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


OBJECTIVE
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.
Broadbent
Julie
J
Department of Psychiatry, Division of Substance Abuse, University of Michigan, Ann Arbor 48109-0720, USA. broadben@umich.edu
Kampmueller
Kathryn M
KM
Koonse
Sharon A
SA
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000145:classification / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects*; D017470:Receptors, Glutamate / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000145:classification / Q000502:physiology*; D013997:Time Factors
D002492:Central Nervous System Depressants; D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol