PHARMACOLOGICAL CHARACTERIZATION OF BEHAVIORAL-RESPONSES TO SK-AND-F-83959 IN RELATION TO D-1-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 [H-3]-SCH 23390 and [H-3]-spiperone indicated SK&F 83959 had a high affinity and >250 fold selectivity for D-1 over D-2 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 D-1 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 behaviour was evident. 4 Grooming to SK&F 83959 (0.05 mg kg(-1)) was blocked by the selective D-1 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 D-2 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 D-1 receptor agonist-induced grooming by SK&F 83959, an agent satisfying criteria for a D-1 receptor antagonist as classically defined, together with its blockade by typical D-1 antagonists, strongly suggests mediation via a 'D-1-like' site that appears to respond similarly to agents independent of whether they exert agonist or antagonist actions at the classical adenylyl cyclase-coupled D-1 receptor. This direct functional evidence for a 'D-1-like' site that is not linked to adenylyl cyclase readily complements neurochemical data suggesting the existence of a cyclase-independent 'D-1-like' receptor that may be coupled to phosphoinositide hydrolysis.