The atypical antipsychotic drugs are a major advance over the older drugs that frequently induced extrapyramidal side effects (EPS). These newer drugs, except for clozapine, continue to induce EPS at higher doses. Despite its superior efficacy in the treatment of refractory schizophrenic patients, clozapine produces measurable cognitive side effects as well as distinctive, but not EPS-like, motor effects in both humans and rats. The over arching purpose of this proposal is to quantify, in rats and in inbred strains of mice, the motor and cognitive side effects of clozapine and other atypical antipsychotic drugs as well as to continue efforts to quantitate low-dose EPS in rodents. Three, primary behavioral measurement procedures will be used: 1) the food-anticipation-operant-microcatalepsy (FAOM) task that models low dose EPS (bouts of immobility that interrupt behavior) and bradykinesia (slowing of movements) in both rats and mice; 2) the sustained attention task (SAT) that concurrently measures reaction time and cognitive performance and closely resembles the continuous performance task that reveals deficits characteristic of schizophrenia; 3) the forelimb tremor task (FT) that uses force-transducer technology and Fourier analysis to quantify drug-induced tremor and detects the hypotonia and antitremor effects of clozapine. In the FAOM procedure, the EPS liability of atypical antipsychotics clozapine, risperidone, sertindole, quetiapine, and olanzapine will be evaluated in haloperidol-sensitized rats. When haloperidol-treated inbred strains of mice were compared in the FAOM task, the C57bl/6 mice showed striking EPS-like effects while the Balb/c mice did not-a result suggesting genetic causes. Several inbred strains of mice will be compared to identify strains likely to express EPS-like effects of atypical antipsychotic drugs. The SAT procedure will be used with rats to assess deleterious cognitive effects of chronic clozapine. The FT task will be used with rats to explore clozapine's recently discovered withdrawal effect (tremor rebound), to evaluate other atypical antipsychotics for clozapine-like motor effects, and to assess clozapine's ability to dampen tremor induced by harmaline or physostigmine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH043429-13
Application #
6391926
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (01))
Program Officer
Winsky, Lois M
Project Start
1988-04-01
Project End
2004-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
13
Fiscal Year
2001
Total Cost
$214,610
Indirect Cost
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
072933393
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Bethel-Brown, Crystal S; Zhang, Hongyu; Fowler, Stephen C et al. (2010) Within-session analysis of amphetamine-elicited rotation behavior reveals differences between young adult and middle-aged F344/BN rats with partial unilateral striatal dopamine depletion. Pharmacol Biochem Behav 96:423-8
Fowler, Stephen C; Miller, Benjamin R; Gaither, Thomas W et al. (2009) Force-plate quantification of progressive behavioral deficits in the R6/2 mouse model of Huntington's disease. Behav Brain Res 202:130-7
Fowler, Stephen C; Pinkston, Jonathan; Vorontsova, Elena (2009) Timing and space usage are disrupted by amphetamine in rats maintained on DRL 24-s and DRL 72-s schedules of reinforcement. Psychopharmacology (Berl) 204:213-25
Pinkston, Jonathan W; Madden, Gregory J; Fowler, Stephen C (2008) Effects of white and infrared lighting on apomorphine-induced pecking in pigeons. Behav Pharmacol 19:347-52
Fowler, Stephen C; Pinkston, Jonathan W; Vorontsova, Elena (2007) Clozapine and prazosin slow the rhythm of head movements during focused stereotypy induced by d-amphetamine in rats. Psychopharmacology (Berl) 192:219-30
Stanford, John A; Osterhaus, Gregory L; Vorontsova, Elena et al. (2006) Measuring forelimb force control and movement in Fischer 344/Brown Norway rats: effects of age and lorazepam. Behav Pharmacol 17:725-30
McKerchar, Todd L; Zarcone, Troy J; Fowler, Stephen C (2006) Use of a force-plate actometer for detecting and quantifying vertical leaping induced by amphetamine in BALB/cJ mice, but not in C57BL/6J, DBA/2J, 129X1/SvJ, C3H/HeJ, and CD-1 mice. J Neurosci Methods 153:48-54
McKerchar, Todd L; Zarcone, Troy J; Fowler, Stephen C (2005) Differential acquisition of lever pressing in inbred and outbred mice: comparison of one-lever and two-lever procedures and correlation with differences in locomotor activity. J Exp Anal Behav 84:339-56
McKerchar, T L; Fowler, S C (2005) Dissimilar effects of subchronic clozapine and haloperidol on operant lever pressing in C57BL/6J, BALB/cJ, and LP/J mice. Behav Pharmacol 16:585-9
Fowler, Stephen C; Birkestrand, Brenda; Chen, Rong et al. (2003) Behavioral sensitization to amphetamine in rats: changes in the rhythm of head movements during focused stereotypies. Psychopharmacology (Berl) 170:167-77

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