Atomoxetine and nicotine enhance prepulse inhibition of acoustic startle in C57BL/6 mice

Abstract

Deficits in sensory-gating, often measured as deficits in prepulse inhibition of acoustic startle (PPI), are associated multiple with disorders including schizophrenia, attention deficit and hyperactivity disorder (ADHD), and withdrawal from nicotine. Drugs that can reverse deficits in PPI may serve as therapeutic agents for nicotine withdrawal, ADHD, and/or schizophrenia. The present study investigated the effects of acute atomoxetine, a norepinephrine reuptake inhibitor, nicotine, and mecamylamine, a nicotinic acetylcholinergic antagonist, on PPI and acoustic startle in C57BL/6 mice. Three doses of atomoxetine (0.2, 2.0, and 20 mg/kg) were administered prior to testing PPI and startle. The 0.2 and 2.0 mg/kg doses enhanced PPI and the 20 mg/kg dose enhanced startle. A second experiment investigated the effects of 2.0 mg/kg atomoxetine and 1.0 mg/kg mecamylamine administered alone or together on PPI and startle. As before, atomoxetine enhanced PPI. Mecamylamine did not alter PPI and did not block the enhancement of PPI by atomoxetine. Neither drug altered startle. A third experiment investigated the effects of 2.0 mg/kg atomoxetine and 0.125 mg/kg nicotine administered alone or together on PPI and startle. Both drugs enhanced PPI when administered alone. However, when co-administered, no enhancement of PPI was seen. Neither nicotine nor atomoxetine altered startle. The present results demonstrate that acute doses of nicotine and atomoxetine enhance PPI independent of effects on startle and that the enhancement of PPI by atomoxetine occurs independent of the nicotinic acetylcholinergic system. Thus, the newly available medication for ADHD, atomoxetine, could be a potential therapeutic agent for disorders associated with disrupted PPI such as withdrawal from nicotine.