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PMID: 15042275 Published · ppublish English Comparative Study Journal Article Research Support, U.S. Gov't, P.H.S.

Effects of extended access to high versus low cocaine doses on self-administration, cocaine-induced reinstatement and brain mRNA levels in rats.

Psychopharmacology ·Vol. 175 ·No. 1 ·2004-08-00 ·Pages 26-36

Mantsch JR, Yuferov V, Mathieu-Kia AM, Ho A, Kreek MJ

Abstract

The investigation of rodent cocaine self-administration (SA) under conditions that promote escalating patterns of intake may provide insight into the loss of control over drug use that is central to human addiction. This study examines the effects of daily long-access (LgA) SA of high or low cocaine doses on drug intake, extinction, reinstatement, and brain mRNA levels. Three groups of male Sprague-Dawley rats were trained to self-administer cocaine during multiple-dose sessions. Short-access (ShA) rats were tested daily for multi-dose SA then remained in the chambers for 7 h with no cocaine available. LgA rats had access to low (0.5 mg/kg per infusion; LgA-LD) or high (2.0 mg/kg per infusion; LgA-HD) cocaine doses for 7 h after multi-dose SA. After 14 days, responding was extinguished, cocaine-induced reinstatement was determined, and preproenkephalin (ppENK), preprodynorphin (ppDYN), corticotropin releasing factor (CRF) and dopamine D(2) receptor (D(2)R) mRNA levels were measured in various brain regions using a quantitative solution hybridization RNase protection assay. Whereas SA was not altered in ShA rats and only increased during the "loading phase" in LgA-LD rats, a general escalation of intake was found in LgA-HD rats. LgA, particularly LgA-HD, rats were more susceptible to reinstatement than ShA rats. Caudate-putamen ppENK and nucleus accumbens D(2)R mRNA levels were elevated in LgA-HD rats. Overall, D(2)R mRNA levels were positively correlated with reinstatement. The escalation of cocaine SA under LgA conditions is dose-dependent and is associated with heightened susceptibility to drug-induced relapse. The characterization of neurobiological alterations that accompany escalated SA should facilitate the identification of mechanisms underlying the onset of human addiction.

MeSH Terms
Animals Behavior, Addictive/psychology Brain/drug effects,metabolism Cocaine/administration & dosage Cocaine-Related Disorders/psychology Corticotropin-Releasing Hormone/genetics,metabolism Dose-Response Relationship, Drug Dynorphins/genetics,metabolism Enkephalins/genetics,metabolism Extinction, Psychological/drug effects Male Opioid Peptides/genetics,metabolism Protein Precursors/genetics,metabolism RNA, Messenger/metabolism Rats Rats, Sprague-Dawley Receptors, Dopamine D2/genetics,metabolism Recurrence Self Administration Time Factors
Chemicals
Enkephalins Opioid Peptides Protein Precursors RNA, Messenger Receptors, Dopamine D2 pre-prodynorphin Dynorphins Corticotropin-Releasing Hormone preproenkephalin Cocaine
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Mantsch John R
The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA. john.mantsch@marquette.edu
Yuferov Vadim
Mathieu-Kia Anne-Marie
Ho Ann
Kreek Mary Jeanne
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Article Info
Journal
Psychopharmacology
Abbr.
Psychopharmacology (Berl)
ISSN
0033-3158
DOI
10.1007/s00213-004-1778-x
Email
john.mantsch@marquette.edu
Published
2004-08-00
Epub
2004-00-20
Pages
26-36
Language
English
Region
Germany
NLM ID
7608025
Subset
IM
Grants
NIDA NIH HHS · DA-K05-00049 · United States
NIDA NIH HHS · DA-P50-05130 · United States
External Links
PubMed source DOI: 10.1007/s00213-004-1778-x View journal details
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