Intrinsic neuronal plasticity in the juxtacapsular nucleus of the bed nuclei of the stria terminalis (jcBNST)

Abstract

The juxtacapsular nucleus of the anterior division of the BNST (jcBNST) receives robust glutamatergic projections from the basolateral nucleus of the amygdala (BLA), the postpiriform transition area, and the insular cortex as well as dopamine (DA) inputs from the midbrain. In turn the jcBNST sends GABAergic projections to the medial division of the central nucleus of the amygdala (CEAm) as well as other brain regions. We recently described a form of long-term potentiation of the intrinsic excitability (LTP-IE) of neurons of the juxtacapsular nucleus of BNST (jcBNST) in response to high-frequency stimulation (HFS) of the stria terminalis that was impaired during protracted withdrawal from alcohol, cocaine, and heroin and in rats chronically treated with corticotropin-releasing factor (CRF) intracerebroventricularly. Here we show that DAergic neurotransmission is required for the induction of LTP-IE of jcBNST neurons through dopamine (DA) D1 receptors. Thus, activation of the central CRF stress system and altered DAergic neurotransmission during protracted withdrawal from alcohol and drugs of abuse may contribute to the disruption of LTP-IE in the jcBNST. Impairment of this form of intrinsic neuronal plasticity in the jcBNST could result in inadequate neuronal integration and reduced inhibition of the CEA, contributing to the negative affective state that characterizes protracted abstinence in post-dependent individuals. These results provide a novel neurobiological target for vulnerability to alcohol and drug dependence.

Fig. 1

A) Extracellular recordings from the jcBNST in coronal brain slices of Wistar rats. Field potential recordings were carried out from the jcBNST in acute brain slices as previously described (Francesconi et al., 2009) and as shown in Fig. 1A. st: stria terminalis; jcBNST: juxtacapsular bed nucleus of the stria terminalis (shown in yellow); BNSTdl: dorsolateral bed nucleus of the stria terminalis; BNSTdm: dorsomedial bed nucleus of the stria terminalis; BNSTv: ventral bed nucleus of the stria terminalis; ac: anterior commissure; LV: lateral ventricle; ic: internal capsule. Modified from Paxinos and Watson (Paxinos and Watson, 1998). B) The D1-class receptors antagonist SCH23390 impairs LTP-IE in the jcBNST when applied during the induction paradigm. Field potential amplitude of slices that received a 30 min application (horizontal bar) of SCH23390 (2μM; open squares; n= 7) during delivery of HFS to the stria terminalis impairs LTP-IE induction. Field potential amplitude of control slices that received the same tetanization paradigm are shown (n = 7, filled squares). Application of the D2 receptor blocker sulpiride (50μM; n= 5) did not block the induction of LTP-IE (**SCH23390 different from Control and Sulpiride, p<0.01). C) Catecholamine depletion decreases LTP-IE in the jcBNST. Rats were treated with reserpine (5 mg/kg i.p.) 6 h before sacrifice to deplete endogenous catecholamines or vehicle. Comparison of LTP-IE in control (n= 7, filled square) and depleted (n= 4, open circle) jcBNST slices showed a decrease of the magnitude of LTP-IE after catecholamine depletion (**=p<0.01). D) The D1-class agonist SKF81297 substantially restores LTP-IE in catecholamine depleted slices. The D1 agonist SKF81297 (10 μM), applied 15 min before HFS for 30 min, facilitated LTP-IE induction in depleted slices (n=4, filled triangle). LTP-IE in depleted slices is shown for comparison (n=4, open circle) (*=p<0.05-0.01).

Fig. 2. Loss of jcBNST intrinsic neuronal plasticity could contribute to the negative affective state that characterizes protracted abstinence in postdependent individuals

A) The jcBNST receives a glutamatergic input from the posterior BLA (BLAp) and the amygdalopiriform transition area (APir) through the stria terminalis, interoceptic sensory information from the insular cortex and dopaminergic afferences from the midbrain. The jcBNST provides GABAergic outputs to the anterior BLA (BLAa) and to the medial central nucleus of the amygdala (CEAm). The activity-dependent plasticity described here could allow the jcBNST to increase its ensemble activity at times of greater stimulation. Outputs of the CEA are key to emotional arousal by acting on targets that include the lateral hypothalamic area (LH) and the paraventricular nucleus (PVN) of the hypothalamus, among others. Arrowheads in the diagram indicate activation, while T bars indicate inhibition. B) Animals with histories of dependent drug use showed impaired plasticity of neuronal excitability and temporal fidelity possibly brought about by increased BLA activation, increase CRF during protracted withdrawal and altered dopaminergic (DA) neurotransmission (see text). Loss of the ability of the jcBNST to plastically increase its output may therefore result in a reduced GABAergic inhibition to the amygdala, which is likely to be anxiogenic. Thus, impaired plasticity of the jcBNST in animals with a history of dependent drug intake could contribute to the negative affective state that is experienced during abstinence in human addicts and that is key to their vulnerability to relapse. An alternative hypothesis is discussed in the text.