The effect of the stereoisomers of butaclamol on neurotensin content in discrete regions of the rat brain

The prevailing hypothesis concerning the mechanism of antipsychotic drug action is principally based on the striking correlation between their clinical potency and their potency in blockade of D₂ dopamine receptors. However, most of these compounds also have effects at serotonin, acetylcholine, histamine, and α-adrenergic receptors and have recently been shown to alter the concentrations of certain neuropeptides in the rat brain after chronic drug administration. One such neuropeptide that is increased in concentration in dopamine terminal regions by clinically effective neuroleptic drugs is neurotensin (NT). Neurotensin is closely associated with dopamine neurons, as demonstrated by evidence derived from anatomic, physiologic, and pharmacologic studies. In this report, we determined the effects of chronic administration of the potent D₂ receptor antagonist (+)-butaclamol and its inactive (-) stereoisomer on regional brain NT content. Moreover, we sought to determine whether the effects of haloperidol on NT concentrations can be antagonized by concomitant administration of an indirect dopamine agonist, d-amphetamine. Neurotensin content in the caudate nucleus and nucleus accumbens of the rat were significantly increased by 3 weeks of daily injections of haloperidol or (+)-butaclamol, but not (-)-butaclamol. d-Amphetamine did not alter this effect of haloperidol on NT concentrations in either the nucleus accumbens or caudate nucleus. These data are concordant with the hypothesis that D₂ receptor blockade is required for NT concentration increases after antipsychotic drug treatment and that the increase in synaptic cleft dopamine content produced by d-amphetamine cannot reverse this effect of dopamine receptor antagonists.