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 [(3)H]nisoxetine, and rates of local cerebral glucose utilization in the BNST were measured in the same monkeys using the 2-[(14)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.

Contribution of a Mesocorticolimbic Subcircuit to Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats

“…This interpretation is supported by anatomical evidence from previous studies (Berger et al, 1991;Dunnett and Robbins, 1992;Frankle et al, 2006;Reynolds et al, 2006;Sesack and Grace, 2010;Watabe-Uchida et al, 2012) and from our retrograde tracing experiment indicating that the VTA (Figure 4a), but not the SN (Figure 4b), projects to the OFC. Moreover, the OFC and BLA share direct, reciprocal intrahemispheric and interhemispheric connections (Figure 4c and d; Carmichael and Price, 1995a;Ghashghaei and Barbas, 2002;Krettek and Price, 1977;McDonald, 1991) as well as indirect connections relayed through the mediodorsal thalamus (Cavada et al, 2000;Demeter et al, 1990;Ghashghaei and Barbas, 2002;Macey et al, 2003;Miyashita et al, 2007). Therefore, we propose that an intricate, intra-and interhemispheric VTA-OFC-BLA neural circuit controls drug context-induced motivation for cocaine.…”

Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task

“…In the CUD, we speculate that these beneficial effects are contingent on an enhancement of dopamine neurotransmission by MPH (which blocks the dopamine transporter) in these dopamine-deficient individuals. However, the direct or downstream effects of other neurotransmitters such as norepinephrine (32), also disrupted with chronic cocaine exposure (33), remain to be empirically tested.…”

Betaxolol, a selective β1-adrenergic receptor antagonist, diminishes anxiety-like behavior during early withdrawal from chronic cocaine administration in rats

“…Indeed, repeated administration of cocaine up-regulates the norepinephrine transporter in limbic regions (Macey et al, 2003;Beveridge et al, 2005), suggesting the hypothesis that the presence of additional norepinephrine transporters may cause a transient depletion in synaptic norepinephrine and, as a result, post-synaptic β 1 -adrenergic receptors may be forced to up-regulate as a compensatory mechanism during this time period.…”