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Characterization of the effects of receptor-selective ligands in rats discriminating the novel antipsychotic quetiapine

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Abstract

Rationale

Drug discrimination studies with clozapine have shown that such assays are of value in analysing the actions of novel antipsychotic agents in vivo.

Objectives

To evaluate the role of specific receptors in the discriminative stimulus properties of the novel "atypical" antipsychotic quetiapine.

Methods

Rats were trained to discriminate quetiapine at 10 mg/kg and tested with a range of ligands, selective for specific classes of receptor.

Results

Full generalization to quetiapine was only seen with quetiapine itself (100%) and with the muscarinic antagonist, scopolamine (87%). Partial generalization was seen with the α1-adrenoceptor antagonist prazosin (63%), the presumed preferential dopamine D3 receptor antagonist PNU 91194A (54%) and the 5-HT/H1/M1 antagonist cyproheptadine (55%). Minimal (<40%) or no (0%) generalization was seen with mepyramine (H1 antagonist), SCH 23390 (D1 antagonist), raclopride (D2/3 antagonist), ketanserin and MDL 100,907 (5-HT2A antagonists), ondansetron (5-HT3 antagonist), SB 242,084 (5-HT2C antagonist), 8-OHDPAT (5-HT1A agonist) yohimbine (α2-adrenoceptor antagonist) and the benzodiazepine, chlordiazepoxide.

Conclusions

Together with data from a previous study (Smith and Goudie 2002) in which we observed full generalization to quetiapine with olanzapine, risperidone and clozapine, but not with typical antipsychotics (such as haloperidol) or the novel antipsychotic amisulpride, these data suggest that: i) the discriminative stimulus properties of quetiapine, like those of clozapine, probably reflect a "compound" stimulus which involves several classes of receptor; ii) the quetiapine cue is of value in analysing, and screening for, quetiapine- and clozapine-like agents in vivo; iii) blockade of muscarinic receptors is sufficient, although not necessary, to achieve full generalization to quetiapine; and iv) α1-adrenoceptors may be implicated in the quetiapine discriminative stimulus.

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Acknowledgements

Dr. J.A. Smith was supported by funds from the UK Medical Research Council. We are greatly indebted to Ms. Juliet McAdams for expert technical assistance.

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Authors and Affiliations

  1. Psychology Department, Eleanor Rathbone Building, Liverpool University, Bedford Street, Liverpool, L69 7ZA, UK

    Andrew J. Goudie & Judith A. Smith

  2. Institut de Recherches Servier, Psychopharmacology Department, 125 Chemin de Ronde, 78290, Croissy-sur-Seine, France

    Mark J. Millan

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  1. Andrew J. Goudie
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  2. Judith A. Smith
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  3. Mark J. Millan
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Correspondence to Andrew J. Goudie.

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Goudie, A.J., Smith, J.A. & Millan, M.J. Characterization of the effects of receptor-selective ligands in rats discriminating the novel antipsychotic quetiapine. Psychopharmacology 171, 212–222 (2004). https://doi.org/10.1007/s00213-003-1576-x

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