Dopamine receptor subtype involvement in the behavioural effects of cocaine
The relationship between the behavioural effects of cocaine and the increase in dopamine caused by its blockade of dopamine re-uptake has been a major focus of research interest. However, little is known regarding the involvement of recently cloned dopamine D2-like receptor subtypes (D2, D3 and D4) in different cocaine induced behaviours. The purpose of the work described in this thesis was to use a series of behavioural tests to assess dopamine receptor subtype involvement in cocaine's effects. In the first series of experiments, we tested the effects of antagonists selective for receptors within the D2-like subfamily on the discriminative stimulus effects of cocaine (10 mg/kg), and compared them with the effects of a Dl-like receptor antagonist. A separate group of rats were trained to discriminate a low dose of cocaine (3 mg/kg). Neither U-99194A (a D3 antagonist) nor L-745,870 (a D4 antagonist) substituted for cocaine, and neither drug shifted the dose-response function for cocaine at the higher training dose. On the other hand, pre-treatment with SCH 39166 (a selective Dl-like antagonist) produced significant dose-related rightward shifts in the cocaine generalisation curve, indicating effective antagonism. Three other centrally-acting D2-like antagonists (L-741,626; haloperidol and raclopride) produced rightward shifts in the dose-response function for cocaine at both training doses. The D2-like antagonists, however, produced dissimilar effects on cocaine-induced hypophagia and hyperactivity in the rat. The D3 and D4 antagonists (which produced minimal effects on feeding and motor behaviours on their own) failed to alter any of the behavioural effects induced by cocaine. The D21D3 antagonist, raclopride, produced only a marginal attenuation of cocaine-induced hyperactivity and rearing, but a marked attenuation of cocaine-induced decreases in grooming. On the other-hand, a Dl-like antagonist potently reversed cocaine-induced hypophagia, hyperactivity and rearing, but failed to affect grooming behaviour. While drug discrimination studies suggests negligible involvement of D3 and D4 receptors in cocaine's effects, an important role for Dl-like and D2 receptors was observed. In contrast, it seems that the Dl-like subfamily may play a more prominent role than the D2-like subfamily in cocaine-induced hypophagia and motor hyperactivity, although cocaine-induced inhibition of grooming appears to be specifically a D2-mediated effect.