Heteroreceptors serotonin

Histaminergic neurons can regulate and be regulated by other neurotransmitter systems. A number of other transmitter systems can interact with histaminergic neurons (Table 14-1). As mentioned, the H3 receptor is thought to function as an inhibitory heteroreceptor. Thus, activation of brain H3 receptors decreases the release of acetylcholine, dopamine, norepinephrine, serotonin and certain peptides. However, histamine may also increase the activity of some of these systems through H, and/or H2 receptors. Activation of NMDA, p opioid, dopamine D2 and some serotonin receptors can increase the release of neuronal histamine, whereas other transmitter receptors seem to decrease release. Different patterns of interactions may also be found in discrete brain regions. 

Serotonin 5-HT1A Human cDNA Alzheimer s disease, anxiety, depression, schizophrenia, hypertension, inflammation, pain, migraine, spasticity ulcers, obesity glaucoma Somatodendritic autoreceptor in hippocampus and raphe nuclei, circadian rhythm, somatodendritic heteroreceptor at cholinergic terminals of myenteric plexus... 

INHIBITION OF NEUROTRANSMITTER RELEASE BY PRESYNAPTIC SEROTONIN HETERORECEPTORS... 

FIGURE 5—43. Shown here are the alpha 2 presynaptic heteroreceptors on serotonin axon terminals. 

FIGURE 5—44. This figure shows how norepinephrine can function as a brake for serotonin release. When norepinephrine is released from nearby noradrenergic neurons, it can diffuse to alpha 2 receptors, not only to those on noradrenergic neurons but as shown here, also to these same receptors on serotonin neurons. Like its actions on noradrenergic neurons, norepinephrine occupancy of alpha 2 receptors on serotonin neurons will turn off serotonin release. Thus, serotonin release can be inhibited not only by serotonin but, as shown here, also by norepinephrine. Alpha 2 receptors on a norepinephrine neuron are called autoreceptors, but alpha 2 receptors on serotonin neurons are called heteroreceptors. 

Fig. 1. Occurrence of H3 receptors inhibiting release of acetylcholine, of amino acid and monoamine neurotransmitters in the mammalian CNS in vitro. The schematic drawing represents a midsagittal section of the human brain three areas with a more lateral position are shown by broken line (substantia nigra and part of the hippocampus and of the striatum). For each of the six regions of the CNS (subregions given in brackets), in which H3 heteroreceptors have been identified, the neurotransmitter(s) and the species are indicated. The superscripts refer to the numbers of the papers as listed under References. Own unpublished data suggest that an H3 receptor-mediated inhibition of noradrenaline release also occurs in the human cerebral cortex and hippocampus and in the guinea-pig cerebral cortex. Note that a presynaptic location has not been verified for each of the H3 heteroreceptors or has been even excluded (for details, see Table 1). Abbreviations ACh, acetylcholine DA, dopamine GABA, y-aminobutyric acid Glu, glutamate 5-HT, 5-hydroxytryptamine, serotonin NA, noradrenaline...

MODULATION OF CATECHOLAMINES AND SEROTONIN RELEASE MEDIATED BY HISTAMINE H3 HETERORECEPTORS... 

However, receptor autoradiography and in vitro studies have suggested that H3 receptors are located on other aminergic neurons in the brain. Since amines such as serotonin and catecholamines are involved in the regulation of pituitary hormone secretion, it is obvious that an action of the H3 receptor compounds may be exerted via these H3 heteroreceptors. Only few studies have evaluated this heteroreceptor action. It has been excluded that the effect of the H3 receptor agonists is due to an effect on H3 receptors located on serotonergic neurons, while an effect on catecholaminergic neurons has yet not been excluded. 

Histamine H3-receptors have been reported to regulate not only the release and turnover of histamine via autoreceptors on histaminerglc nerve endings [1-3], but also the releases of noradrenaline, dopamine, serotonin, and acetylcholine via heteroreceptors on non-histaminerglc axon terminals [22-26], Thioperamide increased the release of these neurotransmitters, while... 

