Generalization of clozapine as compared to other antipsychotic agents to a discriminative stimulus elicited by the serotonin (5-HT)2A antagonist, MDL100,907

Dekeyne, Anne; Iob, Loretta; Millan, Mark J.

doi:10.1016/s0028-3908(03)00040-6

Cited by 22 publications

(13 citation statements)

References 43 publications

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“…This suggests the possibility that the 5-HT 2A antagonist properties of M100907 may not have been responsible for the CLZappropriate responding in the present study. While not as potent at other receptors, M100907 does bind to 5HT 2C , D 2 , and α 1 receptors (Dekeyne et al 2003). Also, ritanserin is an antagonist at both 5-HT 2A and 5-HT 2C receptors.…”

Section: Discussionmentioning

confidence: 88%

“…Fluoxetine does not display any significant occupancy of 5-HT 2A receptors, although it does display up to 43% occupancy of 5-HT 2C receptors at a 20 mg/kg dose (Palvimaki et al 1999). Also, it should be noted that Dekeyne et al (2003) trained rats to discriminate the 5-HT 2A antagonist M100907 and reported that the atypical APDs CLZ, quetiapine, risperidone, and ziprasidone all The atypical APD melperone substituted for CLZ, but has a lower affinity for 5-HT 2A receptors than do the other APDs discussed above. It does display a preferential ratio for 5-HT 2A receptors relative to D 2 receptors, as do all of the atypical APDs that fully substituted for CLZ in the present study (and in the Philibin et al 2005 study).…”

Section: Discussionmentioning

confidence: 99%

“…Many APDs bind to the α 1 -adrenoceptor subtype with relatively high affinity. Comparison with dopamine D 2 receptor affinities suggests that antipsychotic blockade of α 1A -and/or α 1B -adrenoceptor receptors may contribute to the antipsychotic activity of many atypical and several typical APDs (Cahir and King 2005; see also Dekeyne et al 2003). For example, Goudie et al (2004a, b) suggested that α 1 -adrenoceptors play a role in the discriminative stimulus properties of the atypical APDs zotepine and quetiapine.…”

Section: Discussionmentioning

confidence: 99%

“…However, a very high dose of M100907 was needed to produce CLZ-appropriate responding in the present study (ED 50 = 1.95 mg/kg). Dekeyne et al (2003) trained rats to discriminate M100907 and found an ED 50 of 0.002 mg/kg-approximately a 1,000-fold difference in potency. This suggests the possibility that the 5-HT 2A antagonist properties of M100907 may not have been responsible for the CLZappropriate responding in the present study.…”

Section: Discussionmentioning

confidence: 99%

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Further characterization of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in C57BL/6 mice: role of 5-HT2A serotonergic and α1 adrenergic antagonism

et al. 2008

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Rationale The discriminative stimulus properties of the atypical antipsychotic drug (APD) clozapine (CLZ) have recently been studied in C57BL/6 mice, a common background strain for genetic alterations. However, further evaluation is needed to fully characterize CLZ's discriminative cue in this strain of mice. Objectives The objectives of the study were to confirm the previous findings using a shorter pretreatment time and to further characterize the receptor mechanisms mediating the discriminative stimulus properties of CLZ by testing APDs, selective ligands, and N-desmethylclozapine (CLZ's major metabolite) in C57BL/6 mice. Materials and methods C57BL/6 male mice were trained to discriminate 2.5 mg/kg CLZ (s.c.) from vehicle in a two-lever drug discrimination task.Results Generalization testing with CLZ yielded an ED 50 = 1.19 mg/kg. Substitution testing with APDs showed that the atypical APDs quetiapine, sertindole, zotepine, iloperidone, and melperone fully substituted for CLZ (≥80% CLZappropriate responding), but aripiprazole did not. The typical APDs chlorpromazine and thioridazine substituted for CLZ (fluphenazine and perphenazine did not). The serotonin (5-HT) 2A antagonist M100907 and the α 1 -adrenoceptor antagonist prazosin fully substituted for CLZ. The H 1 histaminergic antagonist pyrilamine, dopamine agonist amphetamine, and the selective serotonin reuptake inhibitor fluoxetine did not substitute for CLZ. While N-desmethylclozapine did not substitute for CLZ when tested alone, Ndesmethylclozapine plus a low dose of CLZ combined in an additive manner produced full substitution. Conclusions CLZ's discriminative cue in C57BL/6 mice is a "compound" cue mediated in part by antagonism of 5-HT 2A and α 1 receptors.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Further characterization of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in C57BL/6 mice: role of 5-HT2A serotonergic and α1 adrenergic antagonism

et al. 2008

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“…For reviews of drug discrimination studies in which antipsychotic drugs have been tested for their ability to block the discriminative stimulus properties of other training drugs (like low-dose amphetamine discrimination, DOI discrimination, and MK-801 discrimination) see Arnt and Skarsfeldt (1998) and Goudie and Smith (1999). In addition, the present review did not attempt to review the discriminative stimulus properties of putative antipsychotic drugs such as MDL 100,907 (Dekeyne et al 2003) or S 16924 (Millan et al 1998(Millan et al , 1999.…”

Section: Introductionmentioning

confidence: 99%

Discriminative stimulus properties of atypical and typical antipsychotic drugs: a review of preclinical studies

Porter

Prus

2008

Psychopharmacology

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Background Drug discrimination is an increasingly valuable behavioral assay for the preclinical development of antipsychotic drugs. The majority of studies have used the atypical antipsychotic clozapine because it displays robust discriminative stimulus properties and is the "prototypical" or "gold standard" atypical antipsychotic against which other antipsychotics will undoubtedly be compared for many years. Objectives Pharmacological mechanisms mediating the discriminative stimulus properties of antipsychotics used as training drugs and the usefulness of drug discrimination for distinguishing typical and atypical antipsychotics were reviewed. Results Clozapine appears to have a compound cue involving antagonism of two or more receptors. While muscarinic receptor antagonism is a prominent factor for mediation of clozapine's cue in rats with a 5.0-mg/kg training dose, there are differences in clozapine's cue with a low training dose and in pigeons and mice. With a low training dose, clozapine has consistently produced full or partial generalization to atypical but not to typical antipsychotics. Although not evaluated as extensively, the atypical antipsychotics quetiapine and ziprasidone also appear to generalize to atypical but not typical antipsychotics. This has not been the case for other antipsychotic drugs (olanzapine, chlorpromazine, haloperidol) used as training drugs. Conclusions There are important differences in discriminative stimulus properties both between and within atypical and typical antipsychotics and across species. While lowdose clozapine discrimination in rats appears to provide a more sensitive behavioral assay for distinguishing atypical from typical antipsychotics, the extent to which clozapine's discriminative stimulus properties are predictive of its antipsychotic effects remains to be determined.

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Discriminative Stimulus Properties of Receptor Antagonists

Porter

2011

Drug Discrimination

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Generalization of clozapine as compared to other antipsychotic agents to a discriminative stimulus elicited by the serotonin (5-HT)2A antagonist, MDL100,907

Cited by 22 publications

References 43 publications

Further characterization of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in C57BL/6 mice: role of 5-HT2A serotonergic and α1 adrenergic antagonism

Further characterization of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in C57BL/6 mice: role of 5-HT2A serotonergic and α1 adrenergic antagonism

Discriminative stimulus properties of atypical and typical antipsychotic drugs: a review of preclinical studies

Discriminative Stimulus Properties of Receptor Antagonists

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