Chronic continuous administration of neuroleptic drugs alters cerebral dopamine receptors and increases spontaneous dopaminergic action in the striatum

Abstract

The ‘dopamine hypothesis’ of schizophrenia states that the illness is due to overactivity of dopamine mechanisms in the brain. This hypothesis is based on two facts: (1) drugs, such as amphetamine, that enhance dopaminergic neurotransmission in the brain, may occasionally provoke a schizophrenic psychosis; and (2) acute administration of neuroleptic drugs, which are used to treat schizophrenia and other psychotic illnesses, causes blockade of brain dopamine receptors and initiates a chain of compensatory events which attempt to overcome such an action. We have previously shown that administration of neuroleptic drugs to rats for up to 18 months produces unexpected effects^1,2: after 6 months, all signs of blockade of dopamine receptors in the striatum have disappeared, and thereafter striatal dopamine receptors increase in number and become behaviourally supersensitive to administered dopamine agonists such as apomorphine. We now show that such chronic exposure to neuroleptics completely alters other characteristics of striatal dopamine receptors, and that in the intact animal, these changes are associated with spontaneous overactivity of striatal dopaminergic mechanisms. Unless other dopaminergic brain areas, for example in the mesolimbic or mesocortical regions, react differently from the striatum, the mode of action of neuroleptics, and the dopamine hypothesis of schizophrenia, may have to be reconsidered.