Role of 5-HT1A receptors in the ability of mixed 5-HT1A receptor agonist/dopamine D2 receptor antagonists to inhibit methylphenidate-induced behaviors in rats.

Behavioral effects produced by the indirect-acting dopamine receptor agonist, methylphenidate (40 mg/kg i.p.) were examined in rats after administration of the 5-HT1A receptor agonists (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and flesinoxan, the mixed 5-HT1A receptor agonist/dopamine D2 receptor antagonists buspirone and 1-[-4-fluorobenzoylamino)ethyl]-ethyl]-4-(7-methoxynaphthyl) piperazine (S 14506), the neuroleptics haloperidol and clozapine, and the sigma receptor ligand/partial 5-HT1A receptor agonist alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol (BMY 14802). All of the compounds produced dose-related decreases in methylphenidate-induced stereotyped gnawing, and, as gnawing was inhibited, other methylphenidate-induced responses (i.e. sniffing, rearing and locomotion) appeared. Higher doses of haloperidol and buspirone, but none of the remaining compounds, inhibited these other responses, so that the behavior of the methyphenidate-treated animals became similar to that of normal controls. Pretreatment with the 5-HT1A receptor antagonist N-[2-4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl)- cyclohexanecarboxamide (WAY-100635; 0.63 mg/kg s.c.) blocked the ability of 8-OH-DPAT, S 14506 and flesinoxan to inhibit methylphenidate-induced gnawing, demonstrating the involvement of 5-HT1A receptors in their ability to inhibit methylphenidate-induced behaviors. In contrast, pretreatment with WAY-100635 did not alter the ability of haloperidol, clozapine, buspirone, or BMY 14802 to inhibit methylphenidate-induced gnawing, or in the case of haloperidol and buspirone, to normalize behavior. The results indicate that mixed compounds with 5-HT1A receptor agonist and dopamine receptor antagonist properties can be differentiated on the basis of the ability of WAY-100635 to reverse their effects on methylphenidate-induced behaviors.