene deletion showed reduced synaptic GABA A receptor-mediated responses. Behaviorally, the deletion abolished cocaine's ability to potentiate behaviors conditioned to rewards (conditioned reinforcement), and to support behavioral sensitization. In mice with a point mutation in the benzodiazepine binding pocket of α2-GABA A receptors (α2H101R), GABAergic neurotransmission in medium spiny neurons was identical to that of WT (i.e., the mutation was silent), but importantly, receptor function was now facilitated by the atypical benzodiazepine Ro 15-4513 (ethyl 8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate). In α2H101R, but not WT mice, Ro 15-4513 administered directly into the NAcc-stimulated locomotor activity, and when given systemically and repeatedly, induced behavioral sensitization. These data indicate that activation of α2−GABA A receptors (most likely in NAcc) is both necessary and sufficient for behavioral sensitization. Consistent with a role of these receptors in addiction, we found specific markers and haplotypes of the GABRA2 gene to be associated with human cocaine addiction.GABRA2 | behavioral sensitization | nucleus accumbens | mutant mouse | human genetics

Differential Roles of GABAA Receptor Subtypes in Benzodiazepine-Induced Enhancement of Brain-Stimulation Reward

“…This would suggest that the activation of the a2-and a3-GABA A -Rs in the VTA would inhibit dopaminergic projections from VTA to the NAcc, the opposite of a rewarding effect. Thus, it is likely that the activation of a2-and a3-containing GABA A -Rs in other parts of the reward circuitry is important for the reward-enhancing effects of diazepam in ICSS, similar to the findings by Dixon et al (2010) showing that the NAcc a2-containing GABA A -Rs are required for certain drug effects of cocaine.…”

“…Thus, it is possible that the prefrontal, subicular, and amygdalar excitatory inputs into the NAcc, as well as NAcc output to downstream structures, may be controlled by a2-GABA A -Rs, while the dopaminergic inputs from VTA onto NAcc may be controlled by a1-GABA A -Rs, resulting in a dissociation between the motivational (ie, wanting) and appetitive (ie, liking) components of reward. A recent study provides some initial evidence for the view that the a2-containing GABA A -Rs of the NAcc play a pivotal role in the incentive effects of drugs of abuse by modulating the activity of medium spiny neurons (Dixon et al, 2010), supporting a role for these receptors in certain incentive motivational processes as well.…”

“…Indeed, there is strong evidence showing that the neuronal circuitry underlying different components of reward, such as 'liking' (ie, experience of simple pleasure through the administration of an appetitive stimulus), 'wanting' (ie, incentive salience that leads to motivated behavior) and learning (ie, the acquisition of the associations between reward-predictive cues and the natural reward) is distinct (Berridge et al, 2009). The areas that are implicated in goaldirected behaviors, such as the prefrontal cortex, the subiculum and the basolateral amygdala, as well as the NAcc itself, have a high density of a2-GABA A -Rs, while the VTA contains predominantly a1-GABA A -Rs in the interneurons (Dixon et al, 2010;Fritschy and Mohler, 1995;Pirker et al, 2000;Tan et al, 2010). Thus, it is possible that the prefrontal, subicular, and amygdalar excitatory inputs into the NAcc, as well as NAcc output to downstream structures, may be controlled by a2-GABA A -Rs, while the dopaminergic inputs from VTA onto NAcc may be controlled by a1-GABA A -Rs, resulting in a dissociation between the motivational (ie, wanting) and appetitive (ie, liking) components of reward.…”

Loss of BDNF Signaling in D1R-Expressing NAc Neurons Enhances Morphine Reward by Reducing GABA Inhibition

“…For example, we showed recently that chronic cocaine increases the expression of several GABA A R subunits, including Gabra1, Gabra2, and Gabrb2 in NAc and that GABA A R antagonism blocks behavioral plasticity to cocaine (Kennedy et al, 2013), findings consistent with earlier studies (Dixon et al, 2010;Heiman et al, 2008). In contrast, we show here that chronic morphine decreases levels of several GABA A R subunits, including Gabra2 and Gabrd, in whole NAc and that GABA A R antagonism in this region robustly enhances morphine reward.…”

“…Such morphine-induced downregulation of GABA A R subunits is even more apparent when D1-type MSNs are examined selectively (see below). Interestingly, mRNA expression levels of Gabra2, which encodes the GABA A R-a2 subunit and is implicated in reward learning and behavioral sensitization as well as human cocaine addiction (Dixon et al, 2010), is regulated oppositely in the NAc by morphine vs cocaine. A previous study showed that GABA A R-a2 subunit is not directly associated with cocaine reward as evidenced by no alterations in cocaine CPP and conditioned reinforcement in Gabra2-deficient mice (Dixon et al, 2010).…”