Dopamine agonist effects on startle and sensorimotor gating in normal male subjects: time course studies

Rationale: Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is deficient in schizophrenia and in rodents treated with dopamine (DA) agonists. Reduced PPI is reported in normal humans treated with direct or indirect DA agonists. To facilitate future studies, we assessed the time course of DA agonist effects on PPI in humans, for both direct (bromocriptine: 1.25, 2.5 mg; pergolide: 0.025, 0.1 mg) and indirect DA agonists (amphetamine: 20 mg; amantadine: 200 mg) (n=6-10/dose). Methods: Baseline (no drug) levels of acoustic and tactile startle, as well as uni- and cross-modal PPI, were assessed in 63 normal adult males. Seven to ten days later, subjects were tested in five sessions over 3.5 h after ingestion of placebo or active drug in a double-blind design. Results: Expected drug effects were observed in both autonomic (for example, increased heart rate and blood pressure with amphetamine), somatic (for example, "queasiness" with direct DA agonists), and psychological measures (for example, "happiness", less "drowsiness" with amphetamine). Drugs increased (bromocriptine) or decreased (amantadine) startle magnitude, and caused either no change or modest, time-dependent effects on PPI. Amantadine increased PPI over the test session, a pattern not observed with other DA agonists or placebo. No consistent effects on PPI were observed with either bromocriptine, pergolide, or amphetamine. Drug effects on startle did not consistently correlate with self-assessment measures. Conclusions: Despite evidence of "bioactivity", under the specific experimental conditions of this study, neither direct nor indirect DA agonists had robust effects on startle or PPI. In some cases (for example, amantadine), a time course was identified that will facilitate future studies of DA agonist effects on PPI in humans.