Dopamine 2- and serotonine 2-receptor-antagonism by antipsychotics in man

Abstract

The sequential action of phospholipase A2 and cyclooxygenase leads to the production of prostaglandins in the brain, an event hypothesised to cause dopaminergic stimulation. To investigate this further, we examined the effect of the nonselective cyclooxygenase inhibitors indomethacin and piroxicam on several indices of dopaminergic function in adult male rats. Both drugs inhibited catalepsy induced by the dopamine D1-like receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390), the dopamine D2-like receptor antagonist raclopride and by haloperidol, findings in agreement with a dopaminergic effect of cyclooxygenase inhibitors. However, neither cyclooxygenase inhibitor had an effect upon disruption of prepulse inhibition of the auditory startle reflex by amphetamine or on the rate of amphetamine self-administration. Both drugs reduced amphetamine-stimulated locomotor activity. Our data indicate that the mechanism by which cyclooxygenase inhibitors alter motor behaviour is unlikely to be due to a simple direct action at the dopaminergic synapse. Their apparent ability to antagonise hypoactivity without generalised dopaminergic stimulation suggests that other, possibly multiple, neurotransmitter systems may be involved.