Neuroscience Letters, 152 (1993) 133-136 133 © 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved 0304-3940/93/$ 06.00 NSL 09396 Ethanol prevents the glutamate release induced by N-methyl-D-aspartate in the rat striatum S. Carboni, R. Isola, G.L. Gessa and Z.L. Rossetti B.B. Brodie Department of Neuroscience, University of Cagliari, Cagliari (Italy) (Received 21 December 1992; Revised version received 30 December 1992; Accepted 7 January 1993) Key words: Ethanol; MK-801; NMDA receptor; Microdialysis The administration of ethanol (2 g/kg, i.p.) or of the non-competitive antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloepten-5,10-imine maleate (MK-801; 1 mg/kg, i.p.) induced a decrease in the extracellular concentrations of glutamate, as studied by microdialysis in the striatum of awake rats. Moreover, ethanol and MK-801 completely prevented the increase in extraneuronal glutamate concentration induced by the focal application of N-methyl-D-aspartate (NMDA). The present results suggest that ethanol suppresses glutamate release through an inhibition of NMDA glutamate receptors in the rat striatum. Several lines of evidences suggest that ethanol pos- sesses an inhibitory action on glutamate transmission. Among glutamate receptor subtypes [19], the N-methyl- D-aspartate (NMDA) receptor-coupled cation channel appears to be relatively sensitive to ethanol. Recent elec- trophysiological [15-18, 30] and biochemical [4, 9, 13] studies have demonstrated that ethanol, at concentra- tions associated with mild to moderate intoxication (5- 50 mM), selectively inhibits the NMDA receptor func- tion. Consistent with the antagonist properties of ethanol on NMDA receptors [5, 9, 10, 18, 20, 22], chronic expo- sure of animals to ethanol in vivo leads to an increase in the number of [3H]MK-801 binding in certain brain areas [11, 12], an effect that likely reflects an up-regulation of NMDA receptors. Furthermore, similarly to ethanol also NMDA receptor antagonist drugs prevent the bio- chemical [23] and behavioral [11, 14, 20] effects associ- ated with ethanol withdrawal syndrome. NMDA receptors are thought to be involved in synap- tic plasticity, long-term potentiation, cognitive function, epileptiform seizures and in certain behaviors [2]. There- fore, alterations in NMDA receptor mediated glutamate neurotransmission may underlie certain in vivo effects of ethanol, such as cognitive dysfunctions [13] or ethanol withdrawal-associated epileptiform seizures [11, 14, 20]. Recent microdialysis studies indicate that NMDA re- ceptors have a stimulatory role in the regulation of en- Correspondence: S. Carboni, Dipartimento di Neuroscienze, via Porcell 4, 09124 Cagliari, Italy. Fax: (39) (70) 657237. dogenous glutamate release in the rat striatum [23, 32]. Therefore, due to its antagonist properties on NMDA receptors, ethanol may be expected to affect the NMDA- mediated glutamate response. To test this hypothesis, we used the microdialysis tech- nique to study the effect of the administration of an inter- mediate dose of ethanol on basal and NMDA-stimulated extracellular glutamate levels in the rat striatum. In addi- tion, the effect of ethanol was compared with that of the non-competitive NMDA receptor antagonist MK-801. Male Sprague-Dawley rats (Charles River, Italy) weighing 200-250 g were used. The animals were housed under environmentally controlled conditions with free access to food and water. After the cannula implanta- tion, animals were returned to their cages and 24 h later connected to the perfusion system. NMDA (Sigma Chemical, St. Louis, USA) was dissolved in the perfusion medium. MK-801 was a gift from Merk Sharp & Dohme (England). Drugs were dissolved in saline and adminis- tered i.p. (0.5 ml/100 g of body weight). Mean recovery in vitro was 16 _+ 1.4% (mean _+ S.E.M., n = 3). Microdi- alysis [26] was performed essentially as already described [21]. Under chloral hydrate anesthesia (400 mg/kg i.p.) rats were implanted with dialysis fibers (AN69HF mem- branes, Hospal, France) transversely through the cau- date (A: 2 from the bregma and V: 5 from the cortical dura surface). A modified Krebs buffer, pH 7.4 (compo- sition in mM: CaCl2 1.2, NaC1 147, KCI 3, MgSO4 1.2, KH2PO4 0.4) was perfused at constant rate of 2/d/min, through a microinfusion pump (CMA/100 Carnegie Me-