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Clozapine enhances disruption of prepulse inhibition after sub-chronic dizocilpine- or phencyclidine-treatment in Wistar rats.
Pharmacol Biochem Behav. 2005 Feb; 80(2):213-9.PB

Abstract

Sensitisation (i.e. progressive enhancement) of behavioural abnormalities induced by repeated treatment with non-competitive NMDA receptor antagonists in animals is considered an animal model for schizophrenia. Here, male Wistar rats were treated for 11 days with either dizocilpine (0.1 mg/kg), phencyclidine (PCP, 2 mg/kg), or saline and tested for prepulse inhibition (PPI) of the acoustic startle response (ASR). The aims of this study were twofold: First, we tested whether sensitisation of PPI deficits previously found in Sprague-Dawley rats were also found in Wistar rats, and, second, whether these effects can be ameliorated by the atypical antipsychotic clozapine. PPI is a paradigm for the assessment of sensorimotor gating (and its deficits) and is impaired in schizophrenic patients. After the sub-chronic treatment the rats were tested drug-free (day 12), and on the following days after drug challenge by PCP (2 mg/kg), combinations of PCP (2 mg/kg) and clozapine (5 and 10 mg/kg), or clozapine (5 mg/kg) alone. PPI was significantly reduced by both NMDA receptor antagonists. This effect was not further enhanced by the daily treatment. Startle magnitude was increased after eight days of dizocilpine-treatment only, indicating sensitisation of startle-potentiation by this drug. Testing the rats drug-free on day 12 revealed enhanced PPI and reduced startle (compared to the matching test on day 0) irrespective of previous treatment. Drug challenge with PCP (2 mg/kg) again reduced PPI in all groups. Clozapine (5 and 10 mg/kg) failed to antagonise the PPI-disruptive effects of PCP and even enhanced the PCP-induced PPI-deficits in rats pretreated with PCP or dizocilpine. These findings suggest: (1) that PPI and startle are influenced differently by non-competitive NMDA receptor antagonists, (2) that PCP and dizocilpine reduce PPI in Wistar rats, but do not lead to a sensitisation of this effect; and (3) that under the present schedule of treatments, the antipsychotic compound clozapine does not antagonise but rather enhances PPI-disruptive effects of non-competitive NMDA receptor antagonists, pointing towards a complex interaction of the brain processes underlying the action of psychotomimetic and atypical antipsychotic drugs.

Authors+Show Affiliations

Department of Neuropharmacology, Brain Research Institute, University of Bremen, P.O.B 330440, 28334 Bremen, Germany.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15680174

Citation

Schwabe, Kerstin, et al. "Clozapine Enhances Disruption of Prepulse Inhibition After Sub-chronic Dizocilpine- or Phencyclidine-treatment in Wistar Rats." Pharmacology, Biochemistry, and Behavior, vol. 80, no. 2, 2005, pp. 213-9.
Schwabe K, Brosda J, Wegener N, et al. Clozapine enhances disruption of prepulse inhibition after sub-chronic dizocilpine- or phencyclidine-treatment in Wistar rats. Pharmacol Biochem Behav. 2005;80(2):213-9.
Schwabe, K., Brosda, J., Wegener, N., & Koch, M. (2005). Clozapine enhances disruption of prepulse inhibition after sub-chronic dizocilpine- or phencyclidine-treatment in Wistar rats. Pharmacology, Biochemistry, and Behavior, 80(2), 213-9.
Schwabe K, et al. Clozapine Enhances Disruption of Prepulse Inhibition After Sub-chronic Dizocilpine- or Phencyclidine-treatment in Wistar Rats. Pharmacol Biochem Behav. 2005;80(2):213-9. PubMed PMID: 15680174.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clozapine enhances disruption of prepulse inhibition after sub-chronic dizocilpine- or phencyclidine-treatment in Wistar rats. AU - Schwabe,Kerstin, AU - Brosda,Jan, AU - Wegener,Nico, AU - Koch,Michael, Y1 - 2004/12/20/ PY - 2004/08/18/received PY - 2004/11/04/revised PY - 2004/11/10/accepted PY - 2005/2/1/pubmed PY - 2005/6/25/medline PY - 2005/2/1/entrez SP - 213 EP - 9 JF - Pharmacology, biochemistry, and behavior JO - Pharmacol. Biochem. Behav. VL - 80 IS - 2 N2 - Sensitisation (i.e. progressive enhancement) of behavioural abnormalities induced by repeated treatment with non-competitive NMDA receptor antagonists in animals is considered an animal model for schizophrenia. Here, male Wistar rats were treated for 11 days with either dizocilpine (0.1 mg/kg), phencyclidine (PCP, 2 mg/kg), or saline and tested for prepulse inhibition (PPI) of the acoustic startle response (ASR). The aims of this study were twofold: First, we tested whether sensitisation of PPI deficits previously found in Sprague-Dawley rats were also found in Wistar rats, and, second, whether these effects can be ameliorated by the atypical antipsychotic clozapine. PPI is a paradigm for the assessment of sensorimotor gating (and its deficits) and is impaired in schizophrenic patients. After the sub-chronic treatment the rats were tested drug-free (day 12), and on the following days after drug challenge by PCP (2 mg/kg), combinations of PCP (2 mg/kg) and clozapine (5 and 10 mg/kg), or clozapine (5 mg/kg) alone. PPI was significantly reduced by both NMDA receptor antagonists. This effect was not further enhanced by the daily treatment. Startle magnitude was increased after eight days of dizocilpine-treatment only, indicating sensitisation of startle-potentiation by this drug. Testing the rats drug-free on day 12 revealed enhanced PPI and reduced startle (compared to the matching test on day 0) irrespective of previous treatment. Drug challenge with PCP (2 mg/kg) again reduced PPI in all groups. Clozapine (5 and 10 mg/kg) failed to antagonise the PPI-disruptive effects of PCP and even enhanced the PCP-induced PPI-deficits in rats pretreated with PCP or dizocilpine. These findings suggest: (1) that PPI and startle are influenced differently by non-competitive NMDA receptor antagonists, (2) that PCP and dizocilpine reduce PPI in Wistar rats, but do not lead to a sensitisation of this effect; and (3) that under the present schedule of treatments, the antipsychotic compound clozapine does not antagonise but rather enhances PPI-disruptive effects of non-competitive NMDA receptor antagonists, pointing towards a complex interaction of the brain processes underlying the action of psychotomimetic and atypical antipsychotic drugs. SN - 0091-3057 UR - https://www.unboundmedicine.com/medline/citation/15680174/Clozapine_enhances_disruption_of_prepulse_inhibition_after_sub_chronic_dizocilpine__or_phencyclidine_treatment_in_Wistar_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-3057(04)00385-5 DB - PRIME DP - Unbound Medicine ER -