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Expression of behavioral sensitization to ethanol by DBA/2J mice: the role of NMDA and non-NMDA glutamate receptors

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Abstract

Rationale

Behavioral sensitization has been accorded a central role in contemporary theories of drug addiction. Accordingly, a substantial effort has been made to determine the processes mediating sensitization to psychostimulants. However, few studies have examined the mechanisms underlying sensitization to ethanol.

Objectives

Experiments were conducted to assess the role of N-methyl-d-aspartate (NMDA) and non-NMDA glutamate receptors in expression of sensitization to ethanol's locomotor stimulant effects.

Methods

Sensitization was induced in DBA/2 J mice by administering ethanol (2 g/kg) intraperitoneally (i.p.) before four activity trials. Control groups were given saline (12.5 ml/kg i.p.) before each activity trial. Subsequently, the effects of two NMDA receptor antagonists, MK-801 and ifenprodil, and two non-NMDA glutamate receptor antagonists, DNQX and GYKI 52466, were assessed on expression of the sensitized locomotor response.

Results

MK-801 reduced the stimulant effects of ethanol and completely prevented expression of sensitization at doses exceeding 0.075 mg/kg. In contrast, although ifenprodil also reduced the stimulant effects of ethanol, the antagonist did not alter expression of sensitization. Non-NMDA glutamate antagonists were more consistent in their effects on sensitization. DNQX reduced the magnitude of the sensitized response at a low dose that did not alter the stimulant effects of ethanol. The more selective AMPA antagonist GYKI 52466 reduced the stimulant effects of ethanol and completely blocked expression of sensitization.

Conclusions

The results provide initial evidence to suggest that both NMDA and non-NMDA glutamate receptors play a role in expression of sensitization to ethanol. Additional research will be required to elucidate the mechanisms underlying differences in the efficacy of glutamate antagonists.

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Acknowledgements

The authors thank Dr. Christopher Cunningham for comments on an earlier version of the manuscript. Portions of these data were presented at the annual Research Society on Alcoholism meeting in Montreal, Canada, 2001. This work was supported by grants AA12090 and AA11066 to J.B. from NIAAA.

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  1. Department of Psychiatry, Division of Substance Abuse, University of Michigan, 205 Zina Pitcher Place, Ann Arbor, MI 48109-0720, USA

    Julie Broadbent, Kathryn M. Kampmueller & Sharon A. Koonse

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  1. Julie Broadbent
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  2. Kathryn M. Kampmueller
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  3. Sharon A. Koonse
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Correspondence to Julie Broadbent.

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Broadbent, J., Kampmueller, K.M. & Koonse, S.A. Expression of behavioral sensitization to ethanol by DBA/2J mice: the role of NMDA and non-NMDA glutamate receptors. Psychopharmacology 167, 225–234 (2003). https://doi.org/10.1007/s00213-003-1404-3

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