A role for nucleus accumbens glutamate in the expression but not the induction of behavioural sensitization to ethanol

Abstract

Mechanisms underlying differential sensitivity to behavioural sensitization to ethanol (EtOH) remain poorly understood, although accumulating evidence suggests a role for glutamatergic processes in the ventral striatum. Efforts to address this issue can benefit from the well-documented fact that in any given cohort, some of the mice (High sensitized; HS) show robust sensitization, while others (Low sensitized; LS) show little, if any, sensitization. Here, we examined whether this variability might be differentially associated with nucleus accumbens (NAc) glutamate processes. Male DBA mice received 5 EtOH (2.2g/kg) or saline injections twice a week and were challenged with EtOH (1.8g/kg) 2 weeks after injection 5. When an EtOH challenge was administered 2 weeks following the induction of sensitization, HS, but not LS, mice showed a robust increase in glutamate levels (67%, P<0.01) as measured by in vivo microdialysis. In a separate cohort, the mGlu2/3 agonist LY354740 (10mg/kg), given prior to the EtOH challenge, abolished the expression of sensitization. To ascertain whether enhanced release could also be observed during the induction of sensitization, glutamate levels were measured after the 1st and 5th EtOH injection and were found to be unchanged in HS mice, although briefly elevated in LS mice at injection 5. To further assess possible glutamate involvement during the induction of sensitization, sensitizing EtOH injections were co-administered with NMDAR antagonists. At the doses used, MK-801 (0.25mg/kg) and CGS 19755 (10mg/kg) blocked the expression of sensitization, but did not significantly interfere with the development of EtOH sensitization. Within the limitations of the present design, the results suggest an important role for EtOH-induced glutamate release in the NAc when sensitization is well established, but not necessarily during the development of sensitization.

Keywords: Alcohol sensitization; CGS 19755; LY354740; MK-801; Microdialysis; NMDA receptors.