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Drug-induced plasticity contributing to heightened relapse susceptibility: neurochemical changes and augmented reinstatement in high-intake rats. J Neurosci 2010 Jan 06;30(1):210-7

Date

01/08/2010

Pubmed ID

20053903

Pubmed Central ID

PMC2823262

DOI

10.1523/JNEUROSCI.1342-09.2010

Scopus ID

2-s2.0-74849106113   24 Citations

Abstract

A key in understanding the neurobiology of addiction and developing effective pharmacotherapies is revealing drug-induced plasticity that results in heightened relapse susceptibility. Previous studies have demonstrated that increased extracellular glutamate, but not dopamine, in the nucleus accumbens core (NAcc) is necessary for cocaine-induced reinstatement. In this report, we examined whether drug-induced adaptations that are necessary to generate cocaine-induced reinstatement also determine relapse vulnerability. To do this, rats were assigned to self-administer cocaine under conditions resulting in low (2 h/d; 0.5 mg/kg/infusion, i.v.) or high (6 h/d; 1.0 mg/kg/infusion, i.v.) levels of drug intake since these manipulations produce groups of rats exhibiting differences in the magnitude of cocaine-induced reinstatement. Approximately 19 d after the last session, cocaine-induced drug seeking and extracellular levels of glutamate and dopamine in the NAcc were measured. Contrary to our hypothesis, high-intake rats exhibited a more robust cocaine-induced increase in extracellular levels of dopamine but not glutamate. Further, increased reinstatement in high-intake rats was no longer observed when the D(1) receptor antagonist SCH-23390 was infused into the NAcc. The sensitized dopamine response to cocaine in high-intake rats may involve blunted cystine-glutamate exchange by system x(c(-)). Reduced (14)C-cystine uptake through system x(c(-)) was evident in NAcc tissue slices obtained from high-intake rats, and the augmented dopamine response in these rats was no longer observed when subjects received the cysteine prodrug N-acetyl cysteine. These data reveal a role for drug-induced NAcc dopamine in heightened relapse vulnerability observed in rats with a history of high levels of drug intake.

Author List

Madayag A, Kau KS, Lobner D, Mantsch JR, Wisniewski S, Baker DA

Author

John Mantsch PhD Chair, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cocaine
Cocaine-Related Disorders
Disease Susceptibility
Dose-Response Relationship, Drug
Male
Neuronal Plasticity
Nucleus Accumbens
Rats
Rats, Sprague-Dawley
Secondary Prevention
Self Administration