In relation to the monoaminergic systems we observed that clobenpropit increased turnover rate of noradrenaline only in some brain regions (17), although histamine H3 heteroreceptors modulate the releases of noradrenaline, dopamine, and serotonin [23-26]. Thus, it appears that the contribution of histamine H3 hetero receptors on the modulation of monoaminergic neurotransmitters may be minor, just being similar to the cholinergic system. 

Mirtazapine is an antidepressant that increases both serotonin and noradrenaline by blockade of central a2 auto- and heteroreceptors mirtazapine also blocks 5-HT2 and 5-HT3 serotonin receptor subtypes, and that former property may induce slow-wave sleep. Systemic administration of mirtazapine has been shown to increase genioglossus muscle activity in anesthetized rats in a dose-dependent manner [55]. In a randomized, double-blind, cross-over trial of ten patients with OSA, mirtazapine at a dose of 15 mg reduced the AHI by 50 %, and the arousal index by some 29 % [56], Side-effects with use of mirtazapine include somnolence and hyperphagia/weight gain. 

Abstract Presynaptic receptors for dopamine, histamine and serotonin that are located on dopaminergic, histaminergic and sertonergic axon terminals, respectively, function as autoreceptors. Presynaptic receptors also occur as heteroreceptors on other axon terminals. Auto- and heteroreceptors mainly affect Ca2+-dependent exocytosis from the receptor-bearing nerve ending. Some additionally subserve other presynaptic functions. 

Our knowledge of presynaptic dopamine and serotonin receptors dates back to the 1970s (Famebo and Hamberger 1971). Presynaptic histamine receptors were discovered in 1983 (Arrang et al. 1983). Presynaptic dopamine receptors occur as autoreceptors, i.e., on dopaminergic axon terminals, and as heteroreceptors on nondopaminergic axon terminals. By analogy the same holds true for presynaptic histamine and serotonin receptors. The early days of the dopamine autoreceptors were stormy, but the controversies were finally solved (see Starke et al. 1989). The main function that presynaptic receptors affect is transmitter release, which in this article means Ca2+-dependent exocytosis. However, some receptors discussed in... 

H3 receptor activation inhibits the release of serotonin in several rat brain regions (Table 3). An endogenous histamine tone has been found at the heteroreceptors in rat brain cortex (Schlicker et al. 1988 Fink et al. 1990). At high micromolar concentrations histamine may enhance the release of serotonin (and of noradrenaline) via a tyramine-like mechanism (Starke and Weitzell 1978 Young et al. 1988). 

HTia heteroreceptors depress, whereas 5-HT2A heteroreceptors enhance, the synthesis of dopamine in rat corpus striatum. The former effect (Johnson et al. 1993) occurs even in the absence of any dopamine release, is shared by endogenous serotonin, and may involve adenylyl cyclase inhibition and a diminution of TH phosphorylation as discussed above for dopamine D2 autoreceptors (Section 2.2). The 5-HT2A increase in synthesis, in contrast (Lucas and Spampinato 2000), occurs only when dopamine neurons are activated by blockade of their D2 autoreceptors. 

Finally, serotonin contributes to the pharmacology of cocaine, although less prominently than dopamine. The 5-HTib heteroreceptor mechanism of the inhibition by cocaine of GABA release in the VTA has been explained in Section 4.6. The inhibition of GABA release in turn disinhibits VTA dopamine neurons, thus enhancing dopamine release in the terminal region of the nucleus accumbens, a key structure of addiction (compare Section 2.3). 

Gobert A, Rivet JM, Audinot V, Newman-Tancredi A, Cistarelli L, Millan MJ (1998) Simultaneous quantification of serotonin, dopamine and noradrenaline levels in single frontal cortex dialysates of freely-moving rats reveals a complex pattern of reciprocal auto- and heteroreceptor-mediated control of release. Neurosci 84 413-29 Gothert M (2003) Modulation of noradrenaline release in human cardiovascular tissues. Pharmacol Toxicol 92 156-9... 

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