title: Stability of avoidance behaviour following repeated intermittent treatment with clozapine, olanzapine or D,L-govadine.
abstract: Most antipsychotic drugs act as dopamine D2 receptor antagonists within the basal ganglia. These compounds have efficacy in the treatment of positive symptoms of schizophrenia but do not address the cognitive deficits that define this disorder. D,L-Govadine, a recently synthesized tetrahydroprotoberberine, shows efficacy on preclinical tests of antipsychotic action, as well as procognitive properties. We sought to compare D,L-govadine with two atypical antipsychotics, clozapine and olanzapine, on repeated conditioned avoidance responding (CAR), a task that has recently been utilized to model the effects of repeated antipsychotic treatment. After acquisition of two-way avoidance, rats were given D,L-govadine, clozapine, olanzapine or a vehicle control before repeated testing on CAR. Daily sessions were conducted, with 'drug-on' days spaced by a 'drug-off' test day and a rest day, for a total of five drug administrations. Consistent with previous research, the lower dose of olanzapine showed a modest but progressive increase in disruption of avoidance behaviour as observed with many antipsychotics. In contrast, repeated administration of clozapine led to tolerance, and the novel compound D,L-govadine produced a consistent effect across administrations. This stable effect of D,L-govadine on CAR may indicate a desirable preclinical profile for a candidate antipsychotic compound.
authors.affiliation: aBrain Research Centre bDepartment of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada cDepartment of Psychology, Indiana University-Purdue University Indianapolis dStark Neuroscience Institute, Indiana University School Of Medicine eInstitute for Mathematical Modeling and Computational Sciences, Indiana University-Purdue University Indianapolis School of Science, Indianapolis, Indiana, USA.
authors.forename: Donovan M
authors.initials: DM
authors.lastname: Ashby
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Lapish
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Phillips
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology*; D001600:Berberine Alkaloids / Q000008:administration & dosage / Q000494:pharmacology*; D003024:Clozapine / Q000008:administration & dosage / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D008297:Male; D000077152:Olanzapine; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D014150:Antipsychotic Agents; D001600:Berberine Alkaloids; D001569:Benzodiazepines; C103305:govadine; D003024:Clozapine; D000077152:Olanzapine