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

Abstract

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.

Co‐administration of ethanol and nicotine heightens sensitivity to ethanol reward within the nucleus accumbens (NAc) shell and increasing NAc shell BDNF is sufficient to enhance ethanol reward in naïve Wistar rats

“…These results are consistent with mounting research implicating a role for BDNF in the regulation of drug-related behaviors (Fig. 5;Lu et al 2004;Logrip et al 2009;Vargas-Perez et al 2014;Bobadilla et al 2019;Haun et al 2018).…”

“…Recombinant human BDNF (Sigma-Aldrich, St. Louis, MO, USA) was prepared in aCSF immediately prior to microinfusion. Doses of BDNF were chosen based on previously published reports (Lu et al 2004;Vargas-Perez et al 2014;Bobadilla et al 2019;Haun et al 2018).…”

Cell-Type-Specific Regulation of Nucleus Accumbens Synaptic Plasticity and Cocaine Reward Sensitivity by the Circadian Protein, NPAS2

“…In the NAc, NPAS2 may transcriptionally regulate several key pathways involved in excitatory synaptic homeostasis and plasticity (Ozburn et al, 2015). Our previous findings from NPAS2 ChIP-seq in mouse NAc revealed several strong candidates related to synaptic structure and function, and cocaine reward, including brain derived neurotrophic factor (Bdnf; Graham et al, 2007;Schoenbaum et al, 2007;Heiman et al, 2008;Anderson et al, 2017;Bobadilla et al, 2018), Rho-associated coiled-coilcontaining protein kinase 1 (Rock1; Nakagawa et al, 1996;Henderson et al, 2016), and others which we have recently confirmed, including GABA receptor ␣ 1 (Gabra1; Ozburn et al, 2017). Other intriguing candidates previously linked to cocaine include multiple genes in the nuclear factor -B signaling pathways (Russo et al, 2009).…”

Different doses of methamphetamine alter long-term potentiation, level of BDNF and neuronal apoptosis in the hippocampus of reinstated rats

“…Furthermore, it has been reported that a high concentration of METH reduces hippocampal LTP (maladaptive plasticity) and neurogenesis, and following it there was extended access expression of BDNF in the hippocampus which is necessary for blocking METH-induced neuronal death [66]. However, some research has focused on direct injection of BDNF into brain nuclei and its effects on search behavior [67]. A previous finding showed injection of doses of toxic METH (high dose, probably) facilitated BDNF synthesis or prevention of degradation of BDNF through dopamine and/ or glutamate receptors [68], which appears to be contrary to our result.…”