IN-VIVO EFFECTS OF REMOXIPRIDE AND AROMATIC RING METABOLITES IN THE RAT

The in vivo effects of remoxipride, in relation to some of its identif ied metabolites, were investigated in adult male Sprague-Dawley rats, The methods used included: (1) estimation of the in vivo rate of brain monoamine synthesis by measuring the accumulation of dihydroxyphenyla lanine and 5-hydroxytryptophan after decarboxylase inhibition; (2) obs ervations of spontaneous locomotor activity in a photocell-equipped op en-field arena (approximate to 0.5 m(2)); (3) treadmill locomotion (ap proximate to 4 m min(-1)); (4) inclined grid (60 degrees) catalepsy Ze st; (5) d-amphetamine-induced (1.0 mg kg(-1)) hyperlocomotion;(6) quin pirole-induced (0.4 mg kg(-1)) hypothermia. By use of one or-mo-re of these tests, the findings with remoxipride were as follows: First, rem oxipride had a late onset of action (up to 3 h). Second, potency and e fficacy depended on exposure to hepatic metabolism Thus, intraperitone al administration was more effective than the subcutaneous route, wher eas virtually all biological effects were lost on intracerebroventricu lar administration. The ED,, values (mu mol kg(-1), neostriatal dihydr oxyphenylalanine accumulation) for remoxipride and a range of its phen olic aromatic ring metabolites were: remoxipride (approximate to 20), NCQ-344 (approximate to 0.01), FLA-797 (approximate to 0.1) FLA-908 (a pproximate to 2.2), NCQ-436 (approximate to 25) and NCQ-469 (approxima te to 30). Considering remoxipride as a nonclozapine atypical antipsyc hotic drug, together with the fact that remoxipride behaves as a prodr ug in the laboratory studies above, further characterization of the ph armacodynamic profile of its metabolites remains a challenge.