Self-administration of cocaine induces dopamine-independent self-administration of sigma agonists

Takato Hiranita, Maddalena Mereu, Paul L. Soto, Gianluigi Tanda, Jonathan L. Katz

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)605-615
Number of pages11
JournalNeuropsychopharmacology
Volume38
Issue number4
DOIs
StatePublished - Mar 2013

Fingerprint

Self Administration
Cocaine
Dopamine
Pentazocine
Dopamine Antagonists
Microdialysis
Pharmaceutical Preparations
Substance-Related Disorders
Psychiatry
Food
Injections
2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate
Reinforcement (Psychology)
Proteins

Keywords

  • σ receptor
  • cocaine
  • dopamine
  • drug reinforcement history
  • drug self-administration
  • reinforcement mechanisms

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Self-administration of cocaine induces dopamine-independent self-administration of sigma agonists. / Hiranita, Takato; Mereu, Maddalena; Soto, Paul L.; Tanda, Gianluigi; Katz, Jonathan L.

In: Neuropsychopharmacology, Vol. 38, No. 4, 03.2013, p. 605-615.

Research output: Contribution to journalArticle

Hiranita, Takato ; Mereu, Maddalena ; Soto, Paul L. ; Tanda, Gianluigi ; Katz, Jonathan L. / Self-administration of cocaine induces dopamine-independent self-administration of sigma agonists. In: Neuropsychopharmacology. 2013 ; Vol. 38, No. 4. pp. 605-615.
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