Heteroreceptors dopamine

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. 

Dopamine acts on G-protein-coupled receptors belonging to the D1 -family of receptors (so-called D1-like receptors , or DlLRs, comprised of Dl- and D5-receptors), and the D2-family of receptors ( D2-like receptors , or D2LRs comprised of D2-, D3- and D4-receptors). Dl LRs stimulate adenylate cyclase activity and, possibly, also phosphoinosit-ide hydrolysis, while D2LRs reduce adenylate cyclase activity. In the striatum, DlLRs are predominately associated with medium spiny neurons of the direct pathway, while D2LRs have been found as autoreceptors on dopaminergic terminals, as heteroreceptors on cholinergic interneurons, and on indirect pathway neurons. In the SNr, DlLRs are located on terminals of the direct pathway projection, while D2LRs appear to function as autoreceptors. 

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 Own unpublished data suggest that an H3 receptor-mediated inhibition of noradrenaline release also occurs in the human cerebral cortex and hippocampus and in the guinea-pig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...

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. 

Autoreceptor cortex, hippocampus Autoreceptor striatum Heteroreceptor activation of dopamine release... 

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. 

Dopamine autoreceptors play a role in Parkinson s disease, schizophrenia and drug addiction. Dopamine heteroreceptors affecting the release of acetylcholine and of amino acid neurotransmitters in the basal ganglia are also relevant for Parkinson s disease. Peripheral dopamine heteroreceptors on postganglionic sympathetic terminals influence heart rate and vascular resistance through modulation of noradrenaline release. 

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... 

These receptors were first observed in the sympathetic nervous system in the nictitating membrane of the cat, dopamine reduced the release of noradrenaline via a receptor distinct from the 0,2-autoreceptor (Enero and Langer 1975). Most of the heteroreceptors are D2-like and inhibitory, but in rat nucleus accumbens and medial prefrontal cortex Di receptors enhance noradrenaline release (Table 1). The opposite effects mediated by Di and D2 receptors in rat nucleus accumbens have been explained by location of the inhibitory D2 receptors close to, and location of the fa-cilitatory Di receptors more distant from, dopaminergic varicosities (Vandschuren et al. 1999). 

Although noradrenergic terminals normally contain too little dopamine for presynaptic dopamine heteroreceptors to become activated, and despite the fact that the hippocampus is only sparsely innervated by dopaminergic fibers (Bischoff et al. 1979), the release of [3H]-noradrenaline in rabbit (Jackisch et al. 1985) and rat (Monnet 2002) hippocampus was inhibited by endogenous dopamine as shown by the facilitatory effect of D2 antagonists. Voltage-sensitive calcium channels seem to play a role in the dopaminergic inhibition of noradrenaline release (Monnet 2002). 

The glomerular layer of the olfactory bulb contains a substantial population of dopaminergic neurons. Dopamine acting at D2-like heteroreceptors inhibits glutamate release from terminals of the olfactory sensory neurons and hence may modulate the olfactory nerve synapse (Table 1). 

Presynaptic histamine receptors are more uniform than presynaptic dopamine receptors. Only one type, H3, has been identified with certainty. Like presynaptic dopamine receptors, presynaptic H3 receptors occur as auto- and heteroreceptors... 

The inhibitory H3 heteroreceptors on dopaminergic nerve terminals in mouse striatal slices were not activated by endogenous histamine under the experimental conditions chosen, since their blockade did not enhance the release of dopamine (Schlicker et al. 1993). In the rat nucleus accumbens in vivo, however, indirect evidence (an histamine-evoked increase in acetylcholine release) suggests that dopamine release is permanently inhibited by endogenous histamine (Prast et al. 1999a see Section 3.6). 

Blockade of dopamine autoreceptors increased the extent of H3 receptor-mediated inhibition of dopamine release in mouse striatal slices this another example of an autoreceptor/heteroreceptor interaction (Schlicker et al. 1993 compare Sections 2.4, 3.3, 4.3). 

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. 

The pertussis toxin sensitivity and, hence, Gi/o coupling of 5-HTib autoreceptors in rat striatum (Section4.1) and of the 5-HTib heteroreceptors inhibiting dopamine release in rat striatum (Section4.4) also holds true for the 5-HTib heteroreceptors inhibiting acetylcholine release in rat hippocampus (Sarhan and Fillion 1999). Presynaptic HT4 receptors increase cAMP levels which in turn, by stimulating protein kinase A, may inhibit K+ channels to enhance transmitter release (Eglen et al. 1995). 

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... 

Presynaptic Peripheral Dopamine Heteroreceptor Agonist Lergotrile.566... 

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