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Neurobiological Substrates Mediating the Reinforcing Effects of Psychomotor Stimulant and Opiate Drugs
Published in Edythe D. London, Imaging Drug Action in the Brain, 2017
Carol B. Hubner, George F. Koob
Given this neurochemical profile, behavioral investigations have attempted to determine the relative importance of these neurotransmitters in mediating the reinforcing effects of psychomotor stimulant drugs. An early study by Pickens et al. (1968) found that inhibition of catecholamine synthesis using low doses of alpha-methyl-para-tyrosine (AMPT) increased rates of methamphetamine self-administration. Higher doses of AMPT caused an initial increase in rate of responding, which was followed by a period in which responding was eliminated. Repeated high dose pretreatment with AMPT in rats trained to self-administer amphetamine also disrupted the re-acquisition of self-administration behavior (Davis and Smith, 1972). These results suggested that depletion in catecholamines attenuated the reinforcing efficacy of amphetamine. Since inhibition of tyrosine hydroxylase activity results in a reduction in tissue concentrations of both dopamine and norepinephrine in the CNS, questions remained regarding the relative importance of these neurotransmitters in mediating the reinforcing effects of stimulant drugs.
Complications of Laparoscopic Adrenal Surgery
Published in Kevin R. Loughlin, Complications of Urologic Surgery and Practice, 2007
Alpha-blocking agents can be augmented with alpha-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor, which blocks the rate-limiting conversion of tyrosine to dopa in the catecholamine synthetic pathway as this may result in better blood pressure control, less bleeding, and less of a need for intra-operative fluid replacement (50,51). Catecholamine synthesis can be reduced by 40% to 80% (48). This is particularly useful in patients who haved cardiomyopathy, are resistant to phenoxybenzamine, or who have multiple catecholamine-secreting tumors (36).
Norepinephrine in Depression and Anxiety
Published in Siegfried Kasper, Johan A. den Boer, J. M. Ad Sitsen, Handbook of Depression and Anxiety, 2003
As the synthetic pathways for monoamines were discovered, it became possible to specifically enhance or block a particular step. Experimentation with various substrates for the newly discovered synthetic enzymes revealed that chemical modification of some precursors caused them to act as reversible inhibitors of key rate-limiting enzymes. One example of this was alpha methyl para tyrosine (AMPT). AMPT reversibly inhibits tyrosine hy-droxylase, the rate-limiting enzyme in the synthesis of NA and DA synthesis (Fig. 1).
Effects of nepicastat upon dopamine-β-hydroxylase activity and dopamine and norepinephrine levels in the rat left ventricle, kidney, and adrenal gland
Published in Clinical and Experimental Hypertension, 2020
Diogo Nóbrega Catelas, Maria Paula Serrão, Patricio Soares-Da-Silva
When considering the potential therapeutic benefits of DβH inhibitors, it is worthwhile to mention that inhibition of tyrosine hydroxylase (TH), which catalyzes the rate-limiting step in the synthesis of catecholamines, by alpha-methyl-p-tyrosine causes reserpine-like adverse effects as it enters the central nervous system and depletes brain NE and DA; bearing this in mind, alpha-methyl-p-tyrosine is occasionally used as an adjuvant (with phenoxybenzamine) to treat phaeochromocytomas that cannot be removed surgically, but not for the treatment of essential hypertension (35). Considering the use of a peripheral selective DβH or TH inhibitor (in order to avoid central nervous system adverse effects), DβH inhibition has the potential benefit of increasing DA, ultimately leading to augmentation in vasodilation and natriuresis through activation of dopamine receptors (6,14). Though dopamine itself can activate adrenergic receptors, it should be underscored that dopamine effects upon α-adrenoceptors in the vasculature only take place at very high concentrations (36,37).