In norepinephrine release

Abrupt cessation may lead to rebound hypertension, which is thought to result from a compensatory increase in norepinephrine release that follows discontinuation of presynaptic a-receptor stimulation. 

Neuronal Norepinephrine Depleting Agents. Reserpine (Table 6) is the most active alkaloid derived from Rauwolfia serpentina. The principal antihypertensive mechanism of action primarily results from depletion of norepinephrine from peripheral sympathetic nerves and the brain adrenergic neurons. The result is a drastic decrease in the amount of norepinephrine released from these neurons, leading to decrease in vascular tone and lowering of blood pressure. Reserpine also depletes other transmitters including epinephrine, serotonin [50-67-9] dopamine [51-61-6] ... 

Rgure 22-2. Neurotransmission in the central nervous system. Neurotransmitter molecules (eg, norepinephrine), released by the presynaptic nerve, cross the synapse and bind with receptors in the cell membrane of the postsynaptic nerve, resulting in the transmission of the nerve impulse. 

Studies have now started to clarify the role of histamine Hi and H2 receptors in the cardiovascular manifestations of anaphylaxis. However, histamine can activate H3 and H4 receptors [56, 57]. Levi and coworkers [58-60] identified H3 receptors as inhibitory heteroreceptors in cardiac adrenergic nerve endings. This suggests a mechanism by which endogenous histamine can activate norepinephrine release in normal and ischemic conditions [61,62]. The functional identification ofH3 receptors in the human heart [59] means that these receptors might be directly and/or indirectly involved in the cardiovascular manifestations of anaphylactic reactions. 

Urata H, Kinoshita A, Misono KS, Bumpus FM. Husain A Identification of a highly specific chy-mase as the major angiotensin Il-forming enzyme in the human heart. J Biol Chem 1990 265 22348. Silver RB, Reid AC, Mackins CJ, Askwith T, Schaefer U, Herzlinger D, Levi R Mast cells a unique source of renin. Proc Natl Acad Sci USA 2004 101 13607. Mackins CJ, Kano S, Sevedi N, Schafer U, Reid AC, Machida T, Silver RB, Levi R Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion. J Clin Invest 2006 116 1063. 

Compared to a,-receptors, a2-receptors have only moderate distribution on the effector tissues however, they have important presynaptic effects. Alpha-one receptors are found on effector tissue cells at the neuroeffector junction the a2-receptors are found on the varicosities of the postganglionic neuron. Norepinephrine released from this neuron not only binds to the a.j-receptors on the effector tissue to cause some physiological effect but also binds to the a2-receptors on the neuron. Alpha-two receptor stimulation results in presynaptic inhibition" or in a decrease in the release of norepinephrine. In this way, norepinephrine inhibits its own release from the sympathetic postganglionic neuron and controls its own activity. Both ar and a2-receptors have equal affinity for norepinephrine released directly from sympathetic neurons as well as circulating epinephrine released from the adrenal medulla. 

Because catecholamines travel in the blood, organs and tissues throughout the body are exposed to them. Therefore, they are capable of stimulating tissues that are not directly innervated by sympathetic nerve fibers, hepato-cytes, and adipose tissue, in particular. As a result, the catecholamines have a much wider breadth of activity compared to norepinephrine released from sympathetic nerves. 

Adrenal medulla. Derived from neural crest tissue, the adrenal medulla forms the inner portion of the adrenal gland. It is the site of production of the catecholamines, epinephrine and norepinephrine, which serve as a circulating counterpart to the sympathetic neurotransmitter, norepinephrine, released directly from sympathetic neurons to the tissues. As such, the adrenal medulla and its hormonal products play an important role in the activity of the sympathetic nervous system. This is fully discussed in Chapter 9, which deals with the autonomic nervous system. 

Barraco, R. A., Clough-Helfinan, C., Goodwin, B. P. Anderson, G. F. (1995). Evidence for presynaptic adenosine A2a receptors associated with norepinephrine release and their desensitization in the rat nucleus tractus sohtarius. J. Neurochem. 65 (4), 1604-11. 

The postsynaptic receptors on any given neuron receive information from transmitters released from another neuron. Typically, postsynaptic receptors are located on dendrites or cell bodies of neurons, but may also occur on axons or nerve terminals in the latter case, an axoaxonic synaptic relationship may cause increases or decreases in transmitter release. In contrast, autoreceptors are found on certain neurons and respond to transmitter molecules released from the same neuron. Autoreceptors may be widely distributed on the surface of the neuron. At the nerve terminal, they respond to transmitter molecules released into the synaptic cleft on the cell body, they may respond to transmitter molecules released by dendrites. Functionally, most autoreceptors appear to decrease further transmitter release in a kind of negative feedback loop. Autoreceptors have been identified for all the catecholamines, as well as for several other neurotransmitters. a2-adrenergic receptors are often found on noradrenergic nerve terminals of postganglionic sympathetic nerves, as well as on noradrenergic neurons in the CNS [36], and activation of these receptors decreases further norepinephrine release. Dopamine autoreceptors,... 

