Accumbens brain-derived neurotrophic factor (BDNF) transmission inhibits cocaine seeking.

Brain-derived neurotrophic factor (BDNF) regulates a variety of physiological processes, and several studies have explored the role of BDNF in addiction-related brain regions like the nucleus accumbens core (NAcore). We sought to understand the rapid effects of endogenous BDNF on cocaine seeking. Rats were trained to self-administer cocaine and extinguished. We then microinjected two inhibitors of BDNF stimulation of tropomyosin receptor kinase B (TrkB), the non-competitive receptor antagonist ANA-12 and TrkB/Fc, a fusion protein that binds BDNF and prevents TrkB stimulation. Blocking TrkB or inactivating BDNF in NAcore potentiated active lever pressing, showing that endogenous BDNF tone was present and supplying inhibitory tone on cue-induced reinstatement. To determine if exogenous BDNF also negatively regulated reinstatement, BDNF was microinjected into NAcore 15 minutes before cue-induced reinstatement. BDNF decreased cocaine seeking through TrkB receptor binding, but had no effect on inactive lever pressing, spontaneous or cocaine-induced locomotion, or on reinstated sucrose seeking. BDNF-infusion potentiated within trial extinction when microinjected in the NAcore during cue- and context + cue induced reinstatement, and the inhibition of lever pressing lasted at least 3 days post injection. Although decreased reinstatement endured for 3 days when BDNF was administered prior to a reinstatement session, when microinjected before an extinction session or in the home cage, BDNF did not alter subsequent cued-reinstatement. Together, these data show that endogenous BDNF acts on TrKB to provide inhibitory tone on reinstated cocaine seeking, and this effect was recapitulated by exogenous BDNF.

Accumbens Mechanisms for Cued Sucrose Seeking.

Many studies support a perspective that addictive drugs usurp brain circuits used by natural rewards, especially for the dopamine-dependent reinforcing qualities of both drugs and natural rewards. Reinstated drug seeking in animal models of relapse relies on glutamate spillover from cortical terminals synapsing in the nucleus accumbens core (NAcore) to stimulate metabotropic glutamate receptor5 (mGluR5) on neuronal nitric oxide synthase (nNOS) interneurons. Contrasting the release of dopamine that is shared by sucrose and drugs of abuse, reinstated sucrose seeking does not induce glutamate spillover. We hypothesized that pharmacologically promoting glutamate spillover in the NAcore would mimic cocaine-induced adaptations and potentiate cued reinstatement of sucrose seeking. Inducing glutamate spillover by blocking astroglial glutamate transporters (GLT-1) had no effect on reinstated sucrose seeking. However, glutamate release probability is negatively regulated by presynaptic mGluR2/3, and sucrose reinstatement was potentiated following mGluR2/3 blockade. Potentiated sucrose reinstatement by mGluR2/3 blockade was reversed by antagonizing mGluR5, but reinstated sucrose seeking in the absence of mGluR2/3 blockade was not affected by blocking mGluR5. In cocaine-trained rodents mGluR5 stimulation reinstates drug seeking by activating nNOS, but activating mGluR5 did not promote reinstated sucrose seeking, nor was potentiated reinstatement after mGluR2/3 blockade reduced by blocking nNOS. However, chemogenetic activation of nNOS interneurons in the NAcore reinstated sucrose seeking. These data indicate that dysregulated presynaptic mGluR2/3 signaling is a possible site of shared signaling in drug seeking and potentiated reinstated sucrose seeking, but that downregulated glutamate transport and subsequent activation of nNOS by synaptic glutamate spillover is not shared.