Tolerance to fluphenazine and supersensitivity to apomorphine in central dopaminergic systems after chronic fluphenazine decanoate treatment

Abstract

Fluphenazine decanoate was administered chronically to rats on a schedule for which marked tolerance developed to acute fluphenazine effects on several parameters of dopaminergic neuronal function. DOPAC and HVA levels, indicators of dopaminergic activity, were quantitated in terminal areas of the mesocortical, mesolimbic and nigrostriatal systems. With this fluphenazine regimen tolerance developed not only in the nigrostriatal and mesolimbic but also in the mesocortical dopamine system to the elevation of metabolite levels induced by acute fluphenazine administration. Evidence was obtained that tolerance was functional rather than metabolic and was characterized by a large reduction in the accumulation of metabolites which normally follows a challenge dose of fluphenazine. Other experiments suggested that the results were not due to the effects of chronic fluophenazine on the noradrenergic innervation of the cortex and were not explained by altered catabolism or clearance of the dopamine metabolites. During withdrawal from chronic fluphenazine decanoate treatment supersensitivity to apomorphine developed in the striatum. The time courses of the disappearance of apomorphine supersensitivity and of the reversal of tolerance to a fluphenazine challenge were different.