DA neurons

There is much evidence (e.g. Cheramy, Leviel and Glowinski 1981) from both in vitro and in vivo perfusion studies that DA is released from the dendrites of DA neurons in both A9 and AlO even though those dendrites do not contain many vesicles compared with axon terminals. The release and changes in it may also be slower and longer than that at axon terminals and the synaptic arrangement between the releasing dendrites and postsynaptic target is not clear. DA receptors also appear to be on neurons other than dopamine ones and on the terminals of afferent inputs to A9 (and AlO). It seems that the activation of the DA neurons may partly be controlled by the effects of the dendritically released DA on such inputs. 

Certainly the activity of tyrosine hydroxylase is greater in the DA neurons of the substantia nigra (17.5 nmol dopa synthesised/mg protein/h) than in the NA neurons of the locus coeruleus (4-5), as is the turnover of the amine itself (1.7 pg/h) compared with that of NA (1.0) (see Bacopoulus and Bhatnager 1977). In the caudate nucleus and nucleus accumbens the turnover of DA is even higher at 7.4 and 2-6 pg/g/h respectively. 

Recently much interest has centred on a very specific toxin for DA neurons. This is 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP). It was discovered when a student, who was addicted to pethidine, tried to manufacture l-methyl-4-phenyl-4-propionoxy-piperidine (MPPP) but took a short-cut in synthesis and produced MPTP. When he administered this to himself he developed Parkinsonism. MPTP destroys DA neurons. Again this process depends on the neuronal uptake mechanism, since MPTP itself is not the active material. It needs to be deaminated to MPP+ which is then taken up by DA nerve terminals. 

D3 Much less abundant than D2. Mainly in limbic regions (nucleus accumbens and olfactory tubercle) but also in hypothalamus. Some in caudate and cortex and also expressed on DA neurons in substantia nigra, presumably as autoreceptors. No effect on adenylate cyclase but inhibits Ca + entry (autoreceptor role). High affinity for DA (Ali 25nM). 

DA neurons in this nucleus, that not all the effects are elicited by the release of DA. Most neuroleptics block the inhibitory effects of applied DA but some, e.g. haloperidol, are less active against SN-evoked inhibition. Generally these studies lacked specific agonists and antagonists used microintophoresis which is not really quantitative and with extracellular recording gave little information on the state of polarisation of the neuron. 

Localisation of specific NT terminals. After its injection a labelled precursor should be taken up and detected in appropriate nerve terminals (and possibly cell bodies) so that the intensity of emission reflects the density of nerve terminals and the innervation. Using this procedure it has been possible to show that very little [ F] fluorodopa is concentrated in the striatum of Parkinsonian patients, compared with normals (Fig. 14.1). Whether the label remains on dopa or is transferred to dopamine will not greatly affect the result since both will label DA neurons although some will occur in noradrenergic nerve terminals. 

Recently PET studies with 6-fluorodopa, which is taken up by DA nerve terminals in the striatum and is therefore presumably a measure of both the number of functional DA neurons in the nigrostriatal tract to it as well as its DA content, show that this is more like 50% of normal at the start of symptoms, not the 80% observed at PM (see... 

Since PD is caused by a relatively specific degeneration of the DA nigrostriatal tract and as there are specific toxins, for DA neurons, i.e. 6-OHDA and MPTP, it should be possible to produce appropriate experimental models. Certainly both toxins cause rotational behaviour in rats (Fig. 7.7) but no rodent shows a syndrome suggestive of PD. Tremor and akinesia can be seen, however, in primates after such toxins and these are being more widely used in experimental studies of PD and drug evaluation. Reserpine causes a depletion of all brain monoamines and produces motor defects in rats, which, even if not PD-like, do respond to DA manipulation. 

In addition to therapy it is hoped that the cause of PD can be established and degeneration of DA neurons stopped or even reversed by pharmacological (including trophic) means or genetic manipulation. 

This is an anti-viral agent that has weak levodopa-like effects but its mode of action is not really known. Since the most likely effect is considered to be the release of DA it is not surprising that its value is limited when most DA neurons have been destroyed. 

What are the effects of DA antagonism on the function of DA neurons themselves ... 

The consequences of DA antagonism on DA neuron activity are shown diagrammatically in Fig. 17.4. Acutely neuroleptics increase the firing of DA neurons and the release of DA. This is because DA antagonists ... 

Block the action of DA on similar inhibitory receptors on the DA neuron cell body itself... 

Block postsynaptic DA receptors on neurons inhibited by released DA which can initiate positive feedback to the DA neurons. 

Figure 17.4 The effect of neuroleptics on the activity of DA neurons. Although neuroleptics (DA antagonists) are used primarily to inhibit the postsynaptic effects of released DA they also increase the activity of the DA neuron itself since they (1) inhibit the effect of synaptic DA on nerve terminal autoreceptors and so increase DA release (2) block inhibitory DA autoreceptors on the soma of the DA neuron so that they cannot be stimulated by endogenous DA, possibly released from the neuron s own dendrites and (3) facilitate feedback excitation to the DA neuron from those neurons normally inhibited by distally released DA. All the DA receptors involved are D2 (or possibly D3). — Blocked by D2 antagonists (neuroleptics)...

Figure 17.5 Possible scheme for the initiation of depolarisation block of DA neurons. In (a) the excitatory effect of glutamate released on to the DA neuron from the afferent input is counteracted by the inhibitory effect of DA, presumed to be released from dendrites, acting on D2 autoreceptors. In the absence of such inhibition due to the presence of a typical neuroleptic (b) the neuron will fire more frequently and eventually become depolarised. At5q)ical neuroleptics, like clozapine, will be less likely to produce the depolarisation of A9 neurons because they are generally weaker D2 antagonists and so will reduce the DA inhibition much less allowing it to counteract the excitatory input. Additionally some of them have antimuscarinic activity and will block the excitatory effect of ACh released from intrinsic neurons (see Fig. 17.7)...

Two features require some comment. The induction of depolarisation block in DA neurons needs afferent input to the nuclei, since prior lesion of the striatum and nucleus... 

Dyskinesias are thought to be due to increased DA function, which would not be an obvious effect of a DA antagonist but the early acute ones could reflect the increase in DA neuron firing and release produced by such drugs, in the manner described above, overcoming the postsynaptic DA receptor block achieved in the striatum. 

Fibres from 5-HT neurons in the raphe nucleus innervate and yet, despite the observed 5-HT2A receptor link with neuronal excitation, appear to inhibit DA neurons in the SN (A9). Thus antagonism of 5-HT released onto them would increase their firing and so reduce the likelihood of EPSs, although how 5-HT2A antagonists can... 

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