Adrenergic receptor presynaptic

Localization of Adrenergic Receptors—Presynaptically located and f receptors fulfill important roles in the regulation of neurotransmitter release from sympathetic nerve endings (see above). Presynaptic receptors also may mediate inhibition of release of neurotransmitters other than NE in the central and peripheral nervous systems. Both and f receptors are located... 

The distinction between a- and P-adrenergic receptors was first proposed by Ahlquist in 1948 based on experiments with various catecholamine derivatives to produce excitatory (a) or inhibitory (P) responses in isolated smooth muscle systems. Initially, a further subdivision into presynaptic a2- and postsynaptic oq-receptors was proposed. However, this anatomical classification of a-adrenergic recqrtor subtypes was later abandoned. 

Cionidine. Clonidine dampens sympathetic activity originating at the locus coeruleus by stimulation of presynaptic a2-adrenergic receptors in the sympathetic chain (Covey and Classman 1991 Hughes 1994). It appears to have some efficacy for alcohol and opioid withdrawal and thus was evaluated for treatment of nicotine withdrawal as well (Covey and Classman 1991 Hughes 1994). Several clinical trials used oral or transdermal clonidine in doses of 0.1—0.4 mg/day for 2—6 weeks with or without behavior therapy. Three meta-analytic reviews reported that clonidine improved quit rates (Covey and Classman 1991 Courlay and Benowitz 1995 Law and Tang 1995). 

Stevens, D. R., Kuramasu, A., Eriksson, K. S., Selbach, O. Haas, H. L. (2004). Alpha 2-adrenergic receptor-mediated presynaptic inhibition of GABAergic IPSPs in rat histaminergic neurons. Neuropharmacology 46, 1018-22. 

Clonidine, guanabenz, guanfacine, and methyldopa lower BP primarily by stimulating a2-adrenergic receptors in the brain, which reduces sympathetic outflow from the vasomotor center and increases vagal tone. Stimulation of presynaptic oq-receptors peripherally may contribute to the reduction in sympathetic tone. Consequently, there may be decreases in heart rate, cardiac output, total peripheral resistance, plasma renin activity, and baroreceptor reflexes. 

Some failures will be due to the presence of variants in drug handling. Patients who are rapid acetylators of isoniazid have a slower antituberculous response than slow acetylators (Evans and Clarke, 1961). Asthmatics who do not respond well to (32-agonist bronchodilators may have fewer functioning p2-adrenergic receptors (Drysdale et al., 2000). Variations in the synthesis or structure of the serotonin transporter protein, which is involved in selective reuptake of serotonin by presynaptic neurons, may explain why some patients with depressive disorders respond to selective serotonin reuptake inhibitors and others do not (Steimer et al., 2001). 

Fig. 4. Inhibition of noradrenaline release by and a2c-receptors. In atria from wild-type mice, exogenous noradrenaline completely inhibited release of H-noradrenaline from sympathetic nerves. After deletion of the a2A-receptor gene, the maximal inhibitory effect of noradrenaline was decreased, and knockout of the tt2c-receptor gene led to a rightward shift of the noradrenaline concentration response curve. Only in atria from mice lacking Uja- and a2c-receptors (a2Ac-KO) was the inhibitory effect of noradrenaline completely abolished, indicating that tt2A- and a2c-adrenergic receptors are both required for presynaptic feedback inhibition of transmitter release (adapted from Hein et al. 1999)...

Other available antidepressants have unique mechanisms of action that may have an impact on norepinephrine, serotonin, or dopamine indirectly through other mechanisms. For example, mirtazapine s direct antagonism of presynaptic a2-adrenergic receptors results in an indirect increase in central noradrenergic and serotonergic activity. 

As mentioned in section 4.3.3, there are two kinds of a receptor in brain and peripheral tissues. The crucial experiments have shown that brain tissue prelabeled with pH]NE will release neurotransmitter upon electrical stimulation or exposure to K+. The release is reduced by the a agonist clonidine (4.42) and stimulated by the a antagonist yohimbine (4.43). Since the adrenoreceptor involved in this latter experiment plays a vital role in modulating neurotransmitter release, it must be presynaptic and located on the nerve-ending membrane. A similar selectivity has also been shown by peripheral tissues (heart, uterus), leading to the distinction of aj (postsynaptic) and (presynaptic) adrenergic receptors. There are also presynaptic [3 receptors, which show a feedback regulation opposite to that of the ttj receptors that is, their excitation by a neurotransmitter increases NE release. 

Tizanidine is an a -adrenergic receptor agonist at supraspinal and spinal levels. This effect results in inhibition of spinal polysynaptic reflex activity. It presumably reduces spasticity by increasing presynaptic inhibition of motor neurons. Tizanidine has no direct effect on skeletal muscle, the neuromuscular junction or on monosynaptic reflex activity. 

Important intraspecies differences are found in the relative proportions of MAO-A or MAO-B in tissues [e.g., human brain has more MAO-B (about 70%) activity rat brain has more MAO-A]. After administration of an MAOI, intracellular levels of endogenous amines (e.g., NE) increase, but levels of amines not usually found in humans (tryptamine and phenylethylamine) also increase, followed by a compensatory decrease in amine synthesis because of feedback mechanisms. Levels of other amines or their metabolites (i.e., false transmitters) increase in storage vesicles and may displace true transmitters, while presynaptic neuronal firing rates decrease. After 3 to 6 weeks, brain serotonin may return to normal levels and NE levels may decrease. There is a compensatory decrease in the number of receptors, including b-adrenergic receptor-related functions (e.g., NE-stimulated adenyl cyclase). 

Kubista H, Boehm S (2006) Molecular mechanisms underlying the modulation of exocytotic noradrenaline release via presynaptic receptors. Pharmacol Ther 112 213 12 Lakhlani PP, MacMillan LB, Guo TZ, McCool BA, Lovinger DM, Maze M, Limbird LE (1997) Substitution of a mutant a2A-adrenergic receptor via hit and run gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo. Proc Natl Acad Sci USA 94 9950-5... 

Michelotti GA, Price DT, Schwinn DA (2000) ai-adrenergic receptor regulation basic science and clinical implications. Pharmacol Ther 88 281-309 Miller RJ (1998) Presynaptic receptors. Annu Rev Pharmacol Toxicol 38 201-27 Mishima K, Tanoue A, Tsuda M, Hasebe N, Fukue Y, Egashira N, Takano Y, Kamiya HO, Tsu-jimoto G, Iwasaki K, Fujiwara M (2004) Characteristics of behavioral abnormalities in ocid-adrenoceptors deficient mice. Behav Brain Res 152 365-73 Miyakawa T, Yamada M, Duttaroy A, Wess J (2001) Hyperactivity and intact hippocampus-dependent learning in mice lacking the Mi muscarinic acetylcholine receptor. J Neurosci 21 5239-50... 

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