Metabolism Dopamine

An additional benefit of COMT inhibitors can be found in positron emission tomography (PET) studies. In PET, using 6-[18F]-fluoro-L-dopa (6-FD) to visualize the brain dopamine metabolism, the peripheral formation of 3-0-methyl-6-[18F]-fluoro-L-dopa (3-OMFD) by COMT is harmful. 3-OMFD contaminates the brain radioactivity analysed since it is easily transported like 3-OMD to the... 

MAO converts dopamine to DOPAC (3,4-dihydrox-yphenylacetic acid), which can be further metabolized by COMT to form homovanillic acid (HVA). HVA is the main product of dopamine metabolism and the principal dopamine metabolite in urine. Increased neuronal dopaminergic activity is associated with increases in plasma concentrations of DOPAC and HVA. COMT preferentially methylates dopamine at the 3 -hydroxyl position and utilizes S-adenosyl-L-methio-nine as a methyl group donor. COMT is expressed widely in the periphery and in glial cells. In PD, COMT has been targeted since it can convert l-DOPA to inactive 3-OMD (3-O-methyl-dopa). In the presence of an AADC inhibitor such as carbidopa, 3-OMD is the major metabolite of l-DOPA treatment. 

Snell, L.D. Mueller, Z.M. Gannon, R.L. Silverman, P.B. and Johnson, K.M. A comparison between classes of drugs having phencyclidine-like behavioral properties on dopamine effect i n vitro and dopamine metabolism j n vivo. J. Pharmacol Fxp Ther 231 261-269, 1984. 

Farber J., Miller J. D., Crawford K. A., McMillen B. A. (1983). Dopamine metabolism and receptor sensitivity in rat brain after REM sleep deprivation. Pharmacol Biochem. Behav. 18(4), 509-13. 

Louilot, A., Le Moal, M., and Simon, H., Presynaptic control of dopamine metabolism in the nucleus accumbens. Lack of effect of buspirone as demonstrated using in vivo voltammetry, Life Sci., 40, 2017, 1987. 

Kim HS, Iyengar S and Wood P (1986). Opiate actions on mesocortical dopamine metabolism in the rat. Life Sciences, 39, 2033-2036. 

Michel Morange Yes, but you have another mutation in another gene which is involved in dopamine metabolism which affects the same brain structure, and which gives rise to exactly the same problems with maternal behaviour. So it s an argument to show that you have nothing specific with maternal behaviour but something specific with one brain substructure. 

McKinney E et al. Association between polymorphisms in dopamine metabolic enzymes and tobacco consumption in smokers. Pharmacogenetics 2000 10 1-9. 

A final pharmacological strategy for treatment of Parkinson s disease comes from enzyme inhibition. This was initally done with an MAO inhibitor, L-deprenyl (selegiline, Eldepryl), but more recent drugs have become available that are COMT inhibitors. L-Deprenyl is an inhibitor of MAOB, which is the form of MAO selective to dopamine. Thus, it may increase the amount of available dopamine for release. Second, it may protect dopamine neurons by reducing the oxidative stress concomitant with dopamine metabolism (Olanow 1997). Third, L-deprenyl is metabolized into amphetamine and methamphetamine, which may contribute to their antiparkinsonian effects. Unlike other treatments for Parkinson s disease, L-deprenyl seems to slow the progression of the disease. Tolcapone (Tasmar) is a COMT inhibitor, which prevents extracellular breakdown of dopamine. 

Mereu GP, Pacitti C, Argiolas A. (1983). Effect of (-)-cathinone, a khat leaf constituent, on dopaminergic firing and dopamine metabolism in the rat brain. Life Sci. 32(12) 1383-89. 

Meneguz A, Betto P, Ricciarello G. (1994). Different effects of harmine on plasma concentrations of L-dopa and on cerebral dopamine metabolism in rabbits and rats. Pharmacology. 48(6) 360-66. 

These results led to the suggestion that the functional unit of reward is a population of individual neurons ( hedonistic neurons ) scattered around reward areas of the brain which are specifically responsive to certain transmitters and are presumably connected to pathways controlling motivated behaviour. Phillips and Fibiger (1989) demonstrated an increase in dopamine metabolism, synthesis and release in the ventral tegmental area and nucleus accumbens during ICSS in rats, an increase proportional to the stimulation rate and intensity. 

The inabihty of the neurons to eliminate the oxidative load may result in a self-perpetuating cycle of oxidative damage that ultimately leads to neuronal death. One source of oxidative stress may be dopamine metabolism (Fig. 31.2). The excessive excitatory activity in the substantia nigra created by the loss of dopamine actions within the striatum could lead to excitotoxicity that is mediated by glutamate. 

