Role of accumbens BDNF and TrkB in cocaine-induced psychomotor sensitization, conditioned-place preference, and reinstatement in rats

Abstract

Background Brain-derived neurotrophic factor (BDNF) is involved in the survival and function of midbrain DA neurons. BDNF action is mediated by the TrkB receptortyrosine kinase, and both BDNF and TrkB transcripts are widely expressed in the rat mesolimbic pathway, including the nucleus accumbens (NAc) and the ventral tegmentum area (VTA). Objective BDNF was previously shown to be involved in cocaine reward and relapse, as assessed in rat models. The goal of this study is to explore the role of BDNF and TrkB in the rat nucleus accumbens (NAc) in cocaine-induced psychomotor sensitization and in conditioned-place preference acquisition, expression, and reinstatement. Materials and methods In vivo genetic manipulations of BDNF and TrkB were performed using a lentiviral gene delivery approach to over-express these genes in the NAc and siRNA-based technology to locally knockdown gene expression. Behavioral experiments consisted of locomotor activity monitoring or cocaine-induced conditioned-place preference (CPP). Results BDNF and/or its receptor TrkB in the NAc enhance drug-induced locomotor activity and induce sensitization in rats. Furthermore, LV-BDNF-and LV-TrkB-treated rats display enhanced cocaine-induced CPP, delayed CPPextinction upon repeated measurements, and increased CPP reinstatement. In contrast, expression of TrkT1 (truncated form of TrkB, acting as a dominant negative) inhibits these behavioral changes. This inhibition is also observed when rats are fed doxycycline (to block lentivirusmediated gene expression) or when injected with siRNAsexpressing lentiviruses against TrkB. In addition, we investigate the establishment, maintenance, extinction, and reinstatement of cocaine-induced CPP. We show that BDNF and TrkB-induced CPP takes place during the learning period (conditioning), whereas extinction leads to the loss of CPP. Extinction is delayed when rats are injected LV-BDNF or LV-TrkB, and in turn, priming injections of 2 mg/kg of cocaine reinstates it. Conclusions These results demonstrate the crucial function of BDNF-through its receptor TrkB-in the enhancement of locomotor activity, sensitization, conditioned-place preference, CPP-reinstatement, and rewarding effects of cocaine in the mesolimbic dopaminergic pathway.

Selective lentiviral-mediated suppression of microRNA124a in the hippocampus evokes antidepressants-like effects in rats

“…For qPCR, 20 ml of amplification mixture with SYBRGreen Kit was used containing 3 ml of cDNA and 100 nM primers. Primer sequences used were: GAPDH: 5 0 -ATG ACT CTA CCC ACG GCA AG-3 0 and 5 0 -CAT ACT CAG CAC CAG CAT CAC-3 0 ; miR124a: 5 0 -TCC GTG TTC ACA GCG GAC-3 0 and 5 0 -CAT TCA CCG CGT GCC TTA-3 0 and BDNF: 5 0 -GGT TCG AGA GGT CTG ACG AC-3 0 and 5 0 -CAA AGG CAC TTG ACT GCT GA-3 0 (Bahi et al, 2008a;Bahi and Dreyer, 2013). The PCR protocol used consisted of a 45-s denaturation at 94 8C followed by 45-s annealing and extension at 64 8C for 40 cycles.…”

“…Our lentivirus derived plasmid (pTK431), driven by the cytomegalovirus (CMV) promoter, carried the transgenes for BDNF, miR124a or siR124a described in our previous studies (Bahi et al, 2008a;Bahi and Dreyer, 2013;Chandrasekar and Dreyer, 2009). The empty vector (LV-Mock) was used as negative control.…”

Viral-Mediated Knockdown of mGluR7 in the Nucleus Accumbens Mediates Excessive Alcohol Drinking and Increased Ethanol-Elicited Conditioned Place Preference in Rats

“…Cells were harvested 72 h later and viruses were concentrated from the supernatant by ultracentrifugation. Vectors were resuspended in PBS-BSA and stored at À80 1C until use (Bahi et al, 2008aDreyer, 2008, 2012a,b).…”

“…The Hamilton micro-syringe was held in place for an additional 10 min before being removed. Following surgery, the rats were allowed to recover for mGluR7 blockade increases ethanol reward A Bahi 10 days before undergoing the behavioral assays (Bahi et al, 2004b(Bahi et al, , 2008a.…”

“…Therefore, we have decided to employ a technique of viral-mediated gene transfer to knock down mGluR7 expression using short hairpin RNA (shRNA)-expressing lentiviral vectors (LV) within the NAcc (and the DS) to study the effects of reduced mGluR7 mRNA levels on ethanol-related behaviors. This technique was extensively used in our laboratory to manipulate a number of genes in different CNS regions of both rats and mice (Bahi et al, 2005(Bahi et al, , 2008aBahi and Dreyer, 2012a,b).…”