Brain-derived neurotrophic factor signaling modulates cocaine induction of reward-associated ultrasonic vocalization in rats.
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 D(1)-like or D(2)-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 D(1)-like or D(2)-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.
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, USA.
Stacey N
SN
Williams
Ashiwel S
AS
Undieh
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002227:Carbazoles / Q000008:administration & dosage / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids / Q000008:administration & dosage / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000037:antagonists & inhibitors; D012201:Reward; D015398:Signal Transduction / Q000187:drug effects*; D014465:Ultrasonics; D014828:Vocalization, Animal / Q000187:drug effects*
D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; C049985:staurosporine aglycone; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; D003042:Cocaine