Effects of prenatal haloperidol on brain dopamine development

Abstract

<p>Little is known about the potential toxicity of neuroleptics administered during pregnancy, although they are known to cross the placenta and reach the fetal brain. The neuroleptic, haloperidol, is often the drug of choice for treatment of psychotic and affective disorders and sometimes as an adjunct during labour. Hence it is frequently administered to women of childbearing age and during pregnancy. Haloperidol is a potent antagonist of dopamine (DA) receptors in the brain. The question raised is "Does the administration of haloperidol during the period of DA neuron synaptogenesis (third trimester in the rat) interfere with the normal development of DA neurons and post-synaptic receptors? If so does this alter subsequent brain DA function as reflected in behaviour and hormonal regulation in the offspring?" Haloperidol or vehicle (control) were administered to timed-pregnant rats on gestation days 15 to 21. At birth, all offspring were fostered by untreated lactating dams. The effects of this treatment on three DA systems, (nigrostriatal, mesolimbic and tuberoinfundibular systems) in the brains of offspring were assessed on postnatal day 25 using morphological, pharmacological, biochemical and behavioural analyses. The results indicated that haloperidol treatment during the third trimester produced a deficit in the growth of nigrostriatal DA neurons and decreased postsynaptic DA receptors without affecting the postsynaptic enzyme, adenylate cyclase. Offspring of haloperidol rats showed locomotor hyperactivity even after reaching adulthood. They also showed an abnormal increase in prolactin secretion when challenged with haloperidol on postnatal day 25. There was a significant sex difference in behavioural and hormonal responses to haloperidol, with female offspring showing greater sensitivity. These data demonstrate that treatment with haloperidol for even a short period during pregnancy can produce long term, perhaps even permanent alterations in morphological, pharmacological, behavioural and hormonal development of brain DA neurons, in the absence of overt teratogenic effects. Subtle defects in offspring brain development may pre-dispose them to later difficulties associated with abnormal DA function, especially in situations of stress. These findings emphasize the need for further investigation of the potential toxicity of neuroleptics, especially during prenatal development.</p>