Prenatal stress perturbs nucleus accumbens glutamate signaling: Relation to heightened addiction vulnerability?

摘要

Growing attention has focused on individual differences in vulnerability to substance abuse disorders with both clinical and preclinical data indicating that life stress history and gender differences contribute to both the patterns of drug taking and in the propensity to relapse. Preclinical data indicates that female rats exhibit higher motivation to self-administer cocaine or alcohol and higher non-reinforced cocaine- or alcohol-seeking behavior under a variety of conditions (time-out responding, extinction, and reinstatement) compared to their male counterparts. Conversely, prenatal stress in males alters brain reward circuits to enhance self-administration of cocaine and alcohol, as well as, exhibit higher cocaine-seeking behavior under extinction and reinstatement conditions. However, the molecular substrates mediating enhanced cocaine- and alcohol-seeking due to stress histories and sex differences are unknown. The focus of our work is to determine the impact of sex and prenatal stress on glutamate neurotransmission within the nucleus accumbens - a neural substrate that is necessary and sufficient for cocaine-seeking behavior under a variety of conditions - and the relation of these alterations to drug-seeking behavior. To date, our findings suggest that (1) heightened drug-seeking in females may be related to elevated NMDA receptor levels, (2) heightened drug-seeking in prenatal stressed males may be related to elevated mGluR levels, (3) and the lack of effect of prenatal stress in females may be mediated by a compensatory reduction in Homer1b/c levels. These findings suggest molecular bases underlying individual differences in addiction vulnerability and provide molecular targets to modulate addiction vulnerability.