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Objectives: Long-term abstinence following cocaine exposure up-regulates brain-derived neurotrophic factor (BDNF) expression in the mesocorticolimbic pathway. Given the increased vulnerability to drug abuse typical of adolescence, we hypothesized that changes in BDNF expression may become manifest early after the end of cocaine treatment in the adolescent brain. Methods: Rats received cocaine injections from postnatal day 28 (PND28) to PND42 and the mesocorticolimbic expression of BDNF was measured by real-time PCR and Western blotting at PND43. Results: In the ventral tegmental area, BDNF-tropomyosin receptor kinase B (TrΚB) expression and phosphorylation are enhanced while the intracellular signaling is unaltered. In the nucleus accumbens (NAc) shell and core, BDNF and its signaling were down-regulated. In the prelimbic (PL) cortex, we found reduced BDNF expression and increased phosphoprylation of TrΚB, ERK and AKT. In the infralimbic (IL) cortex, increased BDNF expression was coupled with reduced activity and expression of its downstream targets. To evaluate the role of glutamate on BDNF-independent changes, we investigated the expression of the transporter GLT-1 and the activation of the NMDA receptor subunit GluN2B, which were both increased in the PL cortex while reduced in the IL cortex. Conclusions: Our results show that adolescent cocaine exposure modulates BDNF system early after treatment in the mesocorticolimbic pathway, identifying a complex but specific set of changes that could provide clues for treatment.

A single BDNF microinfusion into prelimbic (PrL) cortex immediately after the last cocaine self-administration session decreases relapse to cocaine-seeking. The BDNF effect is blocked by NMDAR antagonists. To determine whether synaptic activity in putative excitatory projection neurons in PrL cortex is sufficient for BDNF's effect on relapse, the PrL cortex of male rats was infused with an inhibitory Designer Receptor Exclusively Activated by Designer Drugs (DREADD) viral vector driven by an αCaMKII promoter. Immediately after the last cocaine self-administration session, rats were injected with clozapine-N-oxide 30 min before an intra-PrL BDNF microinfusion. DREADD-mediated inhibition of the PrL cortex blocked the BDNF-induced decrease in cocaine-seeking after abstinence and cue-induced reinstatement after extinction. Unexpectedly, DREADD inhibition of PrL neurons in PBS-infused rats also reduced cocaine-seeking, suggesting that divergent PrL pathways affect relapse. Next, using a cre-dependent retroviral approach, we tested the ability of DREADD inhibition of PrL projections to the NAc core or the paraventricular thalamic nucleus (PVT) to alter cocaine-seeking in BDNF- and PBS-infused rats. Selective inhibition of the PrL-NAc pathway at the end of cocaine self-administration blocked the BDNF-induced decrease in cocaine-seeking but had no effect in PBS-infused rats. In contrast, selective inhibition of the PrL-PVT pathway in PBS-infused rats decreased cocaine-seeking, and this effect was prevented in BDNF-infused rats. Thus, activity in the PrL-NAc pathway is responsible for the therapeutic effect of BDNF on cocaine-seeking whereas inhibition of activity in the PrL-pPVT pathway elicits a similar therapeutic effect in the absence of BDNF. SIGNIFICANCE STATEMENT The major issue in cocaine addiction is the high rate of relapse. However, the neuronal pathways governing relapse remain unclear. Using a pathway-specific chemogenetic approach, we found that BDNF differentially regulates two key prelimbic pathways to guide long-term relapse. Infusion of BDNF in the prelimbic cortex during early withdrawal from cocaine self-administration decreases relapse that is prevented when neurons projecting from the prelimbic cortex to the nucleus accumbens core are inhibited. In contrast, BDNF restores relapse when neurons projecting from the prelimbic cortex to the posterior paraventricular thalamic nucleus are inhibited. This study demonstrates that two divergent cortical outputs mediate relapse that is regulated in opposite directions by infusing BDNF in the prelimbic cortex during early withdrawal from cocaine., (Copyright © 2018 the authors 0270-6474/18/388956-11$15.00/0.)

