Protracted Withdrawal from Alcohol and Drugs of Abuse Impairs Long-Term Potentiation of Intrinsic Excitability in the Juxtacapsular Bed Nucleus of the Stria Terminalis

Abstract

The juxtacapsular bed nucleus of the stria terminalis (jcBNST) is activated in response to basolateral amygdala (BLA) inputs through the stria terminalis and projects back to the anterior BLA and to the central nucleus of the amygdala. Here we show a form of long-term potentiation of the intrinsic excitability (LTP-IE) of jcBNST neurons in response to high-frequency stimulation of the stria terminalis. This LTP-IE, which was characterized by a decrease in the firing threshold and increased temporal fidelity of firing, was impaired during protracted withdrawal from self-administration of alcohol, cocaine, and heroin. Such impairment was graded and was more pronounced in rats that self-administered amounts of the drugs sufficient to maintain dependence. Dysregulation of the corticotropin-releasing factor (CRF) system has been implicated in manifestation of protracted withdrawal from dependent drug use. Administration of the selective corticotropin-releasing factor receptor 1 (CRF 1 ) antagonist R121919 [2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-a]pyrimidine)], but not of the CRF 2 antagonist astressin 2 -B, normalized jcBNST LTP-IE in animals with a history of alcohol dependence; repeated, but not acute, administration of CRF itself produced a decreased jcBNST LTP-IE. Thus, changes in the intrinsic properties of jcBNST neurons mediated by chronic activation of the CRF system may contribute to the persistent emotional dysregulation associated with protracted withdrawal.

GluN2B subunit deletion reveals key role in acute and chronic ethanol sensitivity of glutamate synapses in bed nucleus of the stria terminalis

“…First, the reduction of GluN2B achieved in the studies by Brigman et al (7) and von Engelhardt et al (42) was more modest than that achieved within dlBNST in the present breeding strategy. Second, previous studies in the juxtacapsular nucleus of the BNST have emphasized that LTP observed using field potential recordings of this portion of the BNST represents cellular, rather than synaptic, plasticity, which may require fundamentally distinct mechanisms (26). Although this cannot be ruled out as a possibility, at present, our recordings are medial to the juxtacapsular nucleus, which is an extremely narrow nucleus (∼75 μM in width) adjacent to the striatum.…”

“…In the BNST, ethanol dose-dependently inhibits NMDARs, and this effect is attenuated with a GluN2B antagonist (24,25). More chronic ethanol treatments have been shown to alter NMDAR expression, signaling, and plasticity during withdrawal (26,27) in portions of the BNST. Indeed, in many brain regions, withdrawal from chronic ethanol increases GluN2B expression (28)(29)(30)(31)(32)(33).…”

Distinct forms of G q -receptor-dependent plasticity of excitatory transmission in the BNST are differentially affected by stress

“…In addition, CRF administration within the BNST can potentiate anxiety (44). Moreover, animals experiencing protracted withdrawal from alcohol have altered CRF tone in a component of the dlBNST, which leads to decreased plasticity of the intrinsic excitability of these neurons (46). Heightened adrenergic tone may be one mechanism by which the CRF system is dysregulated in these dependent animals.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Also the BNST has a rich expression of CRF, and the region is well connected with many brain regions, including the midbrain DA neurons and the CeA. In the juxtacapsular nucleus of the anterior BNST, a form of LTP in response to HFS of the stria terminalis was impaired during withdrawal from chronic ethanol, and this impairment was reversed by CRF 1 receptor antagonism (Francesconi et al, 2009). Therefore, also the BNST CRF system may undergo persistent changes during development of ethanol dependence.…”