Pharmacological characterization of behavioural responses to SK&F 83959 in relation to 'D1-like' dopamine receptors not linked to adenylyl cyclase.

1. Behavioural responses to the new benzazepine derivative, SK&F 83959, a compound that both fails to stimulate adenylyl cyclase and inhibits the stimulation of adenylyl cyclase induced by dopamine, were characterized in detail. 2. In rat striatal membrane preparations, radioligand binding studies with [3H]-SCH 23390 and [3H]-spiperone indicated SK&F 83959 had a high affinity and >250 fold selectivity for D1 over D2 receptors. 3. Using a rapid time-sampling behavioural check list technique, SK&F 83959 (0.01-1.25 mg kg(-1)) induced grooming in the manner of all known D1 receptor agonists, together with some vacuous chewing, which declined at higher doses with the emergence of directed chewing and rearing as an adjunct to prominent sniffing; no stereotyped behavioural was evident. 4. Grooming to SK&F 83959 (0.05 mg kg(-1)) was blocked by the selective D1 receptor antagonists, SCH 23390 (0.01-1.0 mg kg(-1)) and BW 737C (0.04-5.0 mg kg(-1)) and was attenuated by the selective D2 receptor antagonist, YM 09151-2 (0.005-0.5 mg kg(-1)); vacuous chewing to SK&F 83959 was not influenced by either SCH 23390 or BW 737C and was enhanced by YM 09151-2. 5. The paradoxical induction of typical D1 receptor agonist-induced grooming by SK&F 83959, an agent satisfying criteria for a D1 receptor antagonist as classically defined, together with its blockade by typical D1 antagonists, strongly suggests mediation via a 'D1-like' site that appears to respond similarly to agents independent of whether they exert agonist or antagonist actions at the classical adenylyl cyclase-coupled D1 receptor. This direct functional evidence for a 'D1-like' site that is not linked to adenylyl cyclase readily complements neurochemical data suggesting the existence of a cyclase-independent 'D1-like' receptor that may be coupled to phosphoinositide hydrolysis.