Document Detail

Self-administration of cocaine induces dopamine-independent self-administration of sigma agonists.
MedLine Citation:
PMID:  23187725     Owner:  NLM     Status:  MEDLINE    
Sigma(1) receptors (σ(1)Rs) are intracellularly mobile chaperone proteins implicated in several disease processes, as well as psychiatric disorders and substance abuse. Here we report that although selective σ(1)R agonists (PRE-084, (+)-pentazocine) lacked reinforcing effects in drug-naive rats, over the course of 28 experimental sessions, which was more than sufficient for acquisition of cocaine self-administration, responding was not maintained by either σ(1)R agonist. In contrast, after subjects self-administered cocaine σ(1)R agonists were readily self-administered. The induced reinforcing effects were long lasting; a response for which subjects had no history of reinforcement was newly conditioned with both σ(1)R agonists, extinguished when injections were discontinued, and reconditioned when σ(1)R agonists again followed responses. Experience with food reinforcement was ineffective as an inducer of σ(1)R agonist reinforcement. Although a variety of dopamine receptor antagonists blocked cocaine self-administration, consistent with its dopaminergic mechanism, PRE-084 self-administration was entirely insensitive to these drugs. Conversely, the σR antagonist, BD1063, blocked PRE-084 self-administration but was inactive against cocaine. In microdialysis studies i.v. PRE-084 did not significantly stimulate dopamine at doses that were self-administered in rats either with or without a cocaine self-administration experience. The results indicate that cocaine experience induces reinforcing effects of previously inactive σ(1)R agonists, and that the mechanism underlying these reinforcing effects is dopamine independent. It is further suggested that induced σ(1)R mechanisms may have an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for stimulant abuse.
Takato Hiranita; Maddalena Mereu; Paul L Soto; Gianluigi Tanda; Jonathan L Katz
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-28
Journal Detail:
Title:  Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology     Volume:  38     ISSN:  1740-634X     ISO Abbreviation:  Neuropsychopharmacology     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-13     Completed Date:  2013-10-29     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  8904907     Medline TA:  Neuropsychopharmacology     Country:  England    
Other Details:
Languages:  eng     Pagination:  605-15     Citation Subset:  IM    
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MeSH Terms
Analgesics, Opioid / administration & dosage*
Cocaine / administration & dosage*
Dopamine / physiology
Dopamine Antagonists / administration & dosage*
Pentazocine / administration & dosage*
Rats, Sprague-Dawley
Receptors, sigma / agonists*,  physiology
Self Administration
Reg. No./Substance:
0/Analgesics, Opioid; 0/Dopamine Antagonists; 0/Receptors, sigma; 0/sigma-1 receptor; I5Y540LHVR/Cocaine; RP4A60D26L/Pentazocine; VTD58H1Z2X/Dopamine

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