Dopamine neurons

Kaxp channels under investigation resulted in selective rescue of substantia nigra dopaminergic neurons does not prove a deleterious, neurodegeneration-promoting role of Katp channels, but may simply mean that the dopamine neurons, lacking KATP channels, have developed other, undetected self-protection mechanisms. 

Degeneration and death of dopamine neurons, resulting from neurotoxic agent. 

Both psychostimulants D-amphetamine and cocaine elevate extracellular dopamine concentrations in the terminal region of midbrain dopamine neurons,... 

Dopaminergic neurotoxin that causes parkinsonism via lesion of nigrostriatal dopamine neurons in rat, mice, monkeys. Unlike the dopaminergic neurotoxin MPTP (N-methy 1-4-phenyl-1,2,3,6-tetrahydropyridine) it does not cross the blood-brain barrier. 

A synthetic neurotoxin that causes parkinsonism in human and nonhuman primates, mice, gold fish, and dogs. MPTP is inert but metabolized by MAO-B to the neurotoxin MPP+ (1,2-dihydropyridine ion). This neurotoxin causes depletion of dopamine and degeneration of nigrostriatal dopamine neurons similar to what is observed in Parkinson s disease. 

Several classes of drugs modulate the firing rates or patterns of midbrain dopamine neurons by direct, monosynaptic, or indirect, polysynaptic, inputs to the cell bodies within the ventral mesencephalon (i.e., nicotine and opiates). In contrast, amphetamine, cocaine, and methylphenidate act at the level of the dopamine terminal interfering with normal processes of transmitter packaging, release, reuptake, and metabolism. 

Nicotine is the main psychoactive ingredient of tobacco and is responsible for the stimulant effects and abuse/ addiction that may result form tobacco use. Cigarette smoking rapidly (in about 3 sec ) delivers pulses of nicotine into the bloodstream. Its initial effects are caused by its activation of nicotinic acetylcholine (nACh) receptors. nACh receptors are ligand-gated ion-channels and pre- and postsynaptically located. Reinforcement depends on an intact mesolimbic dopamine system (VTA). nACh receptors on VTA dopamine neurons are normally activated by cholinergic innervation from the laterodorsal tegmental nucleus or the pedunculopontine nucleus. 

French ED, Dillon K, Wu X Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra. Neuroreport 8 649—632, 1997 Fujinaga M, Maze M Neurobiology of nitrous oxide-induced antinociceptive effects. Mol Neurobiol 25 167-189, 2002... 

Toxins that gain access to a neuron through its uptake process and then destroy it in some way. This approach has been used mainly to destroy monoamine neurons with 5,6 or 5,7-dihydroxytryptamine targeting 5-HT neurons, 6-hydroxydopamine for dopamine (and to a lesser extent noradrenergic) neurons and MPTP for dopamine neurons (see Chapter 7). Only the latter is fully specific and effective systemically. The others need to be administered directly into the appropriate brain areas and while they may only affect the intended NT neurons, the injection may not affect all of them. 

Figure 7.1 Dopamine neuronal pathways. AMYG, amygdala CN, caudate nucleus MFB, medial forebrain bundle NcA, nucleus accumbers OT, olfactory tubercle PUT, putamen SN, substantia nigra. For full details see text and Moore and Bloom (1978) and Lindvall and Bjorkland (1978)...

As with many neurons (e.g. NA) there are presynaptic autoreceptors on the terminals of dopamine neurons whose activation attenuate DA release. Although most of these receptors appear to be of the D2 type, as found postsynaptically, D3 receptors are also found. It is possible that in addition to the short-term control of transmitter release they may also be linked directly to the control of the synthesising enzyme tyrosine hydroxylase. It seems that autoreceptors are more common on the terminals of nerves in the nigrostriatal (and possibly mesolimbic) than mesocortical pathway. 

Schultz, W (1997) Dopamine neurons and their role in reward mechanisms. Curr. Opin. 

Bannon, ML and Roth, RH (1983) Pharmacology of mesocortical dopamine neurons. Pharmacol. Rev. 35 53-68. 

Chiodi, LA and Bunney, BS (1983) Typical and at q)ical neuroleptics differential effects of chronic administration on the activity of A9 and AlO midbrain dopamine neurones. J. Neurosci. 3 1607-1619. 

The reinforeing properties of psychomotor stimulants have also been linked to the aetivation of eentral dopamine neurons and their postsynaptie reeep-tors. When the synthesis of eatecholamines is inhibited by administering alpha-methyl-para-tyrosine, an attenuation of the subjective effeets of euphoria assoeiated with psyehomotor stimulants oeeurs in man (Jonsson et al. 1971), and a bloekade of the reinforeing effects of methamphetamine occurs in animals (Pickens et al. 1968). Furthermore, low doses of dopamine antagonists will increase response rates for intravenous injections of h-amphetamine (Risner and Jones 1976 Yokel and Wise 1975 Yokel and Wise 1976). 

