Pharmacological analysis of the functional ontogeny of the nigrostriatal dopaminergic neurons

Functional development of the dopaminergic nigrostriatal projection was studied by determining the age at which the biochemical responses of these neurons to physical or pharmacological manipulation are similar to those of adult neurons. Transection of the pathway acutely elevates striatal dopamine in adult and 8- and 10-day-old rats, but not in the 4- or 6-day-old animal. This axotomy-induced increase in striatal dopamine is believed to be a response of the dopaminergic terminals to cessation of impulse traffic and is secondary to a decrease in dopamine release and a concomitant increase in dopamine synthesis resulting from tyrosine hydroxylase activation. Therefore, this response to axotomy acts as an indicator of (1) the presence of impulse traffic in the pathway, and (2) the ability of tyrosine hydroxylase to be activated in response to a reduction in such impulse traffic. In vivo estimation of tyrosine hydroxylase activity showed that axotomy activates the enzyme at 10 days, but not at 4 days, whereas gamma-hydroxybutyrate is effective at both ages. The fact that the enzyme can be activated by gamma-hydroxybutyrate at 4 days indicates that the lack of effect of axotomy at this age is due to the absence of impulse traffic in the system. This conclusion is supported by the finding that the AMT-induced depletion of striatal dopamine is not related to impulse conduction at 4 days since transection of the pathway has no effect on the rate of dopamine loss whereas such transection blocks the AMT-induced depletion at 10 days of age. Nevertheless, despite the absence of neuronal activity at 4 days of age, these neurons are capable of generating and conducting impulse traffic since both 4- and 10-day-old rats showed increased striatal dihydroxyphenylacetic acid (DOPAC) levels when treated with haloperidol indicating increased dopamine release; such increase in DOPAC being dependent on an intact pathway. Given this data, the most parsimonious explanation of the abrupt development of the response to axotomy after the 6th day of age is that an event occurs which physiologically initiates impulse traffic. This event may be activation of afferent neuronal inputs to the cell bodies of the nigrostriatal projection.