Dopamine D1 receptor involvement in the discriminative-stimulus effects of SKF 81297 in squirrel monkeys

The discriminative-stimulus effects of the selective dopamine D1 agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine (SKF 81297) were investigated in squirrel monkeys trained to discriminate i.v. injections of SKF 81297 from saline in a two-lever drug-discrimination procedure. SKF 81297 produced dose-related increases in responding on the SKF 81297-associated lever with full substitution occurring at the training dose in all monkeys. Pretreatment with the selective D1 antagonist(-)-trans-6-7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N- methyl-5H- benzo(d)naphtho-(2,1-b)azepine 2-(SCH 39166) and the D1 partial agonist 7,8-dihydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine (SKF 75670) produced rightward shifts of the dose-effect curve for the discriminative-stimulus effects of SKF 81297, indicative of surmountable antagonism. Pretreatment with the selective D2 antagonist eticlopride, however, did not systematically alter the discriminative-stimulus effects of SKF 81297. Stereoselectivity was evident in the discriminative-stimulus effects of the enantiomers of the structurally related D1 agonist 3-allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benz azepin e (6-Br-APB), with the R-, but not the S-enantiomer, producing dose-related increases in responding on the SKF 81297-associated lever and full substitution in all monkeys. Another selective D1 agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-3-allyl-[1H]-3- benzazepine (SKF 82958) and the nonselective D1/D2 agonists (-)apomorphine and (-)4,6,6a,7,8,12b-hexahydro-7 methyl-indolo[4,3-ab]phenanthridine (CY 208-243), also engendered dose-related increases in SKF 81297-appropriate responding with full substitution occurring in one-half of the monkeys studied. The D2 agonists, (+)-4-propyl-9-hydroxynaphthoxazine and quinpirole, engendered dose-related increases in SKF 81297-appropriate responding but did not substitute fully in any monkey studied. Other dopaminergic drugs, including the D1 partial agonists SKF 75670 and R(+)-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3- benzazepine (R-SKF 38393), and the indirect dopamine agonists, cocaine, d-amphetamine and 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine (GBR 12909), did not substitute fully for SKF 81297 in any monkey studied. These results suggest that agonist actions at the D1 subtype of dopamine receptor are prominently involved in the discriminative-stimulus effects of SKF 81297.