Stress and Drug Dependence Differentially Modulate Norepinephrine Signaling in Animals with Varied HPA Axis Function

Abstract

Previous work has demonstrated the importance of genetic factors and stress-sensitive circuits in the development of affective disorders. Anxiety and numerous psychological disorders are comorbid with substance abuse, and noradrenergic signaling in the bed nucleus of the stria terminalis (BNST) is thought to be a source of this convergence. Here, we examined the effects of different stressors on behavior and norepinephrine dynamics in the BNST of rat strains known to differ in their HPA-axis function. We compared the effects of acute morphine dependence and social isolation in non-anxious Sprague Dawley (SD) rats, and a depression model, Wistar-Kyoto (WKY) rats. We found a shared phenotype in drug-dependent and singly housed SD rats, characterized by slowed norepinephrine clearance, decreased autoreceptor function, and elevated anxiety. WKY rats exhibited changes in anxiety and autoreceptor function only following morphine dependence. To ascertain the influence of LC inhibition on this plasticity, we administered the LC-terminal-selective toxin DSP-4 to SD and WKY rats. DSP-4-treated SD rats demonstrated a dependence-like phenotype, whereas WKY rats were unchanged. Overall, our findings suggest that individuals with varying stress susceptibilities have different noradrenergic signaling changes in response to stress. These changes may establish conditions that favor stress-induced reinstatement and increase the risk for addiction.

Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal

“…Naloxone treatment produced somatic withdrawal behaviors and global withdrawal scores similar to our previous reports (Fox et al, 2015;McElligott et al, 2013), and scores were significantly higher in morphine-withdrawn animals (Supplementary Figure S5, two-way ANOVA, Bonferroni Post hoc: main effect of morphine F (1,12) = 57.65, Po0.0001. DA: morphine-naloxone, 5.7 ± 1.0 vs vehicle-naloxone, 2.0 ± 0.5; NE: morphine-naloxone, 7.2 ± 0.5 vs vehicle-naloxone, 1.0 ± 0.4 N = 7, respectively).…”

“…We gave morphine s.c. since i.v. catheters require rats to be singly housed and social-isolation produces a stress profile and noradrenergic dysregulation similar to morphine-dependent rats (Fox et al, 2015). We found dopamine transients increased in frequency for a much longer duration (460 min) than in Vander Weele et al (2014), which could arise due to differences in baseline stress or the slower time course of drugs delivered s.c. compared with i.v.…”

“…Additionally, opiate-withdrawal aversion requires forebrain norepinephrine , and morphine-dependence alters noradrenergic synaptic function in the vBNST (Fox et al, 2015;McElligott et al, 2013). We thus measured norepinephrine release in the vBNST during morphine exposure and withdrawal (schematic in Figure 2a).…”

“…We next examined the impact of drug withdrawal by administering naloxone (1 mg/kg s.c.) 4 h after initial morphine (Fox et al, 2015;McElligott et al, 2013;Schulteis et al, 1999). We recorded dopamine transients over 20 min during the peak of somatic withdrawal signs and found dopamine transient frequency decreased in animals undergoing withdrawal relative to initial treatment (9.9 ± 1.5 vs 2.3 ± 0.5 transients per minute, morphine vs morphinenaloxone; 2.1 ± 0.5 vs 1.1 ± 0.1 transients per minute, vehicle vs vehicle-naloxone, N = 7, respectively; Figure 1d).…”

“…However, no work addresses the effect of acute drug exposure or withdrawal on phasic release. Moreover, stress-dependent adaptations in vBNST noradrenergic signaling arise following morphinedependence (Fox et al, 2015;McElligott et al, 2013), yet the source of this plasticity is unknown.…”