ReviewCocaine self-administration causes signaling deficits in corticostriatal circuitry that are reversed by BDNF in early withdrawal

- Cocaine induces signaling deficits in corticostriatal circuitry during early withdrawal.
- STEP is implicated in cocaine-induced dephosphorylation in the prefrontal cortex.
- BDNF restores phosphorylation in the prefrontal cortex and nucleus accumbens.
- Cocaine induces PKA-dependent signaling in corticostriatal circuitry that is reversed by relapse after one week of abstinence.

Cocaine self-administration disturbs intracellular signaling in prefrontal cortical neurons that regulate neurotransmission in the nucleus accumbens. The deficits in dorsomedial prefrontal cortex (dmPFC) signaling change over time, resulting in different neuroadaptations during early withdrawal from cocaine self-administration than after one or more weeks of abstinence. Within the first few hours of withdrawal, there is a marked decrease in tyrosine phosphorylation of critical intracellular and membrane-bound proteins in the dmPFC that include ERK/MAP kinase and the NMDA receptor subunits, GluN1 and GluN2B. These changes are accompanied by a marked increase in STEP tyrosine phosphatase activation. Simultaneously, ERK and PKA-dependent synapsin phosphorylation in presynaptic terminals of the nucleus accumbens is increased that may have a destabilizing impact on glutamatergic transmission. Infusion of brain-derived neurotrophic factor (BDNF) into the dmPFC immediately following a final session of cocaine self-administration blocks the cocaine-induced changes in phosphorylation and attenuates relapse to cocaine seeking for as long as three weeks. The intra-dmPFC BDNF infusion also prevents cocaine-induced deficits in prefronto-accumbens glutamatergic transmission that are implicated in cocaine seeking. Thus, intervention with BDNF in the dmPFC during early withdrawal has local and distal effects in target areas that are critical to mediating cocaine-induced neuroadaptations that lead to cocaine seeking.This article is part of a Special Issue entitled SI:Addiction circuits.