Separable noradrenergic and dopaminergic regulation of prepulse inhibition in rats: implications for predictive validity and Tourette Syndrome.

INTRODUCTION: Startle inhibition by lead stimuli (prepulse inhibition, "PPI"), and the disruption of this process by dopamine agonists and N-methyl-D: -aspartate (NMDA) antagonists, are used in predictive models for antipsychotic development. PPI is also disrupted by the norepinephrine alpha-1 agonist, cirazoline, and the PPI-disruptive effects of the indirect dopamine agonist amphetamine are opposed by the norepinephrine reuptake inhibitor, desipramine. The hypothesis that PPI may be regulated by norepinephrine, or by interactions between dopamine and norepinephrine substrates, was tested in a series of experiments with the alpha-2 agonist, clonidine, which is used clinically to treat Tourette Syndrome (TS). MATERIALS AND METHODS: PPI was measured in male Sprague-Dawley rats after pretreatment with clonidine or the D2 antagonist haloperidol, and treatment with cirazoline, amphetamine, the D1/D2 agonist apomorphine, or the NMDA antagonist, phencyclidine. RESULTS: PPI was disrupted by cirazoline; this effect was prevented by clonidine but not haloperidol. PPI was disrupted by apomorphine; this effect was prevented by haloperidol but not clonidine. Clonidine also failed to oppose the PPI-disruptive effects of amphetamine and augmented the PPI-disruptive effects of phencyclidine. Over a range of prepulse intervals, clonidine enhanced PPI at short intervals and opposed the PPI-disruptive effects of cirazoline at long intervals. CONCLUSIONS: PPI is regulated by both norepinephrine and dopamine substrates that are neurochemically separable. The PPI-protective effects of clonidine suggest that the noradrenergic regulation of PPI may have utility for predicting therapeutic benefit in TS for drugs other than antipsychotics. Clonidine's failure to prevent the PPI-disruptive effects of apomorphine or phencyclidine further support the specificity of these PPI models for detecting drugs with antipsychotic properties.