Alpha2-containing GABAA receptors are involved in mediating stimulant effects of cocaine

a2 subunit-containing GABAA receptors are involved in incentive learning associated with cocaine, and in cocaine addiction. Deletion of a2-containing receptors abolishes cocaine-induced behavioural sensitisation (BS), while selective activation of a2 receptors, achieved using Ro 15-4513's agonist properties in a2(H101R) mice, induced BS. Here, we investigate further the mechanisms underlying Ro 15-4513-induced behavioural sensitisation in a2(H101R) mice. a2(H101R) mice sensitised to Ro 15-4513 (10 mg/kg) showed an enhanced stimulant response to cocaine (10 mg/kg). In contrast, cocaine (10 mg/kg)-sensitised a2(H101R) mice did not show enhanced sensitivity to the stimulant effects of Ro 15-4513 (1, 3 and 10 mg/kg), suggesting that the neural adaptations underlying Ro 15-4513 induced BS are related to, but not identical with those associated with cocaine-induced plasticity. Secondly, we investigated whether a2-containing receptors are involved in mediating the ability of BZs to facilitate cocaine-induced activity. The non-selective (i.e., a1, a2, a3 and a5 subtype) benzodiazepine GABAA receptor agonist midazolam (10 and 30 mg/kg) potentiated cocaine (10 mg/kg) hyperactivity in wildtype mice, but not in a2(H101R) mice, in which a2-containing receptors are insensitive to benzodiazepines. To determine where a2 receptors are localised we compared BZ-insensitive sites between wildtype (a4 and a6) and a2(H101R) (a2, a4 and a6) mice, using quantitative autoradiography to estimate [3H]Ro 15-4513 binding in the presence of 10 µM diazepam. a2 receptors were found in projection areas of the mesolimbic dopamine pathway including accumbens, central amygdala, and basolateral amygdala as well as CA1 and CA3 areas of the hippocampus. The involvement of the a2-containing receptor in mediating BZ's potentiating effect on cocaine hyperactivity suggests that the locomotor stimulant effects of BZs and psychostimulants may be mediated by a common neural system, but the lack of cross sensitisation to Ro 15-4513 in cocaine-sensitised a2(H101R) mice, suggests that this form of BS may occur downstream of plastic events underlying cocaine sensitisation.