Dopaminergic cells

Nitric oxide has also been implicated in PD. Thus animals with MPTP-induced Parkinsonism not only show extensive gliosis in the substantia nigra (like humans) in which the glial cells produce NO, but Liberatore and colleagues have found that in iNOS (inducible nitric oxide synthase) knock-out mice the toxicity of MPTP is halved. Since NO releases iron from ferritin and produces toxic peroxinitrate in the presence of superoxide radicals it could accelerate, even if it does not initiate, dopaminergic cell death (see Hirsch and Hunot 2000 for further details). 

Mercuri, NB, Bond, A and Bemardi, G (1997) Electrophysiological pharmacology of the autoreceptor mediated responses of dopaminergic cells to antiparkinsonian drugs. Trends Pharmacol. Sci. 18 232-235. 

Radad K, Gille G, Moldzio R, Saito H, Ishige K, Rausch WD. Ginsenosides Rbl and Rgl effects on survival and neurite growth of MPP +-affected mesencephalic dopaminergic cells. J Neural Transm 2004 111 37-45. 

Sleep-wake state alterations in PD can be broadly classified into disturbances of (1) thalamocortical arousal state and (2) excessive nocturnal movement (Rye and Bliwise 2004 Rye and Iranzo 2005). The former includes the loss of sleep spindles and SWS, daytime sleepiness, and intrusion of REM sleep into daytime naps (i.e. sleep onset REM periods, or SOREMs), and the latter encompass periodic leg movements of sleep (PLMs) and REM sleep behavior disorder (RBD). The pathophysiological basis of sleepiness and SOREMs appears to be dopaminergic cell loss in PD, though excessive nocturnal movements are not as clearly related to dopaminergic deficits. 

Ventral tegmental area (VTA) The location of the dopaminergic cells projecting to the nucleus accumbens. 

Dihydroxybenzoic acid (DHB) is also a commonly used tool to measure the pharmacological effects of HIF-la stabilization via PHD inhibition. Recently, it was shown that mice pretreated with DHB (100 mg/kg, i.p.) showed a marked resistance to the neurotoxic effects of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) via protection of dopaminergic cell loss and striatal denervation. Importantly, this protection was seen to coincide with HIF-la stabilization, and the prevention of the MPTP-induced loss of ferroportin and striatal iron. Additionally, in these studies, DHB was also observed to block MPTP-induced reduction in mitochondrial pyruvate dehydrogenase, at both the mRNA level and through the measurement of enzyme activity in midbrain substantia nigra [26]. 

Radad, K., Gille, G., Moldzio, R., Saito, H., and Rausch, W.-D. (2004b). Ginsenosides Rbl and Rgl effects on mesencephalic dopaminergic cells stressed with glutamate. Brain Res. 1021, 41-53. 

Dopamine receptors are discussed in detail in Chapters 21 and 29. Dopamine receptors of the Di type are located in the pars compacta of the substantia nigra and presynaptically on striatal axons coming from cortical neurons and from dopaminergic cells in the substantia nigra. The D2 receptors are located postsynaptically on striatal neurons and... 

Pramipexole is not an ergot derivative, but it has preferential affinity for the D3 family of receptors. It is effective as monotherapy for mild parkinsonism and is also helpful in patients with advanced disease, permitting the dose of levodopa to be reduced and smoothing out response fluctuations. Pramipexole may ameliorate affective symptoms. A possible neuroprotective effect has been suggested by its ability to scavenge hydrogen peroxide and enhance neurotrophic activity in mesencephalic dopaminergic cell cultures. 

The hypothesis that a robust rewarding effect depends on continuing novelty is consistent with recent reports that reward-sensitive dopaminergic cells in a monkey s nucleus accumbens respond most when a rewarding stimulus occurs unpredictably (Hollerman, Tremblay, and Schultz 1998). 

The mesolimbic dopamine pathway projects from dopaminergic cell bodies in the ventral tegmental area of the brainstem to axon terminals in limbic areas of the brain, such as the nucleus accumbens (Fig. 10—8). This pathway is thought to have an important role in emotional behaviors, especially auditory hallucinations but also delusions and thought disorder (Fig. 10—9)-... 

The reinforcing actions of nicotine are very similar to those of cocaine and amphetamine, since dopaminergic cells in the mesolimbic dopamine pathway receive direct nicotinic cholinergic input, which is stimulated by cigarette smoking (Figs. 

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-... 

Treatment of Parkinson s does not necessarily improve sleep. In addition to the dopaminergic cells in the substantia nigra being lost in Parkinson s, other non-dopaminergic nerve cells are destroyed. The loss of these nondopaminergic nerve cells may underlie some of the symptoms associated with Parkinson s, which may explain why treatment with dopaminergic drugs does not alleviate all the symptoms of Parkinson s disease. 

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