Glutamatergic mechanisms in behavioural sensitization to ethanol

Repeated exposure to ethanol (EtOH) in mice produces behavioural sensitization. However, not all mice sensitize to EtOH and in any cohort high-sensitizers (HS) can readily be distinguished from low-sensitizers (LS). The neural mechanisms mediating vulnerability and resistance to EtOH sensitization remain unclear. Given the prominent role of glutamate in neuroplasticity, we examined whether this system might explain the variable response to EtOH. In the first set of experiments, we measured nucleus accumbens (NAc) glutamate levels in LS and HS mice following an EtOH challenge two weeks after sensitization development. EtOH-induced glutamate release in the NAc was present in HS mice and use of a glutamate release blocker prevented the expression of sensitization. To ascertain whether NAc glutamate was also elevated in HS mice during the development of sensitization, we measured levels after the 1st and 5th EtOH injection and found them unchanged in HS mice. These results suggest that NAc glutamate may not be necessary for the development of EtOH sensitization, but it appears essential for the expression of a sensitized response. iii We next studied the role of NMDARs in EtOH sensitization. LS mice demonstrated elevated NMDAR subunit gene expression across the brain compared to HS and saline-treated mice. However, NMDAR antagonism with MK-801 and CGS 19755 did not interfere with EtOH sensitization, indicating perhaps that NMDARs may not be crucial to sensitization. A final goal was to examine whether LS and HS mice differ in the expression of the plasticity markers pCREB, Bdnf, trkB, and Arc, and if they show structural changes in NAc neurons. HS mice showed increased pCREB expression in the NAc. LS mice showed reduced trkB and Bdnf expression across the brain, however inhibition of BDNF-TrkB signaling had no effect on EtOH sensitization. LS mice also presented greater stubby spine density in the NAc and increased Arc mRNA in several brain areas when compared to saline controls and HS mice. Taken together, these results demonstrate variation in the glutamate system between LS and HS mice. This thesis discusses these differences and how they may contribute to individual differences in sensitization response.Ph.D