Prior restraint stress counteracts memory deficits associated with adolescent alcohol exposure by targeting both the hippocampal endocannabinoid and glutamatergic systems.

Abstract

Recent studies link intensive adolescent alcohol exposure to adult memory deficits and glutamatergic dysfunction, as shown in preclinical models of binge drinking. Adolescent stress exposure has also been associated with changes in emotional behavior and memory, varying with stress timing and intensity. This study demonstrates that repeated exposure to restraint stress (five sessions of 1.5h from postnatal days 32-36) can prevent memory deficits, but not anxiety, caused by intensive alcohol exposure (four weekly cycles of 3g/kg ethanol doses followed by three washout days) when assessed in adult animals (postnatal day 77). PCR analysis of hippocampal mRNA showed alcohol consumption reduced expression of growth factors (BDNF), glutamate receptor subunits (AMPA: GluR1, GluR2; NMDA: NR1, NR2A), and endocannabinoid signaling genes (CB2, PPARα; DAGLα, DAGLβ; FAAH, MAGL). Restraint stress largely reversed these biochemical changes, suggesting it protects against alcohol's long-term impact on the hippocampus by partially restoring glutamatergic synaptic function and normalizing glutamate receptor and endocannabinoid system expression. Proteomic studies in the dorsal hippocampus further reveal that early stress exposure modifies how adolescent alcohol affects dorsal hippocampal protein expression. These findings imply that early stress habituation could counteract neurodevelopmental changes affecting memory when induced by adolescent alcohol exposure. However, disruption of emotional behavior is still present in animals exposed to alcohol, independently of the stress delivered.