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Clinical studies have suggested therapeutic potential for the non-selective dopamine receptor agonist apomorphine, in treating female sexual dysfunction. However, experimental data suggest apomorphine may inhibit sexual behaviour in female rats. The aims of this study were: evaluate an alternate behavioural endpoint in a conscious, non-contact model of sexual behaviour; and secondly investigate apomorphine in this model. Proceptive behaviour was determined in sexually naïve ovariectomised female rats as time spent actively investigating an inaccessible sexual incentive (sexually vigorous intact male rat) relative to time investigating a social incentive (castrated male rat) in an open field arena. Apomorphine (10, 30 and 100 microg/kg SC) induced a dose-related bell-shaped increase in proceptive behaviour, achieving significance (P<0.05) at 30 microg/kg, in females given a low (estrogen 1 microg/rat+progesterone 100 microg/rat) hormonal prime. This was equivalent to proceptive activity displayed by females given a high (estrogen 5 microg/rat+progesterone 250 microg/rat) hormonal prime in full behavioural oestrous. In contrast, in females given the high hormonal prime all doses tended to decrease proceptive activity. This study demonstrates that pro-sexual effects of apomorphine are critically dependent on hormone levels; sexual motivation is enhanced in animals given a low hormonal prime, but attenuated when given to animals in behavioural oestrous., (2010 Elsevier Inc. All rights reserved.)

The identification of gamma-aminobutyric acid A (GABA(A)) receptor subunit genes over the last twenty years has shown that GABA(A) receptors are made up of many different subtypes. As such the dissection of which receptor subtypes mediate which functions of clinically useful GABAergic drugs, such as benzodiazepines, has been extremely complicated. Two complimentary approaches have been taken: the development of subtype-selective drugs and the genetic manipulation of different receptor subunits. Both have yielded exciting results, but sometimes with contradictory findings. This review highlights the strengths and weaknesses of both approaches, illustrating with specific discussion of the work, to uncover which receptor subtype(s) mediates the anxiolytic effects of benzodiazepines.

alpha2 subunit-containing GABA(A) receptors are involved in incentive learning associated with cocaine, and in cocaine addiction. Deletion of alpha2-containing receptors abolishes cocaine-induced behavioural sensitisation (BS), while selective activation of alpha2 receptors, achieved using Ro 15-4513's agonist properties in alpha2(H101R) mice, induced BS. Here, we investigate further the mechanisms underlying Ro 15-4513-induced behavioural sensitisation in alpha2(H101R) mice. alpha2(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 alpha2(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 alpha2-containing receptors are involved in mediating the ability of BZs to facilitate cocaine-induced activity. The non-selective (i.e., alpha1, alpha2, alpha3 and alpha5 subtype) benzodiazepine GABA(A) receptor agonist midazolam (10 and 30 mg/kg) potentiated cocaine (10 mg/kg) hyperactivity in wildtype mice, but not in alpha2(H101R) mice, in which alpha2-containing receptors are insensitive to benzodiazepines. To determine where alpha2 receptors are localised we compared BZ-insensitive sites between wildtype (alpha4 and alpha6) and alpha2(H101R) (alpha2, alpha4 and alpha6) mice, using quantitative autoradiography to estimate [(3)H]Ro 15-4513 binding in the presence of 10 muM diazepam. alpha2 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 alpha2-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 alpha2(H101R) mice, suggests that this form of BS may occur downstream of plastic events underlying cocaine sensitisation.