Discriminative stimulus effects of cocaine in squirrel monkeys: involvement of dopamine receptor subtypes.
The involvement of dopamine (DA) receptor subtypes in the discriminative stimulus effects of cocaine was investigated in squirrel monkeys trained to discriminate cocaine from vehicle using a two-lever choice procedure. Lever pressing was maintained under a 10-response fixed-ratio schedule of food presentation. In substitution tests, (-)-cocaine and its high-affinity analogs 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (CFT) and 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane (CCT) engendered dose-related increases in the proportion of cocaine-appropriate responses. Full (97-100%) substitution for the training dose of cocaine was observed with all three drugs, the rank order of potency being: CCT greater than CFT greater than cocaine. DA agonists differing in selectivity for D1 and D2 receptor subtypes [6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine (SKF 81297), 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-3-allyl-[1H]-3- benzazepine (SKF 82958), (+)-4-propyl-9-hydroxynapthoxazine [(+)-PHNO], quinpirole, quinelorane, (-)-4,6,6a,7,8,-12b-hexahydro-7-methyl-indolo[4,3-ab]phen ant hridine (CY 208-243) and (-)-apomorphine] also engendered dose-related increases in cocaine-appropriate responses. However, maximally effective doses of these drugs occasioned an average of only 54 to 77% responses on the cocaine-associated lever and markedly reduced response rates. Combinations of the D1 agonist SKF 81297 and the D2 agonist (+)-PHNO did not engender a consistently higher proportion of cocaine-appropriate responses than did either drug alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Spealman
R D
RD
Harvard Medical School, New England Regional Primate Research Center, Southborough, Massachusetts.
Bergman
J
J
Madras
B K
BK
Melia
K F
KF
D000818:Animals; D001552:Benzazepines; D003042:Cocaine / Q000031:analogs & derivatives / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects*; D015259:Dopamine Agents / Q000494:pharmacology; D018492:Dopamine Antagonists; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D010078:Oxazines / Q000494:pharmacology; D011954:Receptors, Dopamine / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D012453:Saimiri; D013997:Time Factors
D001552:Benzazepines; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D010078:Oxazines; D011954:Receptors, Dopamine; C042631:naxagolide; D007980:Levodopa; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; C067113:SK&F 81297; D003042:Cocaine