Behavioural role of dopamine D 1 receptors in the reserpine-treated mouse

Abstract

The effects of 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF 38393) (D 1 agonist) on the motor behaviour of mice rendered hypokinetic with reserpine, were studied in the absence and presence of additional treatment with N-n-propyl- N-phenylethyl- p(3-hydroxyphenyl)ethylamine hydrochloride (RU 24213), lisuride (D 2 agonists) or apomorphine (mixed D 1D 2 agonist). Three hours after reserpine (5 mg/kg) stimulating dopamine D 2 receptors evoked slow, ponderous walking and head-down sniffing. SKF 38393 (1.5–15 mg/kg) had no direct effect of its own, but greatly amplified the D 2 response, giving more fluent locomotion, rearing and grooming. The facilitatory action of SKF 38393 was inhibited by the D 1 antagonist (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SCH 23390) (0.05 mg/kg), whereas D 2-mediated responses were sensitive both to SCH 23390 and the D 2 antagonist metoclopramide (0.5 mg/kg). Mice treated with reserpine for 24 h became more sensitive to the motor stimulant actions of all four agonists. SKF 38393 now promoted rapid locomotion, rearing and grooming directly. The effects of D 2 stimulation were weak by comparison and often antagonistic (not synergistic) with those of the D 1 agonist. Both sets of agonists were now attenuated only by their respective antagonists. Reserpine caused pronounced falls in the concentrations of dopamine, 5-hydroxytryptamine and noradrenaline in the striatum, olfactory tubercle and cerebral cortex, with correspondingly elevated metabolite levels. These results indicate that D 1 and D 2 agonists at doses that are relatively ineffective at stimulating behaviour when given in isolation 3 h after reserpine, interact when given together to partially restore locomotion, rearing and grooming. This interaction is not apparent 24 h post-reserpine, a time at which D 1 and D 2 agonists produce significant effects of their own.