Chronic cocaine self-administration upregulates the norepinephrine transporter and alters functional activity in the bed nucleus of the stria terminalis of the rhesus monkey

Abstract

The bed nucleus of the stria terminalis (BNST) is in a key position to influence the integration of motivational and visceral functions, receiving inputs from limbic regions, including the amygdala, and sending projections to areas central to reward processing, including the ventral tegmental area and nucleus accumbens. The BNST also possesses a high density of noradrenergic fibers. The purpose of the present studies was to characterize the effects of cocaine self-administration on the regulation of norepinephrine transporter (NET) distribution and functional activity in the BNST of rhesus monkeys in the initial (5 d) or chronic (100 d) phases of cocaine self-administration. NET binding site densities in the BNST were assessed with quantitative in vitro receptor autoradiography using [{%N}3{%N}H]nisoxetine, and rates of local cerebral glucose utilization in the BNST were measured in the same monkeys using the 2-[{%N}14{%N}C]deoxyglucose method. Chronic exposure to cocaine self-administration resulted in significantly higher NET binding site densities (up to 52% relative to controls) throughout the BNST. Furthermore, cerebral metabolism was depressed significantly in a time-dependent manner with larger decreases after 100 d of cocaine self-administration. These data represent the first report of significant changes in the regulation of the NET resulting from cocaine exposure in primates. Furthermore, given the role of the BNST in cocaine withdrawal and stress-related reinstatement of self-administration, the changes reported here may provide a substrate for these phenomena.