Dopamine dopaminergic depletion

Moukhles H, Amalric M, Nieoullon A, Daszuta A (1994) Behavioural recovery of rats grafted with dopamine cells after partial striatal dopaminergic depletion in a conditioned reaction-time task. Neuroscience 63 73-84. 

Locomotor activity and akinesia effects in the multidosed animals were, at least in part, a reflection of KCN-induced dopaminergic depletion, because each corresponded with decreased striatal dopamine activity (see also Persson, Cassel, Sellstrom, 1985). Furthermore, the addition of 1-DOPA reversed these effects on performance. Interestingly, 1-DOPA therapy has also successfully mitigated Parkinson-like symptoms in CN-exposed humans (Rosenow et al 1995 Uitti, Rajput, Ashenhurst, Rozdilsky, 1985). 

Mohr B, Pulvermuller F, Zaidel E (1994) Lexical decision after left, right and bilateral presentation of function words, content words and non-words evidence for interhemispheric interaction. Neuropsychologia 32(1) 105-124 Moukhles H, Amalric M, Nieoullon A, Daszuta A (1994) Behavioural recovery of rats grafted with dopamine cells after partial striatal dopaminergic depletion in a conditioned reaction-time task. Neuroscience 63(1) 73-84 Muir JL, Everitt BJ, Robbins TW (1996) The cerebral cortex of the rat and visual attentional function dissociable effects of mediofrontal, cingulate, anterior dorsolateral, and parietal cortex lesions on a five-choice serial reaction time task. Cereb Cortex 6(3) 470-481 Muir JL, Bussey TJ, Everitt BJ, Robbins TW (1996) Dissociable effects of AMPA-induced lesions of the vertical limb diagonal band of Broca on performance of the 5-choice serial reaction task and on acquisition of a conditional visual discrimination. Behav Brain Res 82(1) 31-44... 

A recent study further supported the involvement of dopamine in the mechanism of antidepressants [82]. In this study, the antidepressant-like effect of citalo-pram, paroxetine, desipramine and imipramine in the mouse forced swim test (FST) was compared with and without dopamine depletion. It was found that lesioning with 6-OHDA did not affect the response of mice to desipramine and imipramine, whereas dopamine depletion abolished the antidepressant-like effect of citalopram and paroxetine. These results suggest that the antidepressant-like effect of SSRIs in the FST requires the activation of dopaminergic pathways. 

Dopaminergic activity. Smoke was administered intranasally to mice for 20 minutes twice daily for 3 days before methamphet-amine treatment. The treatment significantly attenuated the neurotoxicity as judged by a lesser depletion of dopamine, dihydrophenylacetic acid, and homovanillic acid. The lesser effect of methamphetamine on the content of serotonin level was unaltered by prior inhalation of smoke h Tobacco glycoside, administered to mice, increased behavior via dopamine 2 neuronal activity but not dopamine 1 activity in a dose-dependent manner. The results indicated that smoking can affect the human brain function via not only the nicotinic cholinergic neuron but also the dopamine 2 neuron . 

The mechanism of the neurological symptoms in Parkinson s disease was discovered from the ability of reserpine to cause akinesia in humans by the depletion of central catecholamine stores. The dopamine levels in patients who died from parkinsonism were found to be extremely low because of deterioration of the dopaminergic neuronal cell bodies and the pathways connecting the substantia nigra with the corpus striatum. 

Figure 7.44 The metabolism and toxicity of MPTP. Diffusion into the brain is followed by metabolism in the astrocyte. The metabolite MPP+ is actively transported into the dopaminergic neuron by DAT. It is accumulated there and is actively taken into mitochondria by another uptake system. Here, it inhibits mitochondrial electron transport between NADH dehydrogenase (NADH DHase) and coenzyme Q (Q10). Consequently, it blocks the electron transport system, depletes ATP, and destroys the neuron. Abbreviations MPTP, 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine DAT, dopamine transporter uptake system.

In addition to MPTP, other endogenously produced neurotoxins, namely, the monoamine-derived 1,2,3,4-tetrahydroisoquinolines and 6,7-dihydroxy-l,2,3,4-tetrahydroisoquinolines, have been proposed as factors accelerating dopamine cell death. A-methylated isoquinolines were found to be oxidized by MAO, and hydroxyl radicals were found to be produced by this reaction. In addition, by incubation with the A-methylated isoquinolines, ATP was depleted from a dopaminergic cell model. Pretreatment of the cells with MAO inhibitors such as selegiline could, however, protect against ATP depletion. These results suggest that oxidation of neurotoxic isoquinolines is directly involved in the oxidative stress to induce the cell death of dopamine neurons. On the other hand, 1 -methyl-1,2,3,4-tetrahydroisoquinoline and 1 -methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquino-... 

Muscle-derived differentiation factor (MDF) induces tyrosine hydroxylase expression in a variety of central nervous system neurons, including those of striatum, cerebellum, and cortex. Normally, i.e., without MDF, these neurons do not express this enzyme of catecholamine synthesis. Further in vitro studies revealed that MDF enhances TH-mRNA 40-fold in fetal mesencephalic neurons. In vivo studies, employing infusion of partially isolated MDF, reported this molecule to enhance tyrosine hydroxylase activity in dopamine-depleted striata of 6-OHDA-lesioned animals. Furthermore, an increase of striatal dopamine concentrations and a partial compensation of rotational asymmetry were observed. In contrast, dopaminergic parameters were not affected by administration of MDF in control animals, suggesting that adult dopaminergic neurons may regain sensitivity toward differentiation factors after lesion. 

Patients with Parkinson s disease show changes in the pre- and postsynaptic dopaminergic neurons which try to compensate for the progressive disappearance of the transmitter. Thus the surviving pre-synaptic terminals become hyperactive, while the postsynaptic D2 receptors become hypersensitive in an attempt to compensate for the reduced dopaminergic function. These compensatory changes probably account for the relative lack of symptoms of the disease until the dopamine content has been depleted by more than 80%. 

Calabresi P, Benedetti M, Mercuri NB, Bernardi G (1988) Endogenous dopamine and dopaminergic agonists modulate synaptic excitation in neostriatum Intracellular studies from naive and catecholamine-depleted rats. 

The authors speculated that dopaminergic dysfunction, reported by some to underlie social phobia, could have resulted in this case from chronic amfetamine-related striatal dopamine depletion. 

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