Discriminative stimulus properties of cocaine in relation to dopamine D2 receptor function in rats

P. M. Callahan, K. A. Cunningham

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Abstract

Previous studies indicate that the discriminative stimulus effects of cocaine are mediated predominantly by indirect activation of dopamine (DA) D2 postsynaptic receptors, although DA D1 receptors may also be involved. In the present study, full or partial D2 agonists and D2 antagonists were tested for their ability to substitute for, potentiate or antagonize the stimulus effects of cocaine in rats (n = 15) trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced task. The full D2 agonists bromocriptine (1.25-20 mg/kg) and quinpirole (0.013-0.2 mg/kg) engendered substantial cocaine-lever responding (>80% drug-lever responding), whereas the partial D2 agonists preclamol (2.5-10 mg/kg) and terguride (0.313-1.25 mg/kg) produced less than 50% cocaine-lever responding. Co- administration of a threshold dose of cocaine (1.25 mg/kg) with low doses of bromocriptine (1.25-5 mg/kg) or quinpirole (0.025-0.1 mg/kg) induced higher percentages of cocaine-lever responding as compared with occasions when these D2 agonists were given alone. However, co-administration of this dose of cocaine with preclamol (2.5-10 mg/kg) or terguride (0.313-1.25 mg/kg) did not alter the percentage of cocaine-lever responding observed when these partial D2 agonists were administered alone. Pretreatment with the D2 antagonists bromuride (0.25-1 mg/kg) and haloperidol (0.125-0.5 mg/kg) significantly reduced the percentage of cocaine-lever responding. Preclamol (0.625-10 mg/kg) and terguride (0.019-5 mg/kg), but not bromocriptine (2.5-20 mg/kg) or quinpirole (0.01-0.08 mg/kg), significantly reduced the percentage of cocaine-lever responding. These results suggest that full D2 agonists substitute completely for cocaine, whereas partial D2 agonists do not produce cocaine-like responding. Furthermore, additive effects amounting to full substitutions (>80% cocaine-lever responding) are observed only when full, not partial, D2 agonists are combined with a low dose of cocaine. Additionally, partial D2 agonists antagonize the discriminative stimulus effects of cocaine to an extent similar to that of classical D2 antagonists.

Original languageEnglish (US)
Pages (from-to)585-592
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume266
Issue number2
StatePublished - Jan 1 1993

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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