THE RELATIONSHIP BETWEEN REINFORCING EFFECTS AND IN-VITRO EFFECTS OF D1 AGONISTS IN MONKEYS

The reinforcing effects of many psychomotor stimulants have been relat ed to increased dopaminergic neurotransmission and stimulation of cent ral nervous system (CNS) dopamine (DA) receptors. Consistent with this notion, some drugs that directly stimulate DA receptors have been fou nd to function as positive reinforcers. The present experiments were d esigned to examine why some, but not all, D1 receptor agonists can fun ction as reinforcers in rhesus monkeys by comparing behavioral and CNS in vitro measures of potency and efficacy. Seven rhesus monkeys were allowed to self-administer cocaine under a progressive-ratio (PR) sche dule until stable responding was established. Various doses of D1 agon ists, previously reported to function as positive reinforcers, were th en made available for self-administration. Stimulation of cAMP product ion in rhesus and rat striatal tissue was studied for these compounds and for D1 agonists previously reported not to function as positive re inforcers in monkeys (SKF 38393, SKF 77434 and S(-)-6-BrAPB). Blockade of DA uptake in rat striata was also examined for all compounds. SKF 81297, SKF 82958 and R(+)-6-BrAPB maintained responding under the PR s chedule and did not differ significantly in efficacy as positive reinf orcers; SKF 81297 was less potent than the other two agonists. SKF 812 97, SKF 82958 and R(+)-6-BrAPB stimulated higher levels of cAMP produc tion in rhesus striata than did SKF 38393, SKF 77434 and S(-)-6-BrAPB. In contrast, all compounds blocked DA uptake. Thus, reinforcing effic acy among D1 agonists increases with efficacy in stimulating D1 recept ors.