The induction of grooming and vacuous chewing by a series of selective D-1 dopamine receptor agonists: two directions of D-1:D-2 interaction.
A range of 3- and 6-substituted 1-phenyl-1H-3-benzazepine analogues of SK&F 38393 with D-1 agonist activity were compared for their behavioural effects in the intact adult rat and for their relative affinities for D-1 and D-2 dopamine receptors in vitro. All compounds showed selective affinity for D-1 receptors and induced prominent grooming behaviour, but those with the lower D-1:D-2 selectivity ratios also induced additional episodes of non-stereotyped sniffing, locomotion and rearing. No vacuous chewing was noted. There were marked differences in in vivo potency, extending over a 100-fold range. These responses to the most potent agonist, SK&F 77434 (3N-allyl-SK&F 38393) were reduced enantioselectively by the D-1 antagonist R-SK&F 83566. They were also reduced enantioselectively by the D-2 antagonist R-piquindone, but this pretreatment additionally released a marked vacuous chewing response to SK&F 77434. Prominent grooming may be a characteristic behavioural response to a range of D-1 agonists. It is suggested that there may be at least two forms of functional interaction between D-1 and D-2 systems, manifested concurrently in distinct elements of behaviour: one co-operative, as in the regulation of grooming, and with correlates in the regulation of pallidal neural activity; the other oppositional, as in the regulation of vacuous chewing, and with correlates in the regulation of striatal adenylate cyclase activity.
Murray
A M
AM
Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin.
Waddington
J L
JL
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006120:Grooming / Q000187:drug effects*; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D013134:Spiperone / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects*
D001552:Benzazepines; D015259:Dopamine Agents; D007546:Isoquinolines; D011954:Receptors, Dopamine; D013134:Spiperone; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C032412:Ro 22-1319