MODULATION OF THE DISCRIMINATIVE STIMULUS PROPERTIES OF COCAINE BY 5-HT1B AND 5-HT2C RECEPTORS

The present study assessed compounds displaying affinity for 5-HT1A, 5 -HT1B, 5-HT2A and 5-HT2C receptors for their ability to substitute for , enhance or antagonize the discriminative stimulus effects of cocaine (IO mg/kg) in rats. In substitution tests, the 5-HT1A receptor agonis t 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT; 0.2-1.6 mg/kg), the 5-HT2A/2C receptor agonists RU 24969 (0.25-2 mg/kg) and CGS 12066B (2-16 mg/kg), the 5-HT1B/2C receptor agonists m-chlorophenylpiperazin e (mCPP; 0.25-2 mg/kg) and m-trifluoromethylphenylpiperazine (TFMPP; 0 .125-2 mg/kg), the 5-HT2A/2C, receptor agonist 1-(4-bromo-2,5-dimethox yphenyl)-2-aminopropane ([+/-]-DOB; 0.0625-0.5 mg/kg), the 5-HT2C rece ptor agonist MK 212 (0.25-1 mg/kg) and the nonselective 5-HT receptor agonist quipazine (1-8 mg/kg) engendered 30% to 70% cocaine-appropriat e responding. The DA receptor antagonists SCH 23390 (0.025 or 0.05 mg/ kg) and haloperidol (0.125 or 0.25 mg/kg) failed to block the partial substitution of RU 24969 (1 mg/kg) for cocaine. In combination tests, a fixed dose of either quipazine (4 mg/kg), RU 24969 (0.25, 0.5 or 1 m g/kg) or TFMPP (0.5 mg/kg) but not 8-OH-DPAT (0.4 mg/kg) or CGS 12066B (16 mg/kg) produced a leftward shift in the cocaine dose-response cur ve (0.625-5 mg/kg). In contrast, coadministration of either mCPP (0.25 -2 mg/kg) or MK 212 (0.125-2 mg/kg) plus a dose of cocaine (5 mg/kg) t hat produced >85% cocaine-appropriate responding when given alone part ially antagonized cocaine; mCPP (1 mg/kg) also produced a rightward sh ift in the cocaine dose-response curve. Neither 8-OH-DPAT (0.2-1.6 mg/ kg), (+/-)-DOB (0.125-0.5 mg/kg) nor quipazine (2-8 mg/kg) blocked the cocaine stimulus, The 5-HT1A receptor antagonist NAN 190 (0.2-0.8 mg/ kg), the 5-HT2A/2C receptor antagonist LY 53857 (0.5-4 mg/kg) and the 5-HT/DA receptor antagonist pirenperone (0.5-4 mg/kg) neither substitu ted for nor enhanced cocaine; however, pirenperone but not NAN 190 or LY 53857 partially blocked the cocaine (10 mg/kg) response. Although 5 -HT receptor compounds do not substitute for cocaine, several 5-HT rec eptor agonists (i.e., the indole derivative RU 24969 and the arylpiper azines mCPP, MK 212, TFMPP and quipazine), but not antagonists, differ entially modulate the stimulus effects of cocaine. Moreover, 5-HT1B an d 5-HT2C receptors may be responsible for the observed enhancements an d antagonisms, respectively, produced by the 5-HT receptor compounds, whereas 5-HT1A and 5-HT2A receptors do not appear to modulate the coca ine discrimination in rats.