Dopamine augmentation

Dopamine has been used for several decades for the treatment of human patients with oliguric ARF (Denton et al 1996, Dishart Kellum 2000). A constant low-dose i.v. infusion (0.5 to 3.0(jLg/ kg/min) produces a dose-dependent increase in the RBF and increases the excretion of sodium and water. Some studies have also reported increases in the GFR but this response is less consistent. A dose-dependent increase in the RBF has also been documented in normal horses (Trim et al 1989). Low doses of dopamine augment the RBF primarily by inducing renal arteriolar vasodilatation by stimulating dopamine D receptors in the intrarenal blood vessels. This effect is typically greater in afferent than in efferent glomemlar arterioles and is the mechanism by which dopamine may also promote an increase in the GFR. A secondary role is the stimulation of D2 receptors on presynaptic sympathetic nerve terminals, which inhibits norepinephrine release. Intermediate doses... 

More than this, there is something called the rewards deficiency syndrome, whereby some people are deficient in neurotransmitters, especially dopamine, and as a result seek dopamine augmentation via junk foods and drugs, even gambling. 

It is possible to deplete the brain of both DA and NA by inhibiting tyrosine hydroxylase but while NA may be reduced independently by inhibiting dopamine jS-hydroxylase, the enzyme that converts DA to NA, there is no way of specifically losing DA other than by destruction of its neurons (see below). In contrast, it is easier to augment DA than NA by giving the precursor dopa because of its rapid conversion to DA and the limit imposed on its further synthesis to NA by the restriction of dopamine S-hydroxylase to the vesicles of NA terminals. The activity of the rate-limiting enzyme tyrosine hydroxylase is controlled by the cytoplasmic concentration of DA (normal end-product inhibition), presynaptic dopamine autoreceptors (in addition to their effect on release) and impulse flow, which appears to increase the affinity of tyrosine hydroxylase for its tetrahydropteridine co-factor (see below). 

All such animal procedures suffer from the obvious and basic problem that laboratory animals do not behave like humans and that humans cannot reliably interpret their reactions and behaviour. Thus we know that Parkinson s disease is caused by a degeneration of the dopaminergic nigrostriatal tract but its lesion in animals does not produce any condition which resembles human Parkinsonism, except in primates, even though there are functional tests (e.g. rotational movements) which readily establish that loss of dopamine function and also respond to its augmentation (Chapter 15). By contrast, there are many ways, e.g. electrical stimulation and the administration of certain chemicals, to induce convulsions in animals and a number of effective antiepileptic drugs have been introduced as a result of their ability to control such activity. Indeed there are some tests, as well as animals with varied spontaneous seizures, that are even predictive of particular forms of epilepsy. But then convulsions are a very basic form of activity common to most species and epileptic seizures that are characterised by behavioural rather than motor symptoms are more difficult to reproduce in animals. 

Parkinsonism is unique among diseases of the CNS, in that it results from the known loss of a particular NT, i.e. DA, resulting from the degeneration of a particular pathway, the nigrostriatal. Dopamine also has a relatively limited distribution in the brain and few peripheral effects. It should therefore be amenable to therapy based on augmenting its function. Also since the role of DA appears to be to maintain a tonic inhibitory control on GABA output pathways from the striatum, possibly in part by an extra synaptic action (Chapter 6), it may not be necessary for it to be released physiologically from nerve terminals. Thus it may be adequate to just provide DA extracellularly. 

Figure 15.3 Mechanisms of augmenting dopamine function at synapses in the striatum. Synaptic DA levels may be increased by blocking its neuronal uptake (la), inhibiting the metabolising enzymes MAOsClb) or COMT (Ic) or by providing its precursor dopa in its levo form (2). The DA receptors may also be stimulated by appropriate D2/D1 agonists (3)...

Stimulants Medications that increase physiologic activity in the body by augmenting dopamine and/or norepinephrine. 

Triple reuptake inhibitors (TRIs), which inhibit reuptake at all three transporters, have attracted considerable interest in recent years [77]. The involvement of dopamine reuptake in the etiology of depression and other CNS disorders has been recognized [29,30]. As a result, TRIs have been proposed to offer a faster onset of action and improved efficacy for depression over currently prescribed single or dual action monoamine reuptake inhibitors. Historically, the mesocorticolimbic dopamine pathway is thought to mediate the anhedonia and lack of motivation observed in depressed patients [78,79]. In addition, methylphenidate, both immediate release and extended release formula, has been found to be effective as an augmenting agent in treatment-resistant depression [4]. Furthermore, clinical studies using the combination of bupropion and an SSRI or SNRI have showed improved efficacy for the treatment of MDD in patients refractory to the treatment with SSRIs, SNRIs, or bupropion alone [5,80,81]. 

Morgan AE, Horan B, DeweySL, Ashby CR Jr. 1997. Repeated administration of 3,4-methylenedioxymethamphetamine augments cocaine s action on dopamine in the nucleus accumbens a microdialysis study. Eur J Pharmacol 331(1) R1-R3. 

Psychostimulants Trigger release, block reuptake of NE tf Dopamine ADHD Augmentation for depression ( )... 

Fedele E, Andrioli GC, Ruelle A, et al Release-regulating dopamine autoreceptors in human cerebral cortex. Br J Pharmacol 110 20-22, 1993 Feder R Lithium augmentation of clomipramine. J Clin Psychiatry 49 458, 1988 Feighner JP Busporine in the long-term treatment of generahsed anxiety disorder. J Chn Psychiatry 48 (suppl) 3-6, 1987... 

Invernizzi R, Pozzi L, Vallebuona F, et al Effect of amineptine on regional extracellular concentrations of dopamine and noradrenaline in the rat brain. J Pharmacol Exp Ther 262 769-774, 1992b Irwin RP, Magarakis NJ, Rogawski MA, et al Pregnenolone sulfate augments NMDA receptor mediated increases in intracellular Ca in cultured rat hippocampal neurons. Neurosci Lett 141 30-34, 1992... 

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