Discriminative-stimulus effects of azaspirodecanedione anxiolytics in baboons trained to discriminate β-carboline-3-carboxylic acid ethyl ester or pentylenetetrazole

N. A. Ator, J. M. Cook, M. S. Allen, R. R. Griffiths

Research output: Contribution to journalArticle

Abstract

Baboons were trained to discriminate either pentylenetetrazole (PTZ) or β-carboline-3-carboxylic acid ethyl ester (β-CCE) from the no-drug condition. Both drugs specifically bind sites in the γ-aminobutyric acid A (GABA(A)) receptor complex and decrease GABAergic transmission. β-CCE occasioned drug-lever responding in baboons trained to discriminate PTZ and vice versa. Flumazenil, the benzodiazepine receptor antagonist, blocked β- CCE, consistent with β-CCE's receptor binding activity. The azaspirodecanedione anxiolytics buspirone and ipsapirone produced full generalization in all baboons; gepirone and tandospirone yielded generalization in some baboons and partial in others. These anxiolytics are inactive in the GABA(A) complex and potently bind 5-HT(1A) sites. A specific 5-HT(1A) ligand, 8-hydroxy-2-(di-n-propylamino)tetralin, produced generalization similar to gepirone and tandospirone, which show the most specific 5-HT(1A) binding. The major azaspirodecanedione metabolite, 1-(2- pyrimidinyl)piperazine (an α2-adrenergic antagonist), occasioned the least drug-appropriate responding. Full generalization to buspirone and ipsapirone may have resulted from dopaminergic or α1-adrenergic activity combined with 5-HT(1A) activity. The molecular mechanism of the generalization profile for PTZ and β-CCE shown by the present results is unclear. The data may reflect altered relationships between GABAergic and serotonergic transmission, and altered stimulus effects of the training drugs, in the context of chronically decreased GABAergic transmission.

Original languageEnglish (US)
Pages (from-to)176-188
Number of pages13
JournalBehavioural Pharmacology
Volume5
Issue number2
DOIs
StatePublished - Jan 1 1994

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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