Heteroreceptors noradrenergic

Mirtazapine enhances central noradrenergic and serotonergic activity through the antagonism of central presynaptic a2-adrenergic autoreceptors and heteroreceptors. It also antagonizes 5-HT2 and 5-HT3 receptors. It also blocks histamine receptors. 

Control of transmitter release is not limited to modulation by the transmitter itself. Nerve terminals also carry regulatory receptors that respond to many other substances. Such heteroreceptors may be activated by substances released from other nerve terminals that synapse with the nerve ending. For example, some vagal fibers in the myocardium synapse on sympathetic noradrenergic nerve terminals and inhibit norepinephrine release. Alternatively, the ligands for these receptors may diffuse to the receptors from the blood or from nearby tissues. Some of the transmitters and receptors identified to date are listed in Table 6-4. Presynaptic regulation by a variety of endogenous chemicals probably occurs in all nerve fibers. 

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. 

Axoaxonic interactions (noradrenergic axons with serotonergic axon terminals) Inhibitory alpha 2 heteroreceptors (negative feedback)... 

Axon terminals are usually endowed with several types of presynaptic receptors which do not act independently. It has been described, in particular, for noradrenergic neurones that activation of a given presynaptic receptor blunts the effect mediated via another type of presynaptic receptor32-3 activated subsequently. H3 heteroreceptors on noradrenergic neurones also participate in such receptor interactions. When, e.g., the... 

Fig. 4. Schematic drawing of an axon terminal of the noradrenergic neurone in the mouse brain cortex. The axon terminal is endowed with several types of presynaptic receptors including the autoreceptor for noradrenaline itself (which is an a2D-adrenoceptor in this species45) and a variety of heteroreceptors (only the H3 and EP3 heteroreceptors are identified).

As mentioned above, the existence of H3 receptors located presynaptically as heteroreceptors on other aminergic neurons, such as serotonergic, noradrenergic and dopaminergic neurons has been suggested [10-13], However, in a series of experiments we found that neither RmHA nor THIOP affected the ACTH response to serotonergic activation induced by administration of the 5-HT precursor 5-hydroxytryptophan in combination with the 5-HT re-uptake inhibitor fluoxetine [27],... 

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). 

Presynaptic receptors, when located on the same terminals, may interact with one another (see Schlicker and Gothert 1998 Trendelenburg et al. 2003). Such cross-talk also occurs between presynaptic D2-like heteroreceptor on noradrenergic neurons and the presynaptic (X2-autoreceptors inhibition by one narrows the scope for inhibition by the other (Jackisch et al. 1985 see also 1.2.3, 1.2.5 and 1.3.3). 

They were the first presynaptic H3 heteroreceptors to be discovered (in guinea pig mesenteric artery Table 1). They mediate inhibition of transmitter release from many noradrenergic neurons, peripheral as well as central (Table 1). They may be activated by histamine from mast cells, as happens in the heart upon myocardial ischemia (see Section 3.10). In the CNS an input of endogenous histamine has not been demonstrated (see references in Table 3). For example, the release of noradrenaline in the hippocampus of freely moving rats remained unchanged upon local... 

Like D2-like heteroreceptors (Section 2.4), the H3 heteroreceptors on noradrenergic terminals may interact with terminal 0G2 autoreceptors preactivation of one receptor attenuates the effect obtainable by activation of the other (see Schlicker and Gothert 1998). 

Scanziani M, Capogna M, Gahwiler BH, Thompson SM (1992) Presynaptic inhibition of miniature excitatory synaptic currents by baclofen and adenosine in the hippocampus. Neuron 9 919-27 Schlicker E, Gothert M (1998) Interactions between the presynaptic alpha2-autoreceptor and presynaptic inhibitory heteroreceptors on noradrenergic neurones. Brain Res Bull 47 129-32. Schmitz D, Mellor J, Nicoll RA (2001) Presynaptic kainate receptor mediation of frequency facilitation at hippocampal mossy fiber synapses. Science 291 1972-6 Schneggenburger R, Neher E (2005) Presynaptic calcium and control of vesicle fusion. Curr Opin Neurobiol 15 266-74... 

Millan MJ, Lejeune F, Gobert A. Reciprocal autoreceptor and heteroreceptor control of serotonergic, dopaminergic and noradrenergic transmission in the frontal cortex relevance to the actions of antidepressant agents. J Psychopharmacol... 

---