Dextromethorphan alters methamphetamine self-administration in the rat

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Abstract

Various lines of evidence indicate that methamphetamine (METH) self-administration in rats is under dopaminergic control, and NMDA receptors have been shown to control the release of dopamine at its synapse. Consequently, the aim of this study was to observe the effects of dextromethorphan (DM), a non-competitive NMDA antagonist, in rats self-administering METH. The hypothesis was that acute pretreatment of DM (25 mg/kg) would alter response to METH. DM significantly altered self-administration by reducing the number of correct responses for three METH self-administration doses (0.05, 0.1, 0.25 mg/kg). The same pretreatment did not affect responding for food reward. These findings show that the DM was able to selectively alter METH self-administration.

Introduction

Dextromethorphan (DM), the dextrorotatory isomer of levomethorphan, is a common antitussive drug that acts as a non-competitive NMDA antagonist [26]. DM has been shown to attenuate morphine tolerance [12], [13], the reinforcing and the rewarding effects of cocaine [20], and the alcohol withdrawal syndrome [6]. These findings suggest the involvement of the glutamate system in various effects of many abused drugs. Specifically, NMDA receptors have been implicated as actively stimulating dopamine receptors. For example, the direct administration of NMDA results in potentiation of D1 receptor effects in the striatal and nucleus accumbens region [8]. Since methamphetamine (METH) and other psychostimulants act through dopamine receptors [22], one would expect that DM might alter the reinforcing effects of these drugs through modulation of dopamine via the NMDA receptor. In fact, previous experiments have shown that DM can alter cocaine self-administration, although the specificity of that effect was not established [20].

With the abuse of METH increasing in recent years, there has been a renewed interest in pursuing pharmacological treatments for its abuse. While the mechanisms of action for cocaine and METH are not identical, their effects on the central nervous system share many of the same properties. Therefore, it is reasonable to expect that pretreatments might affect METH self-administration similarly to cocaine. The purpose of the present experiment was to determine the effects of DM on METH self-administration in rats. The designated dose for METH acquisition was based on previous studies from our laboratory [15], [23] showing optimal acquisition. Like cocaine [21], METH self-administration is acquired rapidly, usually within 5–10 sessions. Unlike cocaine, however, most METH injections are self-administered in the first 30 min of the session, with rate of intake then dropping to a low steady rate for the remainder of the session.

Three different doses of METH were assessed following pretreatment with DM. The DM pretreatment dose was based on the effective dose previously determined for cocaine self-administration [20]. In order to determine the specificity of the effects of DM, a food control group was also included.

Section snippets

Subjects

Naive male Wistar rats (Charles River, Wilmington, MA) were individually housed in a temperature- and humidity-controlled room with a 12 h light/dark cycle (lights on at 7 a.m.). Although the rats had free access to water ad libitum, they were placed on a food restriction schedule to maintain their body weight at approximately 325 g (±50 g). Animals used in this study were maintained in facilities fully accredited by the American Association for the Accreditation of Laboratory Animal Care

Results

Fig. 1 shows the acquisition of METH self-administration. It required up to 21 sessions in order for all the animals to consistently self-administer the training dose of 0.1 mg/kg METH for five consecutive sessions at the FR-5 schedule. Some animals required as little as 14 sessions. Analysis revealed that during criterion sessions, the animals responded in the correct hole significantly more than in the incorrect hole [F(1,70)=855.6, p<0.0001]. When saline was substituted for METH, responding

Discussion

The results of the present study confirm that METH is self-administered [15], [23]. The strong preference to poke the correct hole vs. the incorrect one, and the decrease in responding following saline substitution clearly illustrate these properties in similar fashion to that of cocaine and amphetamine. More importantly, the results also reveal that DM significantly reduces intravenous METH self-administration across a range of METH doses. However, when the same dose of DM was given to animals

Acknowledgements

NIDA Intramural Research Funds supported the research. We would like to thank Eric Thorndike and Dr. Leigh Panlilio for their contributions.

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