Serotonin 5-HT₃ antagonists do not alter the discriminative stimulus properties of cocaine

The central nervous system (CNS) of the rat is known to contain serotonin (5-HT) type -3 receptors (5-HT₃). Behavioral evidence suggests that 5-HT₃ receptors interact with mesolimbic dopamine (DA) systems and that 5-HT₃ antagonists can interfere with the hyperlocomotive effects of amphetamine and cocaine and the rewarding and stimulus effects of morphine, nicotine and ethanol. Cocaine, which blocks the reuptake of DA, norepinephrine (NE), and 5-HT in the CNS, also may be an antagonist at 5-HT₃ receptors. The purpose of the present study was to determine whether systemic administration of the 5-HT₃ antagonists ICS 205930 or MDL 72222 could mimic or block the discriminative stimulus properties of cocaine. Once rats (N=16) were trained to discriminate cocaine (10 mg/kg) from saline, substitution tests with various doses of cocaine (0.313-10 mg/kg), ICS 205930 (2-24 mg/kg), and MDL 72222 (2-16 mg/kg) were conducted. Cocaine produced a doserelated increase in cocaine-appropriate responding while the 5-HT₃ antagonists engendered primarily saline-lever responding. Neither ICS 205930 nor MDL 72222 were able to antagonize the stimulus effects of cocaine (5 mg/kg). Response rates were not significantly reduced when the 5-HT₃ antagonists were given in combination with cocaine. The results indicate that although 5-HT₃ antagonists can inhibit some of the unconditioned behavioral effects of psychomotor stimulants, the discriminative stimulus effects of cocaine remain intact.