Dextromethorphan alters methamphetamine self-administration in the rat
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.
References (27)
- et al.
Effects of corticosterone on excitatory amino acid responses in dopamine-sensitive neurons in the ventral tegmental area
Neuroscience
(1999) - et al.
Dextromethorphan attenuates ethanol withdrawal syndrome in rats
Pharmacol Biochem Behav
(1999) NMDA receptor antagonism produces antinociception which is partially mediated by brain opioids and dopamine
Life Sci
(1999)- et al.
The role of NMDA receptor systems in neuropeptide responses to stimulant of abuse
Drug Alcohol Depend
(1995) - et al.
Continuous co-administration of dextromethorphan or MK-801 with morphine: attenuation of morphine dependence and naloxone-reversible attenuation of morphine tolerance
Pain
(1996) - et al.
Oral administration of dextromethorphan prevents the development of morphine tolerance and dependence in rats
Pain
(1996) - et al.
The role of glutamate in behavioral and neurotoxic effects of methamphetamine
Neurochem Int
(1996) - et al.
Dextromethorphan reduces intravenous cocaine self-administration in the rat
Eur J Pharmacol
(1997) - et al.
N-methyl-d-aspartate receptors mediate dopamine-induced changes in extrapyramidal and limbic dynorphin systems
Brain Res
(1991) - et al.
Neuroadaptations in the dopaminergic system after active self-administration but not after passive administration of methamphetamine
Eur J Pharmacol
(1999)
Dextromethorphan and neuromodulation: old drug coughs up new activities
Trends Pharmacol Sci
Effect of dextromethorphan, a NMDA antagonist, on DNA repair in rat photochemical thrombotic cerebral ischemia
Brain Res
Differences in dopamine clearance and diffusion in rat striatum and nucleus accumbens following systemic cocaine administration
J Neurochem
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