The metabolism of norepinephrine is reported to be altered by other drugs used in the treatment of the affective disorders and a number of studies have shown a change in the metabolism of norepinephrine as a result of Li+ treatment. In rat brain, acute Li+ treatment enhances the uptake of norepinephrine in synaptosomes [151] and the enhanced turnover of this neurotransmitter may be due to an increase in its deamination in the brain, although Li+ also causes a slight increase in the levels of the amino acid precursor, tyrosine, in the brain and plasma of rats [152]. Also, acute Li+ treatment induces a decrease in the release of norepinephrine after electrical stimulation of rat brain [153]. Interest-... 

Kohm, A.R et al., Activation of antigen-specific CD4+Th2 cells and B cells in vivo increases norepinephrine release in the spleen and bone marrow, J. Immunol., 165, 725, 2000. 

Doherty JD, Nishimura K, Kurihara N, Fujita T (1987) Promotion of norepinephrine release and inhibition of calcium uptake by pyrethroids in rat brain synaptosomes. Pestic Biochem Physiol 29 187-196... 

Since the discovery that norepinephrine release at the adrenergic nerve terminal is the mechanism whereby the human body maintains sympathetic tone, medicinal scientists have searched for agents which reduce sympathetic tone through interference with norepinephrine peripherally. Reduction of the effect of norepinephrine should lead to a lowering of blood pressure which might be achieved in the following ways ... 

Nicotine causes a release of norepinephrine from the locus coeruleus and facilitates release of norepinephrine in the hippocampus (Gallardo and Leslie 1998 Mitchell 1993 Sershen etal. 1997 Fu et al. 1999). The norepinephrine released by nicotine, in turn, modulates raphe neurons (Li et al. 1998). 

Fu Y, Matta SG, Sharp BM. (1999). Local alpha-bungarotoxin-sensitive nicotinic receptors modulate hippocampal norepinephrine release by systemic nicotine. J Pharmacol Exp Ther. 289(1) 133-39. Fudala PJ, Iwamoto ET. (1986). Further studies on nicotine-induced conditioned place preference in the rat. Pharmacol Biochem Behav. 25(5) 1041-49. 

Etgen AM, Morales JC. 2002. Somatosensory stimuli evoke norepinephrine release in the anterior ventromedial hypothalamus of sexually receptive female rats. J Neuroendocri-nol 14(3) 213-218. 

Quirarte G, Galvez R, Roozendaal B, McGaugh JL. 1998. Norepinephrine release in the amygdala in response to footshock and opiod peptidergic drugs. Brain Res 808(2) 134-140. 

Williams CL, Men D, Clayton EC. 2000. The effects of noradrenergic activation of the nucleus tractus solitarius on memory and in potentiating norepinephrine release in the amygdala. Behav Neurosci 114(6) 1131-1144. 

Williams CL, Men D, Clayton EC, Gold PE. 1998. Norepinephrine release in the amygdala after systemic injection of epinephrine or escapable footshock contribution of the nucleus of the solitary tract. Behav Neurosci 112(6) 1414-1422. 

Fu Y, Malta SG, Kane VB, Sharp BM (2003) Norepinephrine release in amygdala of rats during chronic nicotine self-administration an in vivo microdialysis study. Neuropharmacology 45 514-523... 

The pattern of data on the role of al receptors (pentamers of the al subunit) is far from clear. Nomikos et al. (1999) reported sharply reduced locomotor activity in nicotine-dependent rats injected with the selective al antagonist methyl-lycaconitine (MLA). Barik and Wonnacott (2006) found increased al sensitivity in the hippocampus of rats during nicotine withdrawal, as evidence by increased norepinephrine release in response to an al agonist. On the other hand, Markou and Paterson (2001) reported that systemically administered ML A failed to precipitate either somatically expressed withdrawal behaviors or altered ICSS thresholds. 

Although this drug is categorized as a local anesthetic, I have chosen to put it in with the hallucinogens because of the psychotomimetic effects that it produces. Cocaine is not a phenylethyl-amine, but it produces central nervous system arousal or stimulant effects which closely resemble those of the amphetamines, the methylenedioxyamphetamines in particular. This is due to the inhibition by cocaine of re-uptake of the norepinephrine released by the adrenergic nerve terminals, leading to an enhanced adrenergic stimulation of norepinephrine receptors. The increased... 

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