Age of stress exposure modulates the immediate and sustained effects of repeated stress on corticolimbic cannabinoid CB₁ receptor binding in male rats.

Chronic stress is known to modulate cannabinoid CB1 receptor binding densities in corticolimbic structures, in a region-dependent manner; however, the ontogeny of these changes and the degree to which they recover following exposure to stress have yet to be determined. To this extent, we examined both the immediate and sustained effects (following a 40-day recovery period) of a repeated restraint stress paradigm (30-min restraint/day for 10 days) on CB1 receptor binding in the prefrontal cortex (PFC), hippocampus and amygdala in both adolescent (stress onset at post-natal day [PND] 35) and adult (stress onset at PND 75) male Sprague-Dawley rats. Consistent with previous reports, we found that repeated stress in adult rats resulted in an increase in CB1 receptor binding in the PFC, a reduction in CB1 receptor binding in the hippocampus and no effect in the amygdala. Interestingly, adolescent rats exposed to repeated restraint stress did not show any change in hippocampal CB1 receptor density, but exhibited an upregulation of CB1 receptor binding in both the PFC and amygdala. In adults, a 40-day recovery period resulted in a normalization of CB1 receptor binding in the PFC, and surprisingly a pronounced upregulation of CB1 receptor binding in the hippocampus, possibly indicative of a rebound effect. Adolescents similarly exhibited this rebound increase in hippocampal CB1 receptor binding, despite a lack in immediate downregulation following repeated restraint. Of particular interest, adolescents exposed to stress were found to have a sustained downregulation of prefrontocortical CB1 receptors in adulthood, which may relate to some of the reported sustained behavioral effects of stress in adolescence. Collectively, these data indicate that the effects of chronic stress on cannabinoid CB1 receptor binding are modulated by the age of stress exposure and period of recovery following the cessation of stress.