Use of microdialysis for monitoring tyrosine hydroxylase activity in the brain of conscious rats.
An on-line microdialysis system was developed which monitored the 3,4-dihydroxyphenylalanine (DOPA) formation in the striatum during infusion of a submicromolar concentration of an L-aromatic amino-acid decarboxylase inhibitor (NSD 1015). The absence of DOPA in dialysates of 6-hydroxydopamine-pretreated rats and the disappearance of DOPA after administration of alpha-methyl-p-tyrosine indicated that the dialyzed DOPA was derived from dopaminergic nerve terminals. Next we investigated whether the steady-state DOPA concentration in striatal dialysates could be considered as an index of tyrosine hydroxylase activity. The increase in DOPA output after intraperitoneal administration of haloperidol or gamma-butyrolactone and the decrease in DOPA output after intraperitoneal administration of apomorphine are in excellent agreement with results of postmortem studies, in which a decarboxylase inhibitor was used to measure the activity of tyrosine hydroxylase. The effect of haloperidol on DOPA formation was not visible when a U-shaped cannula (0.80 mm o.d.) was used. Some methodological problems related to microdialysis of the haloperidol-induced increase in DOPA formation are discussed. We concluded that the proposed model is a powerful and reliable in vivo method to monitor tyrosine hydroxylase activity in the brain. The method is of special interest for investigating the effect of compounds which are not able to pass the blood-brain barrier. As an application of the method in the latter situation, we report the effect of infusion the neurotoxin 1-methyl-4-phenylpyridinium ion (10 mmol/L infused over 20 min) on the activity of striatal tyrosine hydroxylase.
Westerink
B H
BH
Department of Medicinal Chemistry, University of Groningen, The Netherlands.
De Vries
J B
JB
Duran
R
R
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D015107:4-Butyrolactone / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003243:Consciousness; D003956:Dialysis / Q000379:methods*; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D008991:Monitoring, Physiologic / Q000379:methods*; D051381:Rats; D011919:Rats, Inbred Strains; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019805:alpha-Methyltyrosine
D008781:Methyltyrosines; D004295:Dihydroxyphenylalanine; D019805:alpha-Methyltyrosine; D014446:Tyrosine 3-Monooxygenase; D006220:Haloperidol; D001058:Apomorphine; D015107:4-Butyrolactone; D015655:1-Methyl-4-phenylpyridinium