AUTHOR’S COPY European Journal of Pharmacology Volume 450, Issue 2, 23 August 2002, Pages 141-151 Cyclooxygenase inhibitor modulation of dopamine-related behaviours Brian M. Ross, Robert J. Brooks, Margaret Lee, Kathryn S. Kalasinsky, Shawn P. Vorce, Mary V. Seeman, Paul J. Fletcher and Sylvie D. Turenne 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. Keywords: Catalepsy; Locomotor activity; Prepulse inhibition; Amphetamine; Dopamine; Parkinson's disease; Progressive supranuclear palsy Introduction Cyclooxygenase inhibitors comprise a class of drugs conventionally used in the treatment of pain and inflammation. Cyclooxygenase comprises two forms, cyclooxygenase-1 and cyclooxygenase-2, both of which are present in brain. Although the enzymes are expressed in a number of brain structures including the cortex and basal ganglia (Kawasaki and Tocco), their role in brain function and animal behaviour is unclear. Cyclooxygenase catalyses the oxidation of unesterified polyunsaturated fatty acids within the cell membrane to form prostaglandins, a class of eicosanoids, such as prostacyclin and prostaglandin D2 (Smith et al., 1992). Prostaglandins are transported out of the cell and, in general, act as rapidly inactivated "local hormones" exerting an effect very near to where they are synthesised. Operating through G-protein linked cell-surface receptors they act as regulators of second messengers such as cAMP, inositol phosphates and