DESMETHYL METABOLITES OF SEROTONERGIC UPTAKE INHIBITORS ARE MORE POTENT FOR SUPPRESSING CANINE CATAPLEXY THAN THEIR PARENT COMPOUNDS

Our series of pharmacological studies on canine narcolepsy has suggest ed that the adrenergic systems are more critically involved in the reg ulation of cataplexy than the serotonergic and dopaminergic systems. T his, however, is an apparent contradiction to data obtained in human p atients, which show that chronic oral administration of serotonergic u ptake inhibitors, such as clomipramine, zimelidine and fluoxetine, is effective in reducing cataplexy. To explore this discrepancy, we have assessed the anticataplectic effects of various serotonergic uptake in hibitors and their active desmethyl metabolites on canine cataplexy. W e found that the anticataplectic effect of the desmethyl metabolites, which are usually more potent for in vitro adrenergic uptake inhibitio n, was more potent and developed more rapidly than the effect of the p arent compounds. Furthermore, the anticataplectic potency was positive ly correlated to the adrenergic uptake inhibition and was negatively c orrelated with serotonergic uptake inhibition among the 10 compounds t ested. These results are consistent with our hypothesis of a preferent ial involvement of the adrenergic system in the control of cataplexy. Our results also suggest that the anticataplectic effect of ''selectiv e'' serotonergic uptake inhibitors in human narcolepsy might be mediat ed by their less selective active metabolites.