Novel anticoagulants based on inhibition of the factor VIIa/tissue factor pathway

Abstract

Prepulse inhibition (PPI) of the acoustic startle response is a behavioural tool used to assess sensorimotor gating processes and its disturbances in rats and in humans. PPI in rats is reduced by an overactivity of the dopamine (DA) system. Because there are functional interactions between DA and adenosine receptors, we tested whether PPI can be influenced by the mixed DA receptor agonist apomorphine (APO) and by the unselective adenosine antagonist theophylline (THEO). Combined administration of APO (0.5 mg/kg, i.p.) and THEO (20 mg/kg, i.p.) in doses devoid of significant effects on their own significantly reduced PPI. The PPI-disrupting effect of the combined THEO plus APO treatment was dose-dependently antagonized by co-administration of the selective adenosine A1 agonist CPA (0.15–1.5 mg/kg, i.p.), but not by the A2A agonist CGS21680 (0.1–2 mg/kg, i.p.). These data demonstrate that antagonistic interactions between DA and adenosine, involving adenosine A1 receptors, play an important role in the regulation of PPI. The possible implications of these findings for the use of adenosine agonists in the treatment of schizophrenia are discussed.