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

Abstract

α2 subunit-containing GABA A receptors are involved in incentive learning associated with cocaine, and in cocaine addiction. Deletion of α2-containing receptors abolishes cocaine-induced behavioural sensitisation (BS), while selective activation of α2 receptors, achieved using Ro 15-4513's agonist properties in α2(H101R) mice, induced BS. Here, we investigate further the mechanisms underlying Ro 15-4513-induced behavioural sensitisation in α2(H101R) mice. α2(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 α2(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 α2-containing receptors are involved in mediating the ability of BZs to facilitate cocaine-induced activity. The non-selective (i.e., α1, α2, α3 and α5 subtype) benzodiazepine GABA A receptor agonist midazolam (10 and 30 mg/kg) potentiated cocaine (10 mg/kg) hyperactivity in wildtype mice, but not in α2(H101R) mice, in which α2-containing receptors are insensitive to benzodiazepines. To determine where α2 receptors are localised we compared BZ-insensitive sites between wildtype (α4 and α6) and α2(H101R) (α2, α4 and α6) mice, using quantitative autoradiography to estimate [ 3H]Ro 15-4513 binding in the presence of 10 μM diazepam. α2 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 α2-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 α2(H101R) mice, suggests that this form of BS may occur downstream of plastic events underlying cocaine sensitisation.