Effects of amantadine and bromocriptine on startle and sensorimotor gating: parametric studies and cross-species comparisons

Background: We recently reported that prepulse inhibition (PPI) in humans was increased by the dopamine (DA) agonist/N-methyl-D-aspartate (NMDA) antagonist amantadine (200 mg), but was not significantly altered by the DA agonist bromocriptine (1.25-2.5 mg). PPI-enhancing effects of DA agonists occur in rats under specific stimulus conditions, including short prepulse intervals (<30 ins). We characterized the effects of amantadine and bromocriptine on PPI across species, assessing: (1) dose-response effects on PPI in rats over 10- to 120-ms prepulse intervals; (2) drug effects on PPI in humans, using this same range of prepulse intervals; and (3) drug effects on measures related to PPI, including PPI of perceived stimulus intensity (PPIPSI), and startle habituation. Methods: Drug effects on PPI were assessed in male Sprague Dawley rats (n=90) and humans (n=49); startle habituation and PPIPSI were also studied in humans. Results: Amantadine and bromocriptine exhibited dose- and stimulus-dependent effects on PPI in rats, increasing PPI with short (10-20 ms) prepulse intervals, and decreasing PPI with long (60-120 ms) prepulse intervals. In humans, amantadine increased PPI with both short (20 ms) and long (120 ms) prepulse intervals. Bromocriptine had no significant effect on PPI in humans, but tended to increase PPI at short (20 ms) intervals. Amantadine eliminated PPIPSI. Conclusions: Amantadine modifies prepulse effects on startle in rats and humans, and disrupts prepulse effects on perceived stimulus intensity in humans; bromocriptine has clear effects on PPI in rats, but not in humans. The divergent effects of amantadine on sensorimotor and sensory effects of prepulses may reflect a divergence of brain circuitry regulating these processes.