Repeated exposure to cocaine differently modulates BDNF mRNA and protein levels in rat striatum and prefrontal cortex

Abstract

In this report we investigated the modulation of the neurotrophin brain-derived neurotrophic factor (BDNF) following single or repeated injections with cocaine. Dose-response experiments revealed that a single dose of cocaine (5 mg/kg) is sufficient to upregulate BDNF mRNA levels selectively in rat prefrontal cortex 2 h after the injection, an effect that persists at least for 24 h and is paralleled by enhanced expression of mature (m)BDNF protein. Five consecutive injections of the psychostimulant (5 mg/kg) potentiate the increase of BDNF mRNA levels 2 h after the last treatment, presumably as a result of the enhancement of cAMP response element-binding protein (CREB) phosphorylation, an effect that vanishes 72 h later. Conversely, precursor (pro-) and mBDNF protein forms were markedly reduced 2 h and 72 h post-injection in the prefrontal cortex. Interestingly, in the striatum we found that repeated cocaine injection increased pro-BDNF levels without altering the mature form of the neurotrophin. Our results suggest that cocaine differently affects BDNF transcription and translation in a region-selective manner, but might also alter neurotrophin processing. These data further support the notion that the corticostriatal network is highly vulnerable to the effects of cocaine, and suggest that abnormal regulation of BDNF expression could contribute, at least in part, to the functional defects observed in drug abusers.

Brain-Derived Neurotrophic Factor Controls Cannabinoid CB1 Receptor Function in the Striatum

“…With respect to the interaction between DA and BDNF, it has been reported that acute administration of levodopa (Okazawa et al, 1992), dopamine, or direct D 1 R agonists (Kü ppers and Beyer, 2001;Williams and Undieh, 2009) upregulates BDNF signaling in the striatum. In contrast, other studies reported that both activation and inhibition of the DA system with, respectively, chronic cocaine (Fumagalli et al, 2007) and 6-OHDA treatment (Zhang et al, 2006) failed to affect striatal levels of BDNF. Furthermore, blockade of D 2 Rs with haloperidol treatment for 3 d (Dawson et al, 2001) or 90 d (Pillai et al, 2006) significantly reduced striatal BDNF, whereas intermediate time windows of haloperidol exposure (21 d) caused a partial rebound of striatal BDNF immunoreactivity (Pillai et al, 2006).…”

Brain-Derived Neurotrophic Factor Signaling Modulates Cocaine Induction of Reward-Associated Ultrasonic Vocalization in Rats

“…However, repeated daily injections of cocaine did not produce additional increases in BDNF protein beyond the levels observed after the first injection. Although this result may suggest that the levels observed with the first drug exposure may be the maximum the system can yield, it is also possible that drug treatments subsequent to the first exposure produced increases in pro-BDNF that was not being converted to mature BDNF, the form that is detected by the ELISA assay (Fumagalli et al, 2007).…”

TrkB/BDNF-Dependent Striatal Plasticity and Behavior in a Genetic Model of Epilepsy: Modulation by Valproic Acid

“…Interestingly, all these pathologies share the common feature of maladaptive learning. In particular, recent evidences have suggested that abnormal regional-specific BDNF expression contributes to the functional defects observed in drug addiction (Fumagalli et al, 2007) and in depression (Molteni et al, 2009). In this scenario, our data shed new light on the complex role of BDNF in epilepsy and within the striatal microcircuit.…”