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Molecular Pharmacology, Vol 12, 1070-1081, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Dopaminergic Neurons: Effects of Electrical Stimulation on Tyrosine Hydroxylase

L. CHARLES MURRIN 1, VICTOR H. MORGENROTH III 1, and ROBERT H. ROTH 1

1 Departments of Pharmacology and Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06510

Electrical stimulation of the nigro-neostriatal and mesolimbic dopaminergic pathways was employed in order to examine the effects of increased impulse flow on the properties of tyrosine hydroxylase prepared from the neostriatum and olfactory tubercles. Stimulation at a frequency of 15 Hz for 10 min resulted in an increase in the activity of tyrosine hydroxylase prepared from the neostriatum on the stimulated side and assayed in the presence of subsaturating concentrations of substrate and pterin cofactor. Stimulation periods of 15 and 20 min did not produce a further significant increase in tyrosine hydroxylase activity. This activation of the enzyme persisted unchanged for 10 min after cessation of stimulation and was partially present 15 min after stimulation. Further analysis of this activation showed that it was characterized by decreases in Km of tyrosine hydroxylase for substrate, tyrosine, and cofactor, tetrahydrobiopterin, and an increase in Ki for the feedback inhibitor, dopamine. Similar kinetic changes due to electrical stimulation of the mesolimbic pathway were found in the tyrosine hydroxylase isolated from the olfactory tubercles. Addition of adenosine cyclic 3',5'-monophosphate to high-speed supernatants prepared from the neostriatum produced kinetic changes in neostriatal tyrosine hydroxylase similar to those produced by increased impulse flow due to electrical stimulation. However, addition of cyclic AMP produced no further change in the properties of the enzyme already activated by electrical stimulation. These results are discussed in terms of possible mechanisms by which impulse flow may control dopamine synthesis.

Submitted on February 3, 1976
Accepted on July 27, 1976




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