Neurochemical changes in cocaine withdrawal
Trends in Pharmacological SciencesPublished 1 July 1996
M J Kuhar, Nancy S. Pilotte
Citations160
SJR quartileQ1
SJR score3.77
SNIP2.99
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TL;DR
These results suggest a protracted biochemical abstinence syndrome for cocaine, with persistent changes in dopaminergic neurones and innervated areas that underlie withdrawal symptomatology such as anhedonia and relapse.
Abstract
Cocaine withdrawal in animals causes a transient increase followed by a long-lasting decrease in mesolimbic dopamine transporters, dopamine efflux and the number of dopamine cells firing spontaneously. Other changes in the nucleus accumbens and frontal cortex also suggest alterations in dopamine-receptive neurones and circuits. In humans, brain imaging has provided evidence for some similar, long-lasting changes in dopaminergic neurones and innervated areas. These results suggest a protracted biochemical abstinence syndrome for cocaine. In this review, Michael Kuhar and Nancy Pilotte focus on biochemical changes that occur following withdrawal from repeated cocaine administration. A key question for treatment is whether (some of) these persistent changes underlie withdrawal symptomatology such as anhedonia and relapse.
Keywords
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S sensitization of incentive salience can produce addictive behavior even if the expectation of drug pleasure or the aversive properties of withdrawal are diminished and even in the face of strong disincentives, including the loss of reputation, job, home and family.
Psychological ReviewA psychomotor stimulant theory of addiction.
2,700 Citations1987Roy A. Wise, Michael A. Bozarth
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Archives of General PsychiatryAbstinence Symptomatology and Psychiatric Diagnosis in Cocaine Abusers
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Longitudinal evaluations showed a three-phase sequence of post-cocaine abuse abstinence symptoms, and over half the sample also met criteria for ed 3 DSM-III, axis I psychiatric disorders.
Trends in NeurosciencesThe dopamine hypothesis of the reinforcing properties of cocaine
996 Citations1991M. J. Kuhar, Mary C. Ritz +1 more
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Neuroscience & Biobehavioral ReviewsNew concepts in cocaine addiction: The dopamine depletion hypothesis
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Brain ResearchA general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function
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European Journal of PharmacologyMarked inhibition of mesolimbic dopamine release: a common feature of ethanol, morphine, cocaine and amphetamine abstinence in rats
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American Journal of PsychiatryChanges in brain glucose metabolism in cocaine dependence and withdrawal
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Journal of Pharmacology and Experimental TherapeuticsElectrophysiological effects of cocaine in the mesoaccumbens dopamine system: repeated administration.
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186 Citations1991Sally L. Satel, Stephen M. Southwick +1 more
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124 Citations1991Matthew Robertson, Catherine Amoroso Leslie +1 more
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110 Citations1990Sari Izenwasser, Brian M. Cox
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Journal of Pharmacology and Experimental TherapeuticsTime course of tyrosine hydroxylase expression after behavioral sensitization to cocaine.
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Journal of Pharmacology and Experimental TherapeuticsWithdrawal from continuous or intermittent cocaine administration: changes in D2 receptor function.
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