The effects of BDNF synthesized in NAc neurons can involve either activation of TrkB receptors on NAc neurons or binding to TrkB receptors on dopamine afferents, internalization, and retrograde transport to dopamine cell bodies in the VTA (27
). Conversely, BDNF synthesized in VTA dopamine neurons can be released locally and act reciprocally on TrkB receptors to augment dopamine cell excitability (15
) or undergo anterograde transport and release in the NAc to activate TrkB receptors on NAc neurons (9
). In this study, we found that BDNF derived from either VTA or NAc neurons is important for maintaining initial sensitivity to cocaine reward, as indicated by a loss of cocaine place conditioning with localized BDNF deletion in either region. These findings are consistent with a recent report where BDNF and TrkB levels were modulated by lentiviral infusions in the NAc (29
), but the lentivirus also modulates expression in VTA dopamine neurons by strong retrograde infection (30
), so the effects cannot be localized to the infusion site. Importantly, our findings suggest that BDNF activation of TrkB receptors located specifically on NAc neurons is more important for maintaining sensitivity to cocaine reward than actions at TrkB receptors located on VTA neurons. These results establish a prominent role for TrkB receptors on NAc neurons in cocaine reward, but they do not entirely rule out a role for TrkB on VTA dopamine neurons, since TrkB also was deleted in nondopamine VTA neurons with local infusions.
Localized deletion of TrkB receptors on NAc neurons also led to a downward shift in the cocaine self-administration dose response curve, without producing a generalized impairment in instrumental learning capacity, and directionally opposite to changes that signal a transition to more addicted biological states (31
). This effect is remarkably similar to the effect of localized deletion of BDNF in NAc neurons in our previous study (19
). Together, these results indicate that BDNF induction and release with cocaine use is at least partially derived from local synthesis in NAc neurons (19
) and acts reciprocally on TrkB receptors expressed by NAc neurons to promote cocaine reinforcement and the development of cocaine addiction (present findings). Furthermore, given that chronic cocaine self-administration produced a reinforcement-related up-regulation in TrkB receptors in the NAc shell of rats, this neuroadapatation could facilitate the transition to cocaine addiction by augmenting the response to transient BDNF activity during active cocaine self-administration. However, TrkB mRNA failed to increase in the NAc, potentially reflecting limitations of RT-PCR or that cocaine-induced increases in TrkB protein in the NAc could possibly be derived from cortical or VTA afferent terminals in the NAc. In addition, it is not known whether cocaine self-administration would increase TrkB in the NAc shell of mice where TrkB was shown to modulate cocaine self-administration.
Interestingly, passive yoked but not self-administered cocaine increased TrkB in the VTA, even with a single acute 4-hour exposure. This increase in TrkB protein was also not accompanied by increases in TrkB mRNA and potentially emanates from afferent inputs as discussed above. Otherwise, TrkB could increase via nontranscriptional mechanisms including increased translation, protein stability, or reduced degradation in VTA (or NAc shell) neurons. Increased TrkB in the VTA of yoked animals potentially results from the stressful effects of uncontrollable intravenous cocaine injections and highlights the fact that self-administered cocaine often produces different neurobiological changes than experimenter-administered cocaine treatment regimens. Along these lines, chronic social defeat stress is mediated, in part, by BDNF expressed in VTA, but not NAc, neurons (14
). In addition, TrkB up-regulation with yoked cocaine could explain the failure of TrkB knockdown in the VTA to reduce cocaine reward with similar passive cocaine administration in place-conditioning tests. Thus, TrkB up-regulation in non-AAV-infected VTA neurons potentially could counteract the effects of genetic deletion in AAV-infected neurons. Given the fact that local BDNF activation of TrkB receptors potentiates VTA dopamine cell excitability in cocaine withdrawal (15
) and midbrain infusions of BDNF enhance forebrain dopamine release (32
), further experimentation, perhaps employing gain of TrkB function approaches, is needed before the role of TrkB in the VTA in cocaine reward can be ruled out.
Our findings support the notion that therapeutic strategies aimed at neutralizing BDNF-TrkB receptor signaling in the NAc may have utility when given during active cocaine self-administration as suggested previously (19
). These data also suggest that reduced vulnerability to drug abuse in people with a single nucleotide valine 66/methionine (met) polymorphism in the BDNF gene may be related to impairments in BDNF release (33
). Thus, we recently reported that BDNF met66 mice show reduced activity-dependent BDNF signaling within the VTA-NAc circuit (14
), which may result in an attenuated ability of drugs to induce addiction-promoting pathological changes in the NAc. Given that TrkB receptors activate multiple signaling cascades with differential modulation of neuroplasticity and cellular morphology (35
), future studies should identify which of these events contribute to escalation of cocaine intake and a propensity for relapse induced by local BDNF-TrkB activation in NAc neurons.