Noradrenergic Synaptic Function in the Bed Nucleus of the Stria Terminalis Varies in Animal Models of Anxiety and Addiction

Abstract

Lewis rats show increased anxiety-like behaviors and drug consumption compared with Sprague-Dawley rats. Prior work suggests norepinephrine (NE) signaling in the bed nucleus of the stria terminalis (BNST) could have a role in mediating these phenotypes. Here, we investigated NE content and dynamics in the ventral BNST (vBNST) using fast-scan cyclic voltammetry in these two rat strains. We found that NE release evoked by electrical stimulus and its subsequent uptake was dysregulated in the more anxious Lewis rats. Because addiction is a multifaceted disease influenced by both genetic and environmental factors, we hypothesized NE dynamics would vary in these strains after the induction of a physical dependence on morphine. Following naloxone-precipitated morphine withdrawal, NE release and uptake dynamics were not changed in Lewis rats but were significantly altered in Sprague-Dawley rats. The alterations in Sprague-Dawley rats were accompanied by an increase in anxiety-like behavior in those animals as measured with the elevated plus maze. These studies suggest novel mechanisms involved in the development of affective disorders, and highlight the noradrenergic system in the vBNST as a common substrate for the manifestation of pathological anxiety and addiction.

Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal

“…Morphine increased evoked dopamine concentrations (baseline vs morphine: 2.9 ± 1.5 vs 4.4 ± 0.8 μM, N = 4, P = 0.04, paired T-test; Figure 1h and i). Acute exposure/withdrawal did not elicit persistent adaptations, in agreement with our previous study showing dopamine tissue content is unchanged in the NAc after repeated morphine/ naloxone treatment (McElligott et al, 2013).…”

“…Behavioral correlates of opiate withdrawal were measured during the first 20 min of precipitated withdrawal and assigned a global withdrawal score as described previously and in detail in Supplementary Methods (McElligott et al, 2013). We manually assigned time-stamps to each behavior and looked for the presence or absence of dopamine transients or norepinephrine overflow during the withdrawal signs.…”

“…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).…”

“…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).…”

“…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.…”