Molecular and Synaptic Mechanisms of BDNF in Reversing Cocaine Induced Deficits in the dmPFC During Early Abstinence

Medical University Of South Carolina, Charleston SC

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Abstract

? DESCRIPTION (provided by applicant): Cocaine addiction and relapse to drug use remain an important public health issue. Following acquisition of drug use, persistent neuroadaptations occur in mesocorticolimbic circuits that facilitate compulsive drug seeking. For this reason, the most viable therapeutic targets are those that normalize drug-induced neuroadaptations in these circuits to prevent relapse to drug use. The glutamatergic projection neurons from the dorsal medial prefrontal cortex (dmPFC) to the nucleus accumbens core are specifically implicated in reinstatement to drug seeking in preclinical models. We have shown that a single infusion of brain derived neurotrophic factor (BDNF) into the dmPFC during early abstinence from cocaine self-administration results in attenuation of context, cue, and cocaine prime-induced drug seeking up to three weeks post-BDNF infusion. The attenuating effects of this BDNF infusion are contingent upon normalization of p-ERK and p-CREB levels in the dmPFC and require both NMDA activation and TrkB (BDNF's receptor) activation in the dmPFC. This proposal will focus on delineating the neural mechanisms underlying the need for dual activation of TrkB and NMDA receptors following this single BDNF infusion. A potential link between TrkB and NMDA receptors is Src family kinases (SFKs), which phosphorylate and are activated by TrkB. SFKs also phosphorylate NMDA receptor subunits to enhance glutamatergic signaling. My Aims will test the hypothesis that both SFKs and synaptic activity are necessary for BDNF's long-term normalization effects following cocaine self- administration. Aim 1 will test whether a member of the SFK family, Fyn, is the potential mediator of the crosstalk between NMDA receptors and TrkB receptors following exogenous BDNF mediated TrkB activation. Aim 2 will determine if inactivation of glutamatergic pyramidal neurons in the dmPFC immediately before a BDNF infusion will suppress BDNF's long term attenuating effects on cocaine seeking by preventing normalization of phosphoprotein signaling during early abstinence from cocaine seeking.