Heteroceptors

The main advantage of using synaptosomes is that they are free from any influence of the parent axon. Another is that, since the volume of extracellular space (the incubation medium) is functionally infinite, transmitter will not accumulate near the synaptosomes. This means that reuptake of released transmitter is unlikely to occur and that, under drug-free conditions, transmitter release will not be modified by activation of auto- or heteroceptors (see below). 

Even more sophisticated control of neurotransmitter release is suggested by the possibility of heteroceptors . These receptors are thought to be located on the terminals of, and to modulate transmitter release from, one type of neuron, but are activated by transmitter released from a different type of neuron (Laduron 1985). For example, noradrenaline has been proposed to modulate release of a wide range of transmitters (e.g. dopamine, 5-HT and glutamate) through activation of a2-heteroceptors on the terminals of each of these different types of neuron. However, one factor that should be borne in mind is that most of the evidence for heteroceptors comes from studies of... 

There are several ways in which activation of auto- or heteroceptors on nerve terminals could modify the amount of transmitter released by exocytosis. The fact that this will depend on the influence of second messengers is beyond doubt. What remains to be resolved is whether one mechanism is more important than the others, or whether this varies from tissue to tissue. 

Alternative mechanisms are equally likely. One possibility arises from evidence that activation of a2-adrenoceptors reduces Ca + influx this will have obvious effects on impulse-evoked exocytosis. In fact, the inhibition of release effected by a2-adrenoceptor agonists can be overcome by raising external Ca + concentration. Finally, an increase in K+ conductance has also been implicated this would hyperpolarise the nerve terminals and render them less likely to release transmitter on the arrival of a nerve impulse. Any, or all, of these processes could contribute to the feedback inhibition of transmitter release. Similar processes could explain the effects of activation of other types of auto-or heteroceptors. 

Laduron, PM (1985) Presynaptic heteroceptors in regulation of neuronal transmission. Biochem. Pharmacol. 34 467 70. 

Noradrenaline release might also be modulated by receptors on noradrenergic nerve terminals that are activated by other neurotransmitters ( heteroceptors ). Unfortunately, most studies of this type of modulation have been carried out in tissue slices and... 

There is some evidence that receptors for other neurotransmitters on 5-HT nerve terminals also modify release of 5-HT. These include nicotinic receptors (increase release from striatal synaptosomes), a2A-adrenoceptors (depress cortical release) and H3-receptors (cortical depression). Because changes in 5-HT release on activation of these receptors is evident in synaptosomal preparations, it is likely that these are true heteroceptors . 

Administration of 5-HTib receptor agonists increases waking time and reduces REM sleep. This is consistent with recent evidence gathered from 5-HTiB-receptor knockout mice which exhibit more REM sleep and less SWS than the wild-type. Moreover, 5-HTib agonists reduce, while antagonists increase, REM sleep in the wild-type mouse, but neither type of compound has any effect in the knock-outs (Boutrel et al. 1999). Unfortunately, it is not known whether these actions are mediated by presynaptic, postsynaptic or heteroceptors and therefore whether 5-HT activity is increased or decreased. It is also not helped by the limited selectivity of test agents. 

Experimental studies have shown that the release of a transmitter from a nerve terminal can be decreased or increased by a variety of other neurotransmitters. For example, stimulation of 5-HT receptors on noradrenergic terminals can lead to an enhanced release of noradrenaline. While the physiological importance of such a mechanism is unclear, this could be a means whereby drugs could produce some of their effects. Such receptors have been termed heteroceptors (Figure 2.3). 

Figure 2.3. Modulation of 5-HT release by alpha-adrenergic heteroceptors.

Figure 7.4. Summary of the site of action of mirtazepine (NaSSA). The inhibitory 2 adrenoceptors facilitate the release of both noradrenaline and serotonin (via the heteroceptor on the 5-HT neuron). This is further enhanced by the receptor on the serotonin cell body. Thus mirtazepine (and to a lesser extent mianserin) enhance both noradrenergic and serotonergic...

Scruggs JL, Patel S, Bubser M, Deutch AY. DOI-Induced activation of the cortex dependence on 5-HT2A heteroceptors on thalamocortical glutamatergic neurons. J Neurosci 2000 20 8846-8852. 

The pronounced effects of phencyclidine on locomotor activity in both animals and man, and the psychotomimetic effects in man, may be a consequence of its facilitatory effects on dopaminergic transmission, particularly in mesolimbic regions of the brain. This is unlikely to be due to a direct effect of the drug on dopamine receptors, but is probably due to its action on NMDA heteroceptors on dopaminergic terminals in these brain regions. 

Presynaptic receptor that is activated by a neurotransmitter from an adjacent neuron the type of neurotransmitter activating the heteroceptor differs from that released from the axon. 5-Hydroxyindoleacetic acid, the main metabolite of 5-hydroxytryptamine (serotonin) formed by monoamine oxidase. 

Figure 1.6 The nomenclature used to describe receptor location on neurones. Starting with Neurone A , neurotransmitter released at the terminals will interact with POSTSYNAPTIC receptors on Neurone B Similarly, neurotransmitter releasedfrom Neurone D will interact with postsynaptic receptor on Neurone A Neurotransmitter releasedfrom Neurone A will also regulate its own release by interacting with the TERMINAL A UTORECEPTOR or affect neuronal firing by interacting with the SOMATODENDRITIC AUTORECEPTOR Release of neurotransmitter from Neurone A can also be regulated by activation of PRESYNAPTIC HETEROCEPTORS on the terminals, which are postsynaptic receptors activated by neurotransmitter from Neurone C...

Interactions of antipsychotic drugs with central neurotransmitters other than DA may contribute to their antipsychotic effects or other actions. For example, many antipsychotics enhance the turnover of acetylcholine, especially in the basal ganglia, perhaps secondary to the blockade of inhibitory dopaminergic heteroceptors on cholinergic neurons. In addition, there is cm inverse relationship between antimuscarinic potency of antipsychotic drugs in the brain and the likelihood... 

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