Localization of [3H]pimozide in the rat brain in relation to its anti-amphetamine potency

Abstract

Abstract The pharmacological activity of the neuroleptic agent pimozide is well correlated with the concentration of [3H]pimozide in the brain of the Wistar rat. There is an enhanced uptake and retention of [3H]pimozide in the caudate nucleus, an area in which amphetamine and apomorphine act. Its concentration in the caudate nucleus is not correlated with its anti-apomorphine and anti-amphetamine potency. There are, however, significant shifts in the subcellular distribution of [3H]pimozide in the caudate nucleus, from the mitochondrial fraction to the fraction consisting mainly of submicroscopic nerve endings. These shifts correlate well with its pharmacological activity. This points to the small nerve-endings as being the site of action of pimozide. The drug does not influence either the penetration of (+)-[14C]amphetamine into the brain, or its metabolism, indicating that the anti-amphetamine action cannot be due to a decreased penetration of amphetamine into the brain, although a subcellular redistribution of amphetamine induced by pimozide cannot be excluded.