Different Acute Effects of the Tyrosine Hydroxylase Inhibitors a-Methyl-p-Tyrosine and 3-Iodo-L-Tyrosine on Hypothalamic Noradrenaline Activity and Adrenocorticotrophin Release in the Rat

Abstract

Computerized gas chromatography-mass spectrometry techniques using selected ion monitoring and deuterated internal standards were used to assay simultaneously the medial basal hypothalamic concentrations of dopamine (DA) and noradrenaline (NA) and their major metabolites in individual rats 30 min after the administration of two different inhibitors of tyrosine hydroxylase, a-methyl-ptyrosine (a-MT) and 3-iodo-L-tyrosine (MIT). Consistent with inhibition of DA synthesis, administration of both a-MT and MIT resulted in marked reductions (P<O· 005) in the hypothalamic concentrations of DA and its metabolite homovanillic acid as well as in highly significant increases in prolactin secretion. a-MT administration, but not MIT, resulted in a highly significant decrease in NA concentration and a highly significant increase in the concentration of the NA metabolite 3,4-dihydroxyphenylethyleneglycol (DHPG). The hypothalamic ratio DHPG/NA was thus markedly increased (P<O· 005) by a-MT indicating increased NA neuronal activity. a-MT administration also resulted in increased ACTH secretion (P<O· 0005), an effect not observed following MIT.It is proposed that the effects on hypothalamic NA activity and ACTH secretion caused by a-MT are stress-mediated and unrelated to tyrosine hydroxylase inhibition. MIT is devoid of these effects but exhibits DA synthesis blockade activity, thus indicating it to be a preferable drug for the acute inhibition of tyrosine hydroxylase in neuroendocrine investigations.

Mechanisms of 5-Hydroxy-L-Tryptophan-Induced Adrenocorticotropin Release: A Major Role for Central Noradrenergic Drive

“…Our animals studies have assessed central (medial basal hypothalamic) monoaminergic neuronal ac tivity in a number of physiological and drug treatment models. In every model thus far examined in which central NNA was stimulated, we have observed a concurrent in crease in ACTH release [21,[23][24][25][26][27], The converse is also the case and we have not observed a single physiological exam ple where ACTH is elevated without concurrently elevated hypothalamic NNA. On the basis of these findings, it ap peared possible that serotoninergic agents which stimu lated ACTH secretion might also cause increased central NNA and that such a noradrenergic response would be the true effector of hypothalamic CRF release.…”

“…Recent evidence from our own group [21,[23][24][25][26] and others [4,11] supports the hypothesis that the major central monoaminergic drive for stress-induced CRF and ACTH release comes from stimulated noradrenergic neuronal ac tivity (NNA). Our animals studies have assessed central (medial basal hypothalamic) monoaminergic neuronal ac tivity in a number of physiological and drug treatment models.…”

“…The DHPG/NE ratio, as previously shown [21][22][23][24][25][26][27], provides an index of hypothalamic NNA. Similarly, we used previously described techniques to assess the neuronal activities of hypothalamic 5-HT from the ratio 5-hydroxyindoleacetic acid (5-HIAA) to 5-HT concentrations [21,22,26]. Incorporating deuterated analogues of each analyte as internal standards, the GC/MS assays for NE.…”

“…DHPG. 5-HIAA and 5-HT were carried out using a Hewlett-Packard 5987A GC/MS data sys tem with extraction and derivatization procedures identical to those previously described [21][22][23][24][25][26][27], The between-assay coefficient of variation for the various compounds varied from 2.5 to 4.0%. Sensitivity was less than 200 fmol for each compound.…”

Studies on the Central and Peripheral Dopaminergic Control of PRL Secretion in Man: Failure to Demonstrate the Existence of a Dopamine-Mediated Prolactin-Inhibiting Factor

“…In these studies we combined the use of monoiodotyrosine (MIT), domperidone and DA. MIT [22], like a-methyltyrosine, a specific inhibitor of tyrosine hydroxylase, readily penetrates the blood-brain barrier and is a useful pharma cological tool for blocking central dopaminergic activity through synthesis inhibition [10,17,18]. Domperidone, a potent DA receptor antagonist, does not penetrate the blood-brain barrier [II,15] and was used solely to block peripheral DA action.…”