Opiate dependence induces cell type-specific plasticity of intrinsic membrane properties in the rat juxtacapsular bed nucleus of stria terminalis (jcBNST)

Abstract

RATIONALE Drugs of abuse can alter circuit dynamics by modifying synaptic efficacy and/or the intrinsic membrane properties of neurons. The juxtacapsular subdivision of the bed nucleus of stria terminalis (jcBNST) has unique connectivity that positions it to integrate cortical and amygdala inputs and provide feed-forward inhibition to the central nucleus of the amygdala (CeA), among other regions. In this study, we investigated changes in the synaptic and intrinsic properties of neurons in the rat jcBNST during protracted withdrawal from morphine dependence using a combination of conventional electrophysiological methods and the dynamic clamp technique. RESULTS A history of opiate dependence induced a form of cell-type specific plasticity characterized by reduced inward rectification associated with more depolarized resting membrane potentials and increased membrane resistance. This cell type also showed a lower rheobase when stimulated with direct current (DC) pulses as well as a decreased firing threshold under simulated synaptic bombardment with the dynamic clamp. Morphine dependence also decreased excitatory postsynaptic potential amplification, suggesting the downregulation of the persistent Na+-current (INaP). CONCLUSION These findings show that a history of morphine dependence leads to persistent cell type-specific plasticity of the passive membrane properties of a jcBNST neuronal population, leading to an overall increased excitability of such neurons. By altering the activity of extended amygdala circuits where they are embedded, changes in the integration properties of jcBNST neurons may contribute to emotional dysregulation associated with drug dependence and withdrawal.

An extended amygdala-midbrain circuit controlling cocaine withdrawal-induced anxiety and reinstatement

“…These are consistent with our results showing an elevated activity of BNST neuron activity. Opioid dependence, as elicited through chronic implant of a morphine pellet, also induces long-term potentiation (LTP) onto different populations of BNST cells ( Dumont et al, 2008 ; Francesconi et al, 2017 ), suggesting that plasticity onto BNST cell synapses may be a common feature of drugs of abuse, also consistent with our results. CRF may play a key role in this process because it increases the frequency of excitatory glutamatergic post-synaptic currents onto BNST cells that project to the VTA, a process occluded by ethanol withdrawal ( Silberman et al, 2013 ).…”

Gene coexpression patterns predict opiate-induced brain-state transitions

“…Pathway analysis revealed that genes implicated in synaptic long-term potentiation, synaptogenesis, and reelin signaling were among the most significantly associated with increased FOS correlation networks following chronic opiate exposure ( Table 1 ). Many drugs of abuse, including opioids, induce synaptic plasticity, suggesting that this type of neuroadaptation may be a common mechanism underlying the development of substance use disorders ( 29 – 31 ). Moreover, polymorphisms in genes associated with synaptic plasticity have been associated with vulnerability to drug addiction ( 32 , 33 ).…”

Cues conditioned to withdrawal and negative reinforcement: Neglected but key motivational elements driving opioid addiction

“…The BNST has been implicated in opioid withdrawal, drug-induced negative affect (114)(115)(116)(117), and the stress-induced reinstatement of drug seeking (118). BNST neurons are recruited during withdrawal to signal stress/aversion (119), measured by heightened Fos expression (120)(121)(122) and alterations of neuronal excitability during chronic exposure to and withdrawal from opioids (123)(124)(125). Opioid withdrawal-induced Fos immunoreactivity in the extended amygdala parallels the development of opioid-induced place aversion (122).…”