Kelly, P.H., and Iversen, S.D. Selective 6-OHDA-induced destruction of mesolimbic dopamine neurons Abolition of psychostimulant-induced locomotor activity in rats. Eur J Pharmacol 40 45-56, 1976. 

The inhibition of firing of catecholamine neurons resulting from amphetamine administration is likely due to activation of somatodendritic autoreceptors. This causes a hyperpolarization of the somatodendritic membrane of both locus coeruleus noradrenergic and substantia nigra dopamine neurons, probably as a consequence of an increase in potassium conductance (Lacey et al. 1987 Williams et al. 1985). 

ANSWER That is Lacey et al., Allan North s group. It was published in the Journal of Physiology last year. It was also an abstract in the Society 2 years ago. It is the consequence of that application of the agonists, recording intracellularly in the slice of the dopamine neuron. He gets the same thing by virtue of application of norepinephrine agonists to noradrene-gic slice preparation. That is a conventional way to create a hyperpolarization of the cell, to increase the potassium conductance, and so forth. 

ANSWER 1 don t know. There is a change at the cell body the resistance goes way up, and it will set itself into a repetitive firing mode, which is quite an abnormal looking mode of firing, but the dopamine neuron or the norepinephrine neuron or virtually any neuron in slice will go into this bizarre repetitive mode of firing. 

Olds, M.E. Amphetamine-induced increase in motor aetivity is correlated with higher firing rates of non-dopamine neurons in substantia nigra and ventral tegmental areas. Neurosci 24 477-490, 1988. 

COMMENT I would favor the view that lethargy and fatigue of postamphetamine withdrawal during the withdrawal phase would be consistent with the shutting off of the dopamine neuron. Still, it is hard to imagine how that would be. First, the amphetamine-induced release is not regulated by the autoreceptor. And, as you say, if it would be impulse related, however weak, it would be regulated. But we do know that after a period of amphetamine intoxication, an individual is supersensitive behaviorally. 

Lee, T., and Ellinwood, E.H., Jr. Time-dependent changes in the sensitivity of dopamine neurons to low doses of apomorphine following amphetamine infusion Eleetrophysiological and biochemical studies. 

During the 1970s, evidence accumulated that amphetamine and methamphet-amine could also be neurotoxic (Ellison et al. 1978 Hotchkiss and Gibb 1980 Wagner et al. 1980). The effects of amphetamine seem mostly limited to dopamine neurons, whereas methamphetamine affects dopamine and serotonin neurons (Warren et al. 1984). Most recently, MDMA and MDA have been shown to produce neurotoxicity toward brain serotonin neurons much like that of the halogenated amphetamines (Ricaurte et al. 1985 Stone et al. 1986). 

The neurotoxic effects of all these compounds are antagonized by inhibitors of monoamine uptake (table 1), implicating the membrane uptake carrier on serotonin and dopamine neurons in the mechanism of neurotoxicity. In this regard, these amphetamines are like a drug somewhat related in structure, namely l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a Parkinsonism-causing neurotoxic dmg that has been studied intensely since 1983 (Langston and Irwin 1986). In the case of MPTP, the mechanism by which inhibitors of the dopamine uptake carrier block the neurotoxicity toward dopamine neurons (mainly nigrostriatal dopamine neurons) seems clear. A metabolite of MPTP, l-methyl-4-phenylpyridinium (MPP-I-), has been shown to be a substrate for the dopamine uptake carrier (Javitch et al. 1985). Thus accumulation of MPP-I-, formed metabolically from... 

MPTP, into dopamine neurons seems to be essential, and blockade of that aeeumulation prevents the neurotoxieity. MPP+ also ean be transported into norepinephrine neurons (Javitch et al. 1985), leading to neurotoxicity toward cortical norepinephrine neurons, an effect blocked by inhibitors of the norepinephrine uptake carrier (Sundstrom and Jonsson 1985). 

RESPONSE We do not understand all there is to know about the mechanisms of MPTP neurotoxicity, but it seems to involve MPP+, which is potentially cytotoxic to all cells but that attains toxic concentrations after MPTP administration only in cells that concentrate MPP+. Dopamine apparently is not involved in the neurotoxic effects of MPTP. I am attracted to the idea that dopamine itself may be involved in the etiology of Parkinson s disease, that dopamine neurons may be at risk because of the nature of their neurotransmitter. 

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