Rationale: Although brain-derived neurotrophic factor (BDNF) is part of a homeostatic pathway involved in the development of alcohol dependence, it is not clear whether this is also true after recreational ethanol consumption., Objectives: We examined BDNF expression and signaling in the cortico-striatal network immediately and 24 h after either a single intravenous (i.v.) ethanol operant self-administration session or the last of 14 sessions., Methods: To compare contingent and non-contingent ethanol exposure, we incorporated the "yoked control-operant paradigm" in which rats actively taking ethanol (S-Et) were paired with two yoked controls receiving passive infusions of ethanol (Y-Et) or saline., Results: A single ethanol exposure transiently reduced BDNF mRNA levels in the medial prefrontal cortex (mPFC) of Y-Et. Immediately after the last of 14 sessions, mRNA and mature BDNF protein levels (mBDNF) were reduced in the mPFC in both S-Et and Y-Et while mBDNF expression was raised in the nucleus accumbens (NAc), suggesting enhanced anterograde transport from the mPFC. Conversely, 24 h later mBDNF expression and signaling were raised in the mPFC and NAc of S-Et rats but reduced in the NAc of Y-Et rats, with concomitant reduction of downstream signaling pathways., Conclusions: Our findings indicate that recreational-like i.v. doses of ethanol promote early changes in neurotrophin expression, depending on the length and modality of administration, the brain region investigated, and the presence of the drug. A rapid intervention targeting the BDNF system might be useful to prevent escalation to alcohol abuse.

Ketamine is a drug of abuse with a unique profile, which besides its inherent mechanism of action as a non-competitive antagonist of the NMDA glutamate receptor, displays both antidepressant and reinforcing properties. The major aim of our study was to find a molecular signature of ketamine that may help in discriminating between its reinforcing and antidepressant effects. To this end, we focused our attention on BDNF, a neurotrophin that has been shown to play a role in both antidepressant and reinforcing properties of several drugs. Rats were exposed to self-administer intravenous (IV) ketamine (S/A) for 43 days or to receive a single IV ketamine 0.5mg/kg, or vehicle infusion. Although the dose we employed is lower than that reported by the literature, it however yields Cmax values that correspond to those achieved in humans after antidepressant treatment. Our results show that while the single infusion of ketamine increased the neurotrophin expression in the hippocampus while reducing it in the ventral striatum, a feature shared with other antidepressants, the repeated self-administration reduced mBDNF expression and its downstream signalling in both ventral striatum and hippocampus. Further, we here show that phosphorylation of Akt is oppositely regulated by ketamine, pointing to this pathway as central to the different actions of the drug. Taken together, we here point to BDNF and its downstream signalling pathway as a finely tuned mechanism whose modulation might subserve the different features of ketamine., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Although evidence exists that chronic cocaine exposure during adulthood is associated with changes in BDNF expression, whether and how cocaine exposure during adolescence modulates BDNF is still unknown. To address this issue, we exposed rats to repeated cocaine injections from post-natal day (PD) 28 to PD 42, a period that roughly approximates adolescence in humans, and we carried out a detailed analysis of the BDNF system in the medial prefrontal cortex (mPFC) of rats sacrificed 3 d (PD 45) and 48 d (PD 90) after the last cocaine treatment. We found that developmental exposure to cocaine altered transcriptional and translational mechanisms governing neurotrophin expression. Total BDNF mRNA levels, in fact, were enhanced in the mPFC of PD 90 rats exposed to cocaine in adolescence, an effect sustained by changes in BDNF exon IV through the transcription factors CaRF and NF-kB. While a profound reduction of specific BDNF-related miRNAs (let7d, miR124 and miR132) may contribute to explaining the increased proBDNF levels, the up-regulation of the extracellular proteases tPA is indicative of increased processing leading to higher levels of released mBDNF. These changes were associated with increased activation of the trkB-Akt pathway resulting in enhanced pmTOR and pS6 kinase, which ultimately produced an up-regulation of Arc and a consequent reduction of GluA1 expression in the mPFC of PD 90 cocaine-treated rats. These findings demonstrate that developmental exposure to cocaine dynamically dysregulates BDNF and its signaling network in the mPFC of adult rats, providing novel mechanisms that may contribute to cocaine-induced changes in synaptic plasticity.

Brain-derived neurotrophic factor (BDNF) dynamic changes were investigated in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) during use and the early phases of cocaine abstinence after 14 sessions (2 h self-administration/d; 0.25 mg/0.1 ml.6 s infusion) by employing a 'yoked control-operant paradigm'. The effect on BDNF was region-specific and dependent on the withdrawal time. In the NAc, BDNF protein levels increased immediately after the last self-administration session, with a larger increase in passively cocaine-exposed rats. In the mPFC, BDNF expression was elevated 24 h after the last self-administration session, independently of how the drug was encountered. No changes were found in NAc and mPFC 7 d after the last self-administration session. Analysis of transcript levels in the mPFC indicated that action on exon I might contribute to BDNF's cortical induction. These findings indicate a finely tuned modulation of BDNF expression during use and early phases of cocaine abstinence.