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NEUROPHARMACOLOGY

An Investigation of the Efficacy of Mood Stabilizers in Rodent Models of Prepulse Inhibition

Department of Psychiatry, University of California, San Diego, California (J.C.O., S.A.B., M.A.G.); and Psychiatry Centre for Excellence for Drug Discovery, GlaxoSmithKline S.p.A., Verona, Italy (C.H.L.)

Acutely manic bipolar patients, like patients with schizophrenia, Tourette's syndrome, panic disorder, and obsessive compulsive disorder, exhibit deficits in sensorimotor gating, as measured by prepulse inhibition (PPI) of the startle response. Here, we assessed the ability of four drugs used in the treatment of bipolar mania—phenytoin, carbamazepine, valproate, and lithium—to reduce the PPI-disruptive effects of ketamine or amphetamine in the 129SvPasIco inbred strain of mice. For comparison, we also assessed the interaction of lithium and amphetamine in C57BL/6J mice. This set of studies yielded four major results. 1) Lithium chloride (85 mg/kg) prevented amphetamine-induced but not ketamine-induced disruption of PPI in both strains of mice. 2) Carbamazepine (50 mg/kg) prevented ketamine-induced but not amphetamine-induced disruption of PPI. 3) Sodium valproate (100 mg/kg) did not prevent amphetamineor ketamine-induced disruption of PPI. 4) Phenytoin (30 mg/kg) did not prevent amphetamineor ketamine-induced disruption of PPI but increased PPI on its own. These studies did not reveal a consistent relationship between the ability of a drug to protect PPI from disruption by ketamine or amphetamine and efficacy in the treatment of bipolar mania. Instead, the diverse effect profiles of these four treatments in reversing the PPI deficits produced by amphetamine or ketamine in mice presumably reflect the differences in their respective pharmacological mechanisms. Hence, further studies using these dopaminergic and glutamatergic models of deficient PPI may provide valuable insights into the mechanisms underlying the differential therapeutic effects of antimanic and mood-stabilizing treatments.

Address correspondence to: Dr. Mark Geyer, Department of Psychiatry, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 920930804. E-mail: mgeyer{at}ucsd.edu

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