Elsevier

Psychiatry Research

Volume 102, Issue 3, 24 July 2001, Pages 227-233
Psychiatry Research

Risperidone pre-treatment reduces the euphoric effects of experimentally administered cocaine

https://doi.org/10.1016/S0165-1781(01)00255-4Get rights and content

Abstract

Pre-clinical research implicates dopaminergic neurotransmission as critical in producing the effects of stimulants. Previous stimulant challenge studies using volunteers treated with dopaminergic antagonists have generally failed to demonstrate reduction of subjective effects. We performed this study to determine whether repeated dosing with risperidone reduced the subjective effects of experimentally administered cocaine. Nine non-treatment seeking hospitalized cocaine-dependent volunteers received 40 mg cocaine IV before and following 5 days of treatment with risperidone, 2 mg per day. Risperidone pre-treatment reduced the self-rated ‘high’ produced by cocaine. Repeated, rather than single, dosing with a D2 antagonist may be necessary to reduce the subjective effects produced by cocaine. The degree of D2 receptor blockade produced by risperidone appears to be greater than the reduction in euphoric effects produced by cocaine, suggesting that mechanisms other than those involving D2 receptors may be important in drug-induced euphoria.

Introduction

Mesolimbic dopamine systems have long been implicated in the reinforcing properties of abusive drugs such as cocaine and amphetamine. In pre-clinical models, treatment with specific dopamine agonists and antagonists has been used to study the roles played by dopamine receptor subtypes in producing behavioral reinforcement (Self and Nestler, 1998). In particular, dopamine D2 receptor agonists facilitate the reinforcing effects of cocaine; in contrast, D2 receptor antagonists reduce the reinforcement value of stimulant drugs (Bourland and French, 1995).

Compared to the extensive pre-clinical literature, fewer studies have examined the effects of D2 antagonists on effects of stimulants in human subjects (Brauer et al., 1997). Effects of pharmacologic pre-treatment on subjective effects produced by cocaine can be studied in the laboratory using an experimental cocaine administration paradigm (e.g. Haney et al., 1998, Haney et al., 1999, Preston et al., 1992). Sherer and colleagues (Sherer et al., 1989), in a sample of five cocaine-using volunteers, evaluated the effects of intramuscular administration of 8 mg of haloperidol on the subjective effects produced by experimental cocaine administration. Haloperidol treatment reduced ratings of cocaine-associated ‘good’ effects, but did not affect ratings of rush, energetic, happy or other measures of euphoric effect. Brauer and De Wit, 1996, Brauer and De Wit, 1997) showed that oral acute treatment with comparable doses of pimozide (a similar D2 antagonist) did not block or substantially attenuate subjective effects of amphetamine. These findings from studies utilizing human subjects contrast with those from pre-clinical studies that clearly demonstrated antagonism of most stimulant effects by pre-treatment with D2 antagonists.

These studies utilized a design aimed at detecting the acute effects produced by the concurrent administration of a study drug and cocaine. There is some reason to believe that acute effects of D2 antagonists on the dopamine system may be different from the effects produced by repeated administration (Roth and Tam, 1987). For example, in a sample of 18 amphetamine users, chlorpromazine, a non-specific and sedating dopamine antagonist, initially reduced the effects produced by amphetamine by approximately 10%, and the degree of reduction increased to 40% over 7 to 13 days of chlorpromazine treatment (Jönsson, 1972). Less clear results were seen following treatment with pimozide. Although pimozide reduced the subjective effects of experimentally administered amphetamine in a non-dose-dependent manner, it was also associated with side effects, which may have affected ratings of euphoria.

In general, clinical studies using D2 antagonists in repeated dosing designs have found that pre-treatment reduced the effects produced by stimulant administration, whereas those using single dose designs did not. Until recently, implementation of repeated dose designs using D2 antagonists has been problematic due to the unpleasant side effects of older drugs, such as haloperidol, pimozide and chlorpromazine. Risperidone is generally well tolerated at low doses, with fatigue being the prominent side effect. The purpose of this study was to ascertain whether repeated administration of the well-tolerated D2 antagonist risperidone would attenuate the subjective effects produced by cocaine administration.

Section snippets

Subjects

Subjects were non-treatment seeking, cocaine-dependent volunteers recruited from the community. The SCID was used to ensure that all subjects met DSM-III-R criteria for cocaine dependency and that they did not meet criteria for exclusionary psychiatric illnesses. These included current other Axis I psychiatric illness (other than nicotine dependence), including dependence on other drugs of abuse; illicit use of opiates was not permitted within the last month.

A physician screened potential

Results

Thirteen subjects entered (11 males and two females), and nine male subjects completed the entire protocol. Our recruitment population was predominately male, explaining the unbalanced ratio. The three non-completing subjects dropped out for various reasons unrelated to either cocaine or risperidone administration. The mean age of completing subjects was 39 years (range 33–47 years). Subjects’ weekly use of crack cocaine averaged 2.39 g/week [based on the amount of drug subjects reported using,

Discussion

In this study we found that repeated administration of a relatively low dose of risperidone reduced the self-rated ‘high’ produced by experimental cocaine administration. There were minimal baseline differences between the pre-treatment and risperidone conditions, suggesting that risperidone had minimal non-specific effects. Risperidone reduced the ‘high’ to a modest degree, approximately 15% using the AUC index of response. This is consistent with clinical reports that cocaine-dependent

References (29)

  • L.H Brauer et al.

    Dopamine ligands and the stimulus effects of amphetamine: animal models vs. human laboratory data

    Psychopharmacology (Berl)

    (1997)
  • G Di Chiara et al.

    Drugs of abuse: biochemical surrogates of specific aspects of natural reward?

    Biochemistry Society Symposium

    (1993)
  • J Grabowski et al.

    Risperidone for the treatment of cocaine dependence: randomized, double-blind trial

    Journal of Clinical Psychopharmacology

    (2000)
  • M Haney et al.

    Effect of a selective dopamine D1 agonist (ABT-431) on smoked cocaine self-administration in humans

    Psychopharmacology (Berl)

    (1999)
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