The bed nucleus of the stria terminalis (BNST) is a crucial component of the extended amygdala circuitry that has been implicated in the long-lasting dysregulations of the brain stress and reward systems that are induced by drugs of abuse and are believed to play a motivational role in continued drug use. The lateral subdivision of the BNST, which receives ample innervation from the amygdala, is involved in stress responses and in the long-lasting motivational dysregulation associated with drug dependence. High frequency stimulation (HFS) of the area of the stria terminalis in brain slices induces a strong N-Methyl-D-Aspartate (NMDA)-type glutamate receptors-dependent long term potentiation (LTP) of field potential in the dorso-lateral BNST. Rats with a history of ethanol dependence did not show LTP in the dorso-lateral BNST during protracted withdrawal despite normal basal synaptic responses. We have observed that the induction of LTP in the dorso-lateral BNST was impaired during protracted abstinence in alcohol self-administering rats with a history of alcohol dependence and in cocaine self-administering rats with a history of escalated cocaine intake. A less pronounced impairment in the capacity for LTP induction was seen in rats that with a history of stable (non-escalated) self-administration of alcohol or cocaine. These observations of a common dysregulation during protracted abstinence from either alcohol or cocaine intake suggests that synaptic plasticity in the lateral BNST may be key to regulating drug intake in post-dependent individuals. We now propose to extend these studies to define the time-dependence of this phenomenon and to determine whether the same dysregulation of synaptic plasticity can also be demonstrated in the lateral BNST of opiate-dependent rats. The present exploratory proposal from a new investigator will lay the foundations for the systematic investigation of the role of BNST synaptic plasticity in the maladaptive neurobiological events that are believed to be behind the development of compulsive drug intake and vulnerability to relapse.
