Clozapine is the prototypical atypical antipsychotic drug and represents a tremendous improvement over conventional antipsychotics in terms of therapeutic efficacy and reduced side effect liability for the treatment of schizophrenia. Understanding the pharmacological properties that are important for clozapine's unique profile can help lead to the discovery of improved and safer antipsychotic drugs for the treatment of schizophrenia. One approach for investigating the molecular bases underlying the relationship of pharmacological agents and behavior has been the use of gene-targeted knockout or transgenic animals. This technique allows for the manipulation of receptors for which selective pharmacological ligands do not exist. One restriction of this approach is that most of the knockout mutations that have been developed are available only in mice - not rats. Therefore, it is necessary to have preclinical assays for mice in order to utilize these new and potentially powerful new techniques. The current proposal represents an important first step in this process. Two-lever drug discrimination is a valuable preclinical behavioral model that has been used to investigate the discriminative stimulus properties of clozapine in rats and has helped identify neurotransmitter receptor targets for putative atypical antipsychotics. Wild-type mice (C57BL/6J) will be trained to discriminate clozapine from vehicle and then a series of atypical and typical antipsychotic drugs will be tested to determine which drugs generalize to clozapine's discriminative cue. Establishing this procedure in wild-type mice will allow for the future use of knockout and transgenic mice and will expand the tools available to molecular geneticists and behavioral pharmacologists. This will help to increase our understanding of the perplexing pharmacology of schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31GM070974-02
Application #
6796633
Study Section
Special Emphasis Panel (ZRG1-SSS-C (29))
Program Officer
Toliver, Adolphus
Project Start
2003-08-18
Project End
2006-08-17
Budget Start
2004-08-18
Budget End
2005-08-17
Support Year
2
Fiscal Year
2004
Total Cost
$28,147
Indirect Cost
Name
Virginia Commonwealth University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Prus, Adam J; Pehrson, Alan L; Philibin, Scott D et al. (2009) The role of M1 muscarinic cholinergic receptors in the discriminative stimulus properties of N-desmethylclozapine and the atypical antipsychotic drug clozapine in rats. Psychopharmacology (Berl) 203:295-301
Porter, Joseph H; Walentiny, David Matthew; Philibin, Scott D et al. (2008) A comparison of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in DBA/2 and C57BL/6 inbred mice. Behav Pharmacol 19:530-42
Philibin, Scott D; Prus, Adam J; Pehrson, Alan L et al. (2005) Serotonin receptor mechanisms mediate the discriminative stimulus properties of the atypical antipsychotic clozapine in C57BL/6 mice. Psychopharmacology (Berl) 180:49-56