Differential effects of 5-HT agonists and antagonists on the repeated acquisition and performance of response sequences in monkeys

As a means of characterizing the role of 5-HT1A and 5-HT2A receptors in lea rning, 5-hydroxytryptamine (5-HT) agonists and antagonists with selective a ffinities for each receptor subtype (i.e. 8-hydroxy-dipropylaminotetralin ( 8-OH-DPAT), (-)-4-(dipropylamino)-1,3,4,5-tetrahydrobenz-{c,d,}indole-6-car boxamide (LY228729), (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-amino propane h ydrochloride (DOI), 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2 -pyridinyl-benzamide hydrochloride (p-MPPI), N-[2-[4-(2-methoxyphenyl)-1-pi perazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide maleate (WAY-100635), 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide (NAN -190) and ritanserin) were administered to monkeys responding under a multi ple schedule of repeated acquisition and performance. In addition, a select ive 5-HT1A receptor agonist (8-OH-DPAT) was administered in combination wit h a 5-HT2A receptor antagonist (ritanserin) to examine any potential intera ctions between the two 5-HT receptor subtypes. When administered alone, 8-O H-DPAT (0.1-3.2 mg/kg), LY228729 (0.32-3.2 mg/kg) and DOI (0.018-3.2 mg/kg) dose-dependently decreased overall response rate in both schedule componen ts, and generally increased the percentage of errors in the acquisition com ponents at doses lower than those that increased the percentage of errors i n the performance components. At the doses of each drug tested (i.e, 0.1 or 0.32 mg/kg), both p-MPPI and WAY-100635 antagonized the disruptive effects of 8-OH-DPAT, by shifting the dose-effect curves for overall response rate and the percentage of errors to the right. In contrast, ritanserin (0.32 o r 1 mg/kg) had little or no effect on the disruptions produced by 8-OH-DPAT , but it effectively antagonized the rate-decreasing and error-increasing e ffects produced by the 3-HT2A agonist DOI. Administration of the 5-HT1A ant agonists WAY-100635 and NAN-190 alone produced dose-dependent rate-decreasi ng effects, but the effects on accuracy of responding in the acquisition co mponents differed from those of the 5-HT1A agonists (8-OH-DPAT and LY228729 ), in that they did not produce an increase in the percentage of errors. To gether, these results suggest that 5-HT is capable of disrupting learning i n monkeys through actions at both the 5-HT1A and 5-HT2A receptors, and that 5-HT2A receptor antagonism does not unilaterally modify the effects produc ed by 5-HT1A receptor activation. (C) 2000 Lippincott Williams & Wilkins.