The effects of acute haloperidol or risperidone on subjective responses to methamphetamine in healthy volunteers

Abstract

Despite extensive evidence that selective dopamine antagonists attenuate the reinforcing effects of stimulants in laboratory animals, there is little evidence that dopamine antagonists block the positive subjective effects of stimulants in humans. However, recent evidence suggests that the subjective effects of stimulants in humans may depend in part on serotonin. The goal of this study was to examine the effects of haloperidol, a drug that primarily blocks dopamine receptors, and risperidone, a drug that blocks both dopamine and serotonin receptors, on the physiological and subjective effects of methamphetamine in healthy volunteers. Two groups of subjects participated in a placebo-controlled, within-subject, 2×2 repeated measures design. One group was tested with haloperidol (3 mg; N=18), the other with risperidone (0.75 mg; N=18). Each subject participated in four sessions receiving all combinations of antagonist or placebo and methamphetamine (20 mg) or placebo. Dependent measures included vital signs and standardized questionnaires of subjective effects. At these doses, both haloperidol and risperidone produced mild sedative-like effects compared to placebo. However, neither drug consistently reduced the stimulant-like effects of methamphetamine. These results add to the growing body of literature suggesting that D₂ dopamine receptor antagonists do not block the euphorigenic subjective effects of stimulant drugs in humans, and also do not support the idea that serotonin contributes significantly to these effects.

Introduction

A large body of evidence clearly demonstrates a critical role of mesolimbic dopaminergic projections in the rewarding or reinforcing effects of psychostimulants in laboratory animals (Wise and Bozarth, 1987, Koob and Bloom, 1988). In neurochemical studies, classical stimulants such as amphetamine and cocaine increase dopamine in the nucleus accumbens, either by enhancing its release (Carboni et al., 1989) or by blocking its reuptake (Johanson and Fischman, 1989, Seiden et al., 1993). The importance of dopamine is also clearly evident in behavioral studies in animals. For example, both self-administration and discrimination of stimulants are blocked by dopamine antagonists (Wise and Bozarth, 1987 for review). Similarly, direct dopamine agonists, like stimulant drugs, induce place preferences (McGregor and Roberts, 1994, Mackey and van der Kooy, 1985).

Despite the large number of studies linking dopamine systems and rewarding effects of stimulants in laboratory animals, few studies have been conducted to explore the role of dopamine in humans. The few studies that have been conducted have yielded inconsistent results. In early research, it was found that a drug that inhibited dopamine synthesis (the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine) and high doses (up to 20 mg) of the dopamine receptor antagonist pimozide, reduced the euphoric response to d-amphetamine in amphetamine abusers (Jonsson et al., 1969, Jonsson, 1972, Gunne et al., 1972, Angrist et al., 1974). However, these studies were complicated by the possibility that the treatments themselves may have produced sedative-like and unpleasant subjective effects. More recent studies have found that lower doses of dopamine antagonists did not alter the response to cocaine in cocaine abusers, or the response to d-amphetamine in normal healthy volunteers. Gawin et al. (1989) found that neither chlorpromazine nor haloperidol reduced cocaine-induced euphoria in cocaine abusers and Brauer and de Wit, 1995, Brauer and de Wit, 1996, Brauer and de Wit, 1997 found that behaviorally active doses of pimozide and fluphenazine did not attenuate the subjective effects of moderate doses of d-amphetamine in normal healthy volunteers.

Studies with dopamine agonists have also provided only limited and inconsistent support for the role of dopamine in the rewarding effects of stimulants in humans. In brain imaging studies, the occupancy of dopamine transporter receptors is positively correlated with subjective reports of high and euphoria after cocaine (Volkow et al., 1997). Similarly, in double-blind, placebo-controlled clinical trials, dopamine agonists such as bromocriptine and amantadine reduced cocaine use and decreased self-reported craving for cocaine (Dackis et al., 1987, Giannini and Billett, 1987, Tennant and Sagherian, 1987). However, these drugs do not appear to modify the effects of cocaine in cocaine abusers (Tennant and Sagherian, 1987, Giannini and Billett, 1987, Preston et al., 1992). Thus, the role of dopamine in the euphoric and reinforcing effects of stimulants in humans is complex.

The conflicting results of studies of dopamine and stimulants in humans raise the possibility that other neurotransmitter systems may be involved. Indeed, there is accumulating evidence that serotonin may mediate some of the effects of psychostimulants. First, in addition to their actions on the dopamine system, drugs such as cocaine, methamphetamine, and methylphenidate also interact with the serotonin transporter (Schmidt and Gibb, 1985, Ritz and Kuhar, 1989) and increase serotonin levels (Koe, 1976, Kuczenski and Segal, 1989, Kuczenski and Segal, 1997, Kuczenski et al., 1987). In particular, both methamphetamine and cocaine have substantial effects on serotonin systems (Peat et al., 1985, Kuczenski et al., 1995, Essman et al., 1994, Teneud et al., 1996, Reith et al., 1997). Second, there is evidence that serotonin antagonists, particularly serotonin₂ receptor antagonists, can modulate the discriminative-stimulus, reinforcing, and subjective effects of cocaine in primates and humans (Walsh and Cunningham, 1997). In primates, serotonin antagonists attenuate the discriminative-stimulus effects of cocaine (Schama et al. 1997). In humans, there are preliminary reports that ritanserin, a serotonin₂ receptor antagonist, and ondansetron, a serotonin₃ receptor antagonist, reduce the subjective effects of cocaine (Sullivan et al., 1992, Sullivan et al., 1994). Similarly, ondansetron has also been shown to attenuate some of the physiological and behavioral effects of d-amphetamine (Grady et al., 1996), and Walsh et al. (1994) reported that fluoxetine, a selective serotonin reuptake inhibitor, decreased subjective ratings of the positive mood effects of cocaine in humans. Interestingly, serotonin antagonists do not appear to block the discriminative effects of cocaine in rats (Peltier et al., 1994, Callahan and Cunningham, 1993). Nevertheless, this preliminary evidence in humans suggests that serotonin may play a role in mediating the subjective effects of stimulants in humans.

Thus, the present experiments were designed to compare the role of dopamine and serotonin systems in the subjective effects of methamphetamine in normal, healthy human volunteers. Subjects were tested with one of two drugs that vary in their receptor specificity profiles: haloperidol is primarily a dopamine receptor antagonist whereas risperidone acts on both dopamine and serotonin receptors. Therefore, it was hypothesized that haloperidol would not dampen the subjective effects of methamphetamine, consistent with previous studies using d-amphetamine and other dopamine antagonists. However, because of its action on both dopamine and serotonin receptors, it was hypothesized risperidone would dampen the subjective effects of methamphetamine.