MOTOR DEPRESSION - A NEW ROLE FOR D1 RECEPTORS

The aims of this study were two-fold. Firstly, to characterize the behavioural properties of a potential new dopamine D1 receptor agonist, (-)-4,6,6a,7,8,12b-hexahydro-7-methyl-indolo[4,3-ab]phenanthridine (CY 208-243), to determine its suitability as a tool for investigating D1 receptor function in vivo. Secondly, to investigate how the behavioural properties of D1 agonists are modified in the presence of D2 receptor blocking drugs. For this purpose, using mice, we employed CY 208-243 and 2,3,4,5-tetra-hydro-7, 8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF 38393) as reference D1 agonists, and the substituted benzamides metoclopramide and sulpiride as selective D2 antagonists. CY 208-243 (0.25-10 mg/kg) caused only a modest increase in grooming in non-habituated mice, but stimulated locomotion, rearing, grooming and orofacial activities in habituated animals. These responses were inhibited by a D1 antagonist, but not by D2 antagonists, suggesting CY 208-243 behaves as a selective agonist of D1 receptors in vivo. In non-habituated mice, doses of metoclopramide and sulpiride which had little or no effect on motor behaviour by themselves, interacted synergistically with CY 208-243 (4 mg/kg) and SKF 38393 (30 mg/kg) to cause extended periods of immobility. Other species-typical behaviours were not affected in this way. For example, grooming was decreased by metoclopramide and increased by sulpiride, indicating that an increase in behavioural competition from this parameter was not the cause of the hypokinesia. To explain the apparent ability of D1 receptor stimulation to increase exploratory activity in earlier experiments and to decrease it here, it is proposed that this behaviour is regulated by D1 receptors coupled to two functionally opposite postsynaptic D2 receptors. In the presence of the benzamides metoclopramide and sulpiride, it is suggested that the locomotion-stimulating D2 receptor is somehow suppressed, while the locomotion-inhibiting D2 receptor becomes disclosed, whose actions are facilitated by concomitant D1 receptor activation. © 1990.