Another drug used in the treatment of Parkinson s disease is selegiline (also known as deprenyl, or Eldepryl). It is an irreversible inhibitor of MAO-B, an important enzyme in the metabolism of dopamine (Fig. 33.2). Blockade of dopamine metabolism makes more dopamine available for stimulation of its receptors. Selegiline, as monotherapy, may be effective in the newly diagnosed patient with parkinsonism because its pharmacological effect enhances the actions of endogenous dopamine. 

The antischizophrenic actions of these drugs may not consist simply of postsynaptic blockade of hyperactive dopamine systems. Such a blockade occurs within hours, while most symptoms improve over weeks. This discrepancy in the latency to therapeutic effect has been hypothesized to be linked to drug-induced changes in dopaminergic activity after initiation of therapy, dopamine turnover increases, but after continued antipsychotic treatment, tolerance develops and dopamine metabolism returns to normal. This downward adjustment of dopaminergic activity is consistent with the decreased plasma concentrations of the dopamine metabolite homovanillic acid, an observation that correlates temporally with the clinical response to drug treatment. 

Roth. Persistent and anatomically selective reduction in prefrontal cortical CS358 dopamine metabolism after repeated, intermittent cannabinoid administration to rats. Synapse 2003 49(1) 61-66. 

CS434 Jentsch, J. D., C. D. Verrico, D. Le, and R. H. Roth. Repeated exposure to delta 9-tetrahydrocannabinol reduces prefrontal cortical dopamine metabolism in the rat. NeurosciLett 1998 246(3) 169-172. 

Mecfianism of Action A phenylalkylamine sympathomimetic with activity similar to amphetamines that stimulates the central nervous system (CNS) and elevates blood pressure (BP) most likely mediated via norepinephrine and dopamine metabolism. Causes stimulation of the hypothalamus. Therapeutic Effect Decreases appetite. Pharmacokinetics The pharmacokinetics of phendimetrazine tartrate has not been well established. Metabolized to active metabolite, phendimetrazine. Excreted in urine. Half-life 2-4 hr. 

Mechanism of Action A sympathomimetic amine structurally similar to dextroamphetamine and is most likely mediated via norepinephrine and dopamine metabolism. Causes stimulation of the hypothalamus. Therapeutic Effect Decreased appetite. 

Further evidence concerning anxiolytic effects of neurosteroids involves its action on the prefrontal cortical dopamine system. This system has been identified as one of the neuroanatomically involved CNS areas in stress and anxiety responses, where increases in dopamine metabolism are observed following a variety of stressors [A. Y. Deutch and Roth 1990]. Grobin et al. [1992] demonstrated that intracerebroventricularly administered allo-THDOC effectively reduced dopamine metabolism in rats, thereby antagonizing stress-induced activation of the prefrontal cortical dopamine innervation. 

Hesketh JE, Nicolaou NM, Arbuthnott GW, et al The effect of chronic lithium administration on dopamine metabolism in rat striatum. Psychopharmacology 56 163-166, 1978... 

Rowell PP, Winkler DL Nicotinic stimulation of [ HJacetylchoUne release from mouse cerebral cortical synaptosomes. J Neurochem 43 1593-1598, 1984 Roy A, Karoum F, Pollack S Marked reduction in indexes of dopamine metabolism among patients with depression who attempt suicide. Arch Gen Psychiatry 49 447-450, 1992... 

Di Rocco A, Brannan T, Prikhojan A, et al Sertraline induced parkinsonism a case report and an in-vivo study of the effect of sertraline on dopamine metabolism. J Neural Transm 105 247—251, 1998 Doughty Ml, Lyle WM Medications used to prevent migraine headaches and their potential ocular adverse effects. Optom Vis Sci 72 879-891, 1995... 

Dopamine metabolism was covered in the discussion of general catecholamine biochemistry. Dopamine is stored in synaptic vesicles, and this storage can be manipulated. Although the reuptake of released DA is the major deactivating mechanism, MAO and COMT act enzymatically on DA in the same way as on NE. However, following the degradative pathway of NE, DA will finally be metabolized to homovanillic acid (3-methoxy-4-hydroxy-phenylacetic acid), since it lacks the P-hydroxyl group. 

Dopamine metabolism inhibitors interfere with monoamine oxidase and catecholamine-0-methyltransferase. Monoamine oxidase will be discussed separately in chapter 8. 

Leenders, K.L., Palmer, A.J., Quinn, N., Clark, J.C., Firnau, G., Garnett, E.S., Nahmias. C., Jones. T.. Marsden. C.D. Brain dopamine metabolism in patients with Parkinson s disease measured with positron emission tomography. J. NeuroL Neurcsurg. Psychiatry 49, 853-860, 1986. 

Schrater, Paul A., Albert C. Russo, Toni I.. Stanton, J. Robert Newman, Lynn M. Rodriguez, and Alexander L. Beckman. 1993. "Changes in Striatal Dopamine Metabolism During the Development of Morphine Physical Dependence in Rats Observations Using In Vivo Microdialysis." Life Sciences 52 1535—45. 

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