Andrew J Goudie1, Judith A Smith, Mark J Millan. 1. Psychology Department, Eleanor Rathbone Building, Liverpool University, Bedford Street, L69 7ZA, Liverpool, UK. ajg@liverpool.ac.uk
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 alpha(1)-adrenoceptor antagonist prazosin (63%), the presumed preferential dopamine D(3) receptor antagonist PNU 91194A (54%) and the 5-HT/H(1)/M(1) antagonist cyproheptadine (55%). Minimal (<40%) or no (0%) generalization was seen with mepyramine (H(1) antagonist), SCH 23390 (D(1) antagonist), raclopride (D(2/3 )antagonist), ketanserin and MDL 100,907 (5-HT(2A ) antagonists), ondansetron (5-HT(3) antagonist), SB 242,084 (5-HT(2C) antagonist), 8-OHDPAT (5-HT(1A) agonist) yohimbine (alpha(2)-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) alpha(1-)adrenoceptors may be implicated in the quetiapine discriminative stimulus.
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 alpha(1)-adrenoceptor antagonist prazosin (63%), the presumed preferential dopamine D(3) receptor antagonist PNU 91194A (54%) and the 5-HT/H(1)/M(1) antagonist cyproheptadine (55%). Minimal (<40%) or no (0%) generalization was seen with mepyramine (H(1) antagonist), SCH 23390 (D(1) antagonist), raclopride (D(2/3 )antagonist), ketanserin and MDL 100,907 (5-HT(2A ) antagonists), ondansetron (5-HT(3) antagonist), SB 242,084 (5-HT(2C) antagonist), 8-OHDPAT (5-HT(1A) agonist) yohimbine (alpha(2)-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) alpha(1-)adrenoceptors may be implicated in the quetiapine discriminative stimulus.
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