Resistance to ethanol sensitization is associated with a loss of synaptic plasticity in the hippocampus

Abstract

Behavioral sensitization to repeated ethanol (EtOH) exposure induces an increase in locomotor activity in mice. However, not all animals express such sensitization. Although the literature indicated that the hippocampus may play a role in EtOH sensitization, it is not known whether behavioral sensitization to EtOH is associated with preferential changes in bidirectional synaptic plasticity, i.e., LTP and LTD, two markers of learning capabilities that have also been shown to be involved in addictive behavior. In the present study, we examined whether the vulnerability to develop and express behavioral sensitization to EtOH is associated with altered bidirectional synaptic plasticity in the CA1 area of the dorsal hippocampus. For this purpose, we analyzed both LTP and LTD in resistant and sensitized mice during the expression phase, i.e., 7 days after 10 days of repeated EtOH i.p. administration. We found that resistant mice showed a lack of LTD without changes in LTP. The lack of LTD was associated with an increase in GluN2A protein level and was not due to an altered level of neuronal activity, since no difference was observed between the number of c-FOS positive neurons in sensitized and resistant mice. Given that both types of synaptic plasticity signals may have distinct roles in specific learning and behaviors, our results suggest that resistant mice could exhibit different phenotypes in terms of learning/memory and addictive behaviors compared to sensitized ones. Synapse 71:e21899, 2017. © 2016 Wiley Periodicals, Inc.

Alcohol and the Brain: Neuronal Molecular Targets, Synapses, and Circuits

“…Impairment of mGluR5-LTD in hippocampal slices following ethanol vapor exposure (Wills et al, 2017) indicates that other types of plasticity may be affected by chronic ethanol. Relevant to the role of plasticity in ethanol-related behaviors, mice susceptible to the development of locomotor sensitization to ethanol show normal hippocampal LTD, whereas mice resistant to ethanol sensitization lack LTD (Coune et al, 2017). We still have an incomplete understanding of how changes in synaptic plasticity are associated with behavioral adaptations produced by chronic ethanol treatment.…”

“…Another study found impaired expression of NMDAR-LTD in the NAc core, but not shell, of mice that showed robust locomotor sensitization to ethanol after 2 weeks of withdrawal from chronic ethanol treatment (Abrahao et al, 2013) (Figure 3P). Thus, plasticity deficits in the NAc and hippocampus may contribute to behavioral adaptations to chronic ethanol (Coune et al, 2017).…”

Synaptic plasticity mechanisms common to learning and alcohol use disorder

“…Chronic EtOH exposure impairs LTD in hippocampus (Roberto et al 2002;Thinschmidt et al 2003;Coune et al 2017), dorsal striatum (Cui et al 2011;DePoy et al 2013DePoy et al , 2015 the dopamine D1 receptor-containing neurons of the nucleus accumbens (NAc) shell (Jeanes et al 2011;Spiga et al 2014;Renteria et al 2018b) and the NAc core (Abrahao et al 2013). Both NMDA and CB1-dependent LTD are impaired by chronic EtOH exposure.…”

“…The Prosapip-1-dependent changes in AMPAR-mediated synaptic transmission in NAc appear to play a role in controlling EtOH selfadministration (Laguesse et al 2017). LTD impairment in the accumbens core is also associated with behavioral sensitization: while blunted NMDA dependent accumbal LTD is associated with the development of sensitization (Abrahao et al 2013), blunted hippocampal LTD is observed only in sensitization-resistant mice (Coune et al 2017).…”

Long-term exposure to daily ethanol injections in DBA/2J and Swiss mice: Lessons for the interpretation of ethanol sensitization

“…Finally, the last aim of the present study was to investigate the reliability of several recent procedures that were used to categorize mice into low and high ethanol sensitized mice or “ethanol sensitization respondent” and “ethanol sensitization resistant” mice. In several published studies, mice were so classified according to the distance travelled during the sensitization sessions after a few days of ethanol injections [10,14,16,19–21,27–40]. The categorized groups of mice were then used to study the neurobiological and epigenetic bases of ethanol sensitization vulnerability.…”