Acute and Chronic Corticotropin-Releasing Factor 1 Receptor Blockade Inhibits Cocaine-Induced Dopamine Release:Correlation with Dopamine Neuron Activity

摘要

Corticotropin-releasing factor(CRF)is a neuropeptide associated with the integration of the physiological and behavioral responses to stress.Recently,CRF-1 receptor antagonists have been shown to decrease cocaine self-administration and inhibit stress-induced reinstatement of cocaine-seeking behavior.The exact mechanisms underlying this effect are not clear.Based on the large amount of literature demonstrating an association between dopaminergic neurotransmission and reward-related behavior,the aim of the present study was to examine the effects of acute versus chronic CRF-1 receptor blockade on mesencephalic dopamine(DA)neuron activity(determined by in vivo extracellular recordings)and extracellular DA levels in the nucleus accumbens(Acb)(using in vivo microdialysis).In addition,the effect of CRF-1 receptor antagonism on cocaine-induced DA overflow in the Acb was examined and correlated with DA neuron activity in the ventral tegmental area(VTA).Acute(but not chronic)CRF-1 receptor blockade by CRA-0450 [1-[8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl]-1,2,3,6-tetrahydropyridine-4-carboxamide benzenesulfonate] was found to significantly increase DA neuron population activity without affecting burst firing,average firing rate,or Acb DA levels.In addition,both acute and chronic CRF-1 receptor antagonism significantly reduced cocaine-stimulated DA overflow in the Acb,and this reduction was correlated with an attenuated cocaine-induced inhibition of DA population activity.Taken as a whole,these data demonstrate that,although DA neuron population activity exhibits tolerance to chronic CRF-1 receptor antagonism(by CRA-0450),tolerance does not develop to the selective inhibition of cocaine-induced DA release(in the Acb)and,as such,may be beneficial in the treatment of cocaine addiction.