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-HT(1A) receptor agonists (±)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and flesinoxan, the mixed 5-HT(1A) receptor agonist/dopamine D2 receptor antagonists buspirone and 1-[-4-fluorobenzoylamino)ethyl]-ethyl]-4-(7-methoxy-naphthyl)piperazine (S 14506), the neuroleptics haloperidol and clozapine, and the σ receptor ligand/partial 5-HT(1A) receptor agonist α-(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-HT(1A) 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-HT(1A) 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-HT(1A) 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.
- 5-HT(1A) receptor agonist
- 8-OH-DPAT ((±)-8-hydroxy-2-(di-n-propylamino)tetralin)
- BMY 14802
- S 14506
ASJC Scopus subject areas