Pharmacological characterization of locomotor sensitization induced by chronic phencyclidine administration

Melissa Phillips, Cheng Wang, Kenneth M. Johnson

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Phencyclidine (PCP) administration in rats acutely in high doses or chronically in lower doses causes neurotoxicity characterized by neuronal vacuolization and apoptotic neuronal death, respectively. The purpose of this study was to determine whether drugs that previously had been reported to prevent either type of neurotoxicity were also able to prevent locomotor sensitization following chronic PCP administration, PCP (5 or 20 mg/kg) was administered once a day for 5 days following drug pretreatment. After withdrawal, rats were challenged with 3.2 mg/kg PCP and locomotor activity was assessed. Haloperidol and clozapine significantly attenuated sensitization elicited by PCP (20 mg/kg). The D1-like antagonist SCH23390 was much less effective than clozapine, showing a marginal inhibition. Risperidone, a D2/serotonin (5-HT2) antagonist, also resulted in a marginal attenuation of 15%. Ketanserin, a 5-HT2 antagonist, had no effect. Atropine retarded sensitization by 35% and (+)-sulpiride caused a 50% reduction. The AMPA/kainate antagonist, 6,7-dinitroquinoxaline-2,3-dione, had no effect, but barbital sodium reduced sensitization by 54%. These data suggest that γ-aminobutyric acid A, D2, and muscarinic receptors play a major role in the complex pathway underlying sensitization to PCP, whereas D1, 5-HT2 and AMPA receptors have little or no relevance in the behavioral sensitization produced by 20 mg/kg PCP. In a model using 5 mg/kg PCP, the effects of sulpiride and SCH23390 replicated those observed with 20 mg/kg PCP and further showed that acute locomotor activation is not a strict requirement for the development of sensitization. These data argue that there is overlap, but non-identity, between the mechanisms underlying PCP-induced sensitization and neurotoxicity.

Original languageEnglish (US)
Pages (from-to)905-913
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume296
Issue number3
StatePublished - 2001

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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