Received for publication June 23, 2005.
Revised August 23, 2005.
Accepted for publication August 23, 2005.

An Investigation of the Effects of Mood Stabilizers on Murine Prepulse Inhibition Deficits induced by Dopamine or Glutamate Dysregulation

Abstract

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 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 amphetamine- or ketamine-induced disruption of PPI; 4) phenytoin (30 mg/kg) did not prevent amphetamine- or 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 anti-manic and mood-stabilizing treatments.

Key words: bipolar mania, carbamazepine, dopamine, glutamate, lithium, prepulse inhibition

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