title: The effects of chronic administration of established and putative antipsychotics on natural prepulse inhibition deficits in Brattleboro rats.
abstract: We previously reported that vasopressin deficient Brattleboro (BRAT) rats exhibit deficits in prepulse inhibition (PPI) of the startle reflex that are consistent with PPI deficits exhibited by patients with schizophrenia and other neuropsychiatric disorders. Preliminary evidence indicates that this may be the basis of a predictive model for antipsychotic drug efficacy. Here we report the effects of acute and chronic administration of established and putative antipsychotics on these PPI deficits. BRAT rats, compared to their derivative strain, Long Evans rats, exhibited significantly decreased PPI and startle habituation consistent with patients with schizophrenia and other neuropsychiatric disorders. The second generation antipsychotics, risperidone and clozapine as well as a neurotensin agonist (PD149163) increased BRAT rat PPI, whereas saline, the typical antipsychotic, haloperidol, and a vasopressin analog (1-desamino-D-arginine vasopressin) did not. Similar to their effects in humans, chronic administration of antipsychotic drugs produced stronger effects than acute administration. These results further support the BRAT rat as a model of sensorimotor gating deficits with predictive validity for antipsychotics. The model appears to be able to differentiate first generation from second generation antipsychotics, identify putative antipsychotics with novel mechanisms (i.e., peptides) and reasonably model the therapeutic time course of antipsychotic drugs in humans.
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA, United States. dfeifel@ucsd.edu <dfeifel@ucsd.edu>
authors.forename: David
authors.initials: D
authors.lastname: Feifel
authors.forename: Gilia
authors.initials: G
authors.lastname: Melendez
authors.forename: Kristianne
authors.initials: K
authors.lastname: Priebe
authors.forename: Paul D
authors.initials: PD
authors.lastname: Shilling
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001127:Arginine Vasopressin / Q000031:analogs & derivatives / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003024:Clozapine / Q000494:pharmacology; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006185:Habituation, Psychophysiologic / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects*; D009496:Neurotensin / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011910:Rats, Brattleboro; D020318:Rats, Long-Evans; D011922:Rats, Mutant Strains; D013216:Reflex, Startle / Q000187:drug effects*; D018967:Risperidone / Q000494:pharmacology; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology; D018709:Statistics, Nonparametric
chemical_list: D014150:Antipsychotic Agents; C117269:PD 149163; D001127:Arginine Vasopressin; D009496:Neurotensin; D003894:Deamino Arginine Vasopressin; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone