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

Abstract

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 dose-related 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.

5-HT 3 receptor antagonist MDL 72222 attenuates cocaine- and mazindol-, but not methylphenidate-induced neurochemical and behavioral effects in the rat

“…In self-administration and drug discrimination tests, however, 5-HT 3 receptor antagonists repeatedly failed to antagonize the effects of COC (Paris and Cunningham 1991;Peltier and Schenk 1991;Lane et al 1992). These results do not, however, necessarily conflict with each other.…”

The effect of a 5-HT3 receptor antagonist, ondansetron, on brain stimulation reward, and its interaction with direct and indirect stimulants of central dopaminergic transmission

“…On the other hand, amphetamine and cocaine act directly on the dopaminergic synapse by displacing DA from synaptic terminals or by inhibiting synaptic reuptake; they do not produce increased firing of the dopaminergic neuron and thus they do not depend on presynaptic 5-HT3 receptors for their effects. This account is supported by electrophysiological and neurochemical evidence (see , but a difficulty arises from findings which appear to show that 5-HT 3 antagonists, whilst sparing the discriminative and rewarding properties of cocaine and amphetamine (Carboni et al, 1989 b;Paris and Cunningham, 1991;Peltier and Schenk, 1991), do block the locomotor stimulant and exploration-inducing properties of these drugs (Costall et al, 1987;van der Hoek and Cooper, 1990a, b). These findings are difficult to reconcile with the proposed presynaptic action of 5-HT3 antagonists, and the precise effects of 5.-HT3 antagonists on dopaminergic transmission remain uncertain.…”

“…Treatment with 5-HT 3 antagonists (ondansetron, ICS 205930 or MDL 72222) has been shown to inhibit hyperactivity elicited by the neurokinin analogue, DiMe-C 7 (Hagan et al, 1990), and to prevent the acquisition of habits conditioned to morphine, nicotine, phencyclidine, picrotoxin or naloxone (Carboni et al, 1989 b;Acquas et al, 1990;Higgins et al, 1992) though not amphetamine (Carboni et al, 1989 b) or cocaine (Paris and Cunningham, 1991;Peltier and Schenk, 1991; but cf. Costall et al, 1987).…”

Serotonin involvement in the discriminative stimulus effects of κ opioids in pigeons

“…The drug discrimination procedure has been used successfully to examine the role of various neurotransmitters, including 5HT, in the action of numerous drugs (Colpaert and Slangen 1982;Cunningham et al 1985;Colpaert and Balster 1988;Paris and Cunningham 1991). In addition, a large literature indicates that animals can be trained to discriminate between the presence and absence of ~c opioids, and the discriminative stimulus properties of the ~c opioids relate to their action at ~c opioid receptors (Hein et at.…”