Tropomyosin-Related Kinase B in the Mesolimbic Dopamine System: Region-Specific Effects on Cocaine Reward

Abstract

Background Previous studies found that brain-derived neurotrophic factor (BDNF) derived from nucleus accumbens (NAc) neurons can mediate persistent behavioral changes that contribute to cocaine addiction. Methods To further investigate BDNF signaling in the mesolimbic dopamine system, we analyzed tropomyosin-related kinase B (TrkB) messenger RNA (mRNA) and protein changes in the NAc and ventral tegmental area (VTA) in rats following 3 weeks of cocaine self-administration. To study the role of BDNF-TrkB activity in the VTA and NAc in cocaine reward, we used localized viral-mediated Cre recombinase expression in floxed BDNF and floxed TrkB mice to knockdown BDNF or TrkB in the VTA and NAc in cocaine place conditioning tests and TrkB in the NAc in cocaine self-administration tests. Results We found that 3 weeks of active cocaine self-administration significantly increased TrkB protein levels in the NAc shell, while yoked (passive) cocaine exposure produced a similar increase in the VTA. Localized BDNF knockdown in either region reduced cocaine reward in place conditioning, whereas only TrkB knockdown in the NAc reduced cocaine reward. In mice self-administering cocaine, TrkB knockdown in the NAc produced a downward shift in the cocaine self-administration dose-response curve but had no effect on the acquisition of cocaine or sucrose self-administration. Conclusions Together, these data suggest that BDNF synthesized in either VTA or NAc neurons is important for maintaining sensitivity to cocaine reward but only BDNF activation of TrkB receptors in the NAc mediates this effect. In addition, up-regulation of NAc TrkB with chronic cocaine use could promote the transition to more addicted biological states.

Loss of BDNF Signaling in D1R-Expressing NAc Neurons Enhances Morphine Reward by Reducing GABA Inhibition

“…A role for BDNF-TrkB signaling in NAc in enhancing the behavioral effects of cocaine is well established (Graham et al, 2007;Graham et al, 2009;Horger et al, 1999). By contrast, less is known about the influence of BDNF-TrkB signaling in NAc on morphine action.…”

“…Brain-derived neurotrophic factor-tyrosine receptor kinase B (BDNF-TrkB) signaling in NAc is also important in the actions of drugs of abuse (Graham et al, 2007;Graham et al, 2009;Horger et al, 1999;Pickens et al, 2011;Russo et al, 2009). Interestingly, BDNF-TrkB signaling modulates the function of GABA A receptors (GABA A Rs) in other brain regions.…”

Ablation of Kappa-Opioid Receptors from Brain Dopamine Neurons has Anxiolytic-Like Effects and Enhances Cocaine-Induced Plasticity

“…Use of these mice would provide deeper insight on the development of long-term compensatory mechanisms that affect the phenotypes of the mutants. Similarly, viral vectors expressing Cre could be micro-infused into discrete brain areas (Berton et al, 2006;Graham et al, 2009), enabling an alternative method with which to accomplish time-and tissue-selective gene ablation. Viral vectors expressing KORs could also be used in the KOR À / À mice to 'rescue' behavioral phenotypes or reestablish sensitivity to drugs that act at KORs.…”

microRNA-Seq reveals cocaine-regulated expression of striatal microRNAs

“…Nonetheless, we confirmed changes in protein levels for three predicted targets (TRKB, MTDH, and PC2) and one indirect target (ECAD) upon exposure to cocaine. One of the validated targets, TRKB (NTRK2), has also been shown to increase in the NAc of rats after chronic cocaine self-administration (Graham et al 2009), and TRKB-BDNF signaling in the NAc may modulate behavioral responses to cocaine (Lobo et al 2010). Importantly, several other predicted targets have been implicated in various aspects of the cocaine response (Przew1ocka and Lasoń 1995;Hemby et al 2005;Hubert et al 2008).…”