BDNF as a therapeutic candidate for cocaine use disorders.

Cocaine self-administration disturbs intracellular signaling in multiple reward circuitry neurons that underlie relapse to drug seeking. Cocaine-induced deficits in prelimbic (PL) prefrontal cortex change during abstinence, resulting in different neuroadaptations during early withdrawal from cocaine self-administration than after one or more weeks of abstinence. Infusion of brain-derived neurotrophic factor (BDNF) into the PL cortex immediately following a final session of cocaine self-administration attenuates relapse to cocaine seeking for an extended period. BDNF affects local (PL) and distal subcortical target areas that mediate cocaine-induced neuroadaptations that lead to cocaine seeking. Blocking synaptic activity selectively in the PL projection to the nucleus accumbens during early withdrawal prevents BDNF from decreasing subsequent relapse. In contrast, blocking synaptic activity selectively in the PL projection to the paraventricular thalamic nucleus by itself decreases subsequent relapse and prior intra-PL BDNF infusion prevents the decrease. Infusion of BDNF into other brain structures at different timepoints after cocaine self administration differentially alters cocaine seeking. Thus, the effects of BDNF on drug seeking are different depending on the brain region, the timepoint of intervention, and the specific pathway that is affected.