Abstract
Cocaine exhibits high liability for inducing addictive behaviors, but the mechanisms of neuroplasticity underlying the behavioral effects remain unclear. As a crucial mediator of neuroplasticity in diverse functional models, brain-derived neurotrophic factor (BDNF) could contribute to the mechanisms of addiction-related neuroplasticity. Here, we addressed the hypothesis that cocaine increases synaptic dopamine, which induces BDNF protein expression to initiate addiction-related behavior in the rat. An enzyme-linked immunosorbent assay was used to measure BDNF protein expression in rat striatal tissues. For behavioral readout, we used a noninvasive measurement system to measure the emission of 50-kHz ultrasonic vocalization (USV), a response that correlates with electrical brain stimulation and conditioned place preference behavior in rodents. A single injection of cocaine significantly increased BDNF protein expression, but this effect was not further augmented by repeated cocaine administration. A single administration of cocaine elicited significant and dose-related USV responses, and the magnitude of the behavior increased with repeated drug administration. R-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390), but not raclopride, significantly attenuated cocaine-induced BDNF protein expression, whereas either the D1-like or D2-like receptor antagonist blocked cocaine-induced USV behavior. Furthermore, significant USV behavior was elicited by the nonselective dopamine agonist, apomorphine, but not by agonists that are selective for D1-like or D2-like receptors. Intracerebroventricular injection of the neurotrophin TrkB receptor inhibitor, K252a, blocked cocaine-induced USV behavior but not locomotor activity. These results suggest that neurotrophin signaling downstream of dopamine receptor function probably constitutes a crucial link in cocaine induction of USV behavior and may contribute to the mechanisms underlying the development of addiction-related behaviors.
Footnotes
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant R01-DA017614].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.158535
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ABBREVIATIONS:
- BDNF
- brain-derived neurotrophic factor
- SKF38393
- (±)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol
- SCH23390
- R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine
- ELISA
- enzyme-linked immunosorbent assay
- USV
- 50-kHz ultrasonic vocalization
- ANOVA
- analysis of variance
- NAc
- nucleus accumbens.
- Received July 9, 2009.
- Accepted October 20, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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