The Neurobiology of Addiction Research Center (NARC)
Project 2 - BDNF Prevents Cocaine Abstinence-Induced Neuroadaptations
Principle Investigator: Jacqueline McGinty, Ph.D.
In this project, we are investigating the neurobiological mechanisms underlying the ability of BDNF/TrkB stimulation in the prelimbic cortex (PLC) during early withdrawal from cocaine self-administration to suppress persistent cocaine-seeking and the underlying neuroadaptations. We have demonstrated that BDNF infusion into the PLC of rats immediately after the last cocaine self-administration session suppresses conditioned cue-induced or drug-primed cocaine-seeking after forced abstinence or extinction. Such a single intra-PLC BDNF infusion during early withdrawal normalized basal, and prevented a cocaine prime-induced increase in, extracellular glutamate levels in the NAc three weeks later. Further, local inhibition of the ERK MAP kinase cascade blocked the ability of intra-PLC BDNF to suppress cocaine-seeking. The latter study also demonstrated that BDNF infusion immediately after the last cocaine SA exposure reversed a marked cocaine-induced dephosphorylation of ERK and CREB in the PLC 2 hr later. In contrast, after 7 days of forced abstinence, phospho-ERK is normal but phospho-CREB and phospho-Ser845-GluR1 in the PLC are elevated in a PKA-dependent manner. Thus, BDNF-induced reversal of cocaine-induced ERK dephosphorylation (or ERK “shutoff”) in the PLC during early withdrawal appears to be a critical step in restoring homeostatic regulation of the PFC-accumbens pathway that leads to lasting suppression of cocaine-seeking. Recent data implicate a reduction in GluN2B receptors and increased activation of the striatal-enriched tyrosine phosphatase (STEP) in cocaine self-administration-induced ERK dephosphorylation in the PLC during early withdrawal. The role of synaptic activity and kinase-phosphatase balance in the ability of intra-PFC BDNF to normalize ERK phosphorylation in PLC during early withdrawal and suppress cocaine-seeking in rats with a cocaine SA history is under investigation.