Vulnerability of the Mesencephalic Dopaminergic Neurons of the Human Neonate to Prolonged Perinatal Hypoxia: An Immunohistochemical Study of Tyrosine Hydroxylase Expression in Autopsy Material

Abstract

Experimental studies indicate that hypoxia to the fetus, a common occurrence in many birth complications in humans, results in long-term disturbances of the central dopaminergic (DA) systems that persist in adulthood. Because dysregulation of DA systems is involved in the pathophysiology of many neurological and psychiatric disorders, we investigated the effects of perinatal hypoxia on the mesencephalic DA neurons of the human neonate using immunohistochemistry. We studied the expression of tyrosine hydroxylase (TH), the first and rate-limiting enzyme in catecholamine synthesis, in substantia nigra, and ventral tegmental area of 18 neonates in relation to the age and severity/duration of hypoxic injury estimated by neuropathological criteria. In severe/abrupt perinatal hypoxia, intense TH staining was observed in substantia nigra, ventral tegmental area, and, surprisingly, in the nonpreganglionic Edinger-Westphal nucleus. In severe/prolonged hypoxia, there was a striking reduction or even absence of TH immunoreactivity in all the mesencephalic nuclei. These observations suggest that at early states of perinatal hypoxia, there is a massive increase in dopamine synthesis and release that is followed by feedback blockage of dopamine synthesis through inhibition of TH by the end product dopamine. Early dysregulation of DA neurotransmission could predispose infant survivors of severe perinatal hypoxia to dopamine-related neurological and/or cognitive deficits later in life.