The effects of d-amphetamine, methylphenidate, sydnocarb, and caffeine on prepulse inhibition of the startle reflex in DBA/2 mice

Abstract

Rationale: Dopamine (DA) agonists decrease prepulse inhibition (PPI) and are widely used in translational models for the sensorimotor gating deficits in schizophrenia. Reductions in PPI induced by DA agonists are routinely reversed by antipsychotics in these translational models. Nevertheless, under conditions of low-baseline PPI, DA agonists may increase PPI in humans and experimental animals. DBA/2 mice have naturally low-baseline PPI, which as in the drug-induced translational models, is increased by antipsychotics.

Objective: Determine whether DBA/2 mice respond like other models of low-baseline PPI by evaluating the effect of psychostimulants (caffeine, 30-100 mg/kg IP) and the indirect DA agonists d-amphetamine (0.3-10 mg/kg IP), methylphenidate (10-100 mg/kg IP), and sydnocarb (10-30 mg/kg IP), a selective DA transporter inhibitor on PPI. Furthermore, baseline PPI in DBA/2 mice was increased by noise exposure and the effect of d-amphetamine was assessed.

Results: PPI was increased at one dose for each of the psychostimulants when baseline PPI was low in naïve DBA/2 mice. Effective doses were 3 mg/kg of d-amphetamine, 30 mg/kg of methylphenidate, 30 mg/kg of sydnocarb, and 100 mg/kg of caffeine. Higher doses of d-amphetamine (10 mg/kg) and methylphenidate (100 mg/kg IP) decreased PPI. When the baseline PPI was increased by noise exposure, 10 mg/kg of d-amphetamine only reduced PPI.

Conclusion: Lower doses of psychostimulants increased PPI in naïve DBA/2 mice in a manner consistent with their naturally low-baseline PPI, and higher doses decreased PPI, consistent with effects observed in most mouse strains.