255 Nicotine Norepinephrine

The phenothiazines have a variety of actions at different receptor types. However, they do NOT appear to interact with receptors for (A) Dopamine Histamine Nicotine Norepinephrine Muscarine... 

The various stimulants have no obvious chemical relationships and do not share primary neurochemical effects, despite their similar behavioral effects. Cocaines chemical strucmre does not resemble that of caffeine, nicotine, or amphetamine. Cocaine binds to the dopamine reuptake transporter in the central nervous system, effectively inhibiting dopamine reuptake. It has similar effects on the transporters that mediate norepinephrine and serotonin reuptake. As discussed later in this chapter in the section on neurochemical actions mediating stimulant reward, dopamine is very important in the reward system of the brain the increase of dopamine associated with use of cocaine probably accounts for the high dependence potential of the drug. 

Figure 25-7. Metabolism of adipose tissue. Hormone-sensitive lipase is activated by ACTH, TSH, glucagon, epinephrine, norepinephrine, and vasopressin and inhibited by insulin, prostaglandin E, and nicotinic acid. Details of the formation of glycerol 3-phosphate from intermediates of glycolysis are shown in Figure 24-2. (PPP, pentose phosphate pathway TG, triacylglycerol FFA, free fatty acids VLDL, very low density lipoprotein.)...

Figure 9.2 Autonomic nerve pathways. All preganglionic neurons release acetylcholine (Ach), which binds to nicotinic receptors (N) on the postganglionic neurons. All postganglionic neurons in the parasympathetic system and some sympathetic postganglionic neurons innervating sweat glands release Ach that binds to muscarinic (M) receptors on the cells of the effector tissue. The remaining postganglionic neurons of the sympathetic system release norepinephrine (NE), which binds to alpha (a) or beta (P) receptors on cells of the effector tissue. The cells of the adrenal medulla, which are modified postganglionic neurons in the sympathetic system, release epinephrine (EPI) and NE into the circulation.

Westfall, T.C., Effect of nicotine and other drugs on the release of 3H-norepinephrine and 3H-dopamine from rat brain slices, Neuropharmacology, 13, 693, 1974. 

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). 

Nicotinic receptors are present in the pineal gland (Stankov et al. 1993). Although there appear to be no direct effects of nicotine on the release of melatonin, it indirectly reduces the accumulation of melatonin stimulated by norepinephrine. Nicotine increases circulating levels of norepinephrine and epinephrine (Pomerleau et al. 1983). 

Bupropion is another alternative pharmacological approach to tobacco abstinence. It is an antidepressant drug that blocks reuptake of norepinephrine and dopamine, and also blocks nicotinic receptors in the low to intermediate micromolar range (Fryer and Lukas 1999). Thus, the effects of bupropion on nicotine addiction may be through dual effects on dopaminergic and nicotinic systems. Further, it has been an effective treatment in controlled studies, both alone and in combination with the nicotine patch. Bupropion alone or in combination with a nicotine patch was more effective than placebo or the nicotine patch alone. 

Lobeline also increases basal release of norepinephrine, but norepinephrine release may be reduced at higher lobeline concentrations (Rao et al. 1997). Unlike acetylcholine, lobeline does not reduce the release of dopamine or norepinephrine by NMDA receptors, but it does block nicotine-induced release of norepinephrine from the locus coeruleus (Gallardo and Leslie 1998). Lobeline also evokes release of serotonin, which is mediated by uptake transporters and unaffected by mecamylamine (Lendvai et al. 1996). 

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. 

Gallardo KA, Leslie FM. (1998). Nicotine-stimulated release of [3FI]norepinephrine from fetal rat locus coeruleus cells in culture. J Neurochem. 70(2) 663-70. 

Anderson DJ, Puttfarcken PS, Jacobs 1, Faltynek C (2000) Assessment of nicotinic acetylcholine receptor-mediated release of [ H]-norepinephrine from rat brain slices using a new 96-well format assay. Neuropharmacology 39 2663-2672 Anney RJ, Olsson CA, Lotfi-Miri M, Patton GC, Williamson R (2004) Nicotine dependence in a prospective population-based study of adolescents the protective role of a functional tyrosine hydroxylase polymorphism. Pharmacogenetics 14 73-81 Auerbach A, Akk G (1998) Desensitization of mouse nicotinic acetylcholine receptor channels. 

Fagen ZM, Mitchum R, Vezina P, McGehee DS (2007) Enhanced nicotinic receptor function and drug abuse vulnerability. J Neurosci 27 8771-8778 Fu Y, Malta SG, Brower VG, Sharp BM (2001) Norepinephrine secretion in the hypothalamic paraventricular nucleus of rats during unlimited access to self-administered nicotine an in vivo microdialysis study. J Neurosci 21 8979-8989... 

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... 

Schechter MD, Rosecrans JA (1972) Nicotine as a discriminative cue in rats depleted of norepinephrine or 5-hydroxytryptamine, Psychopharmacologia 24 417 29 Schreiber R, Brocco M, MiUan Ml (1994) Blockade of the discriminative stimulus effects of DOI by MDL 100,907 and the atypical antipsychotics, clozapine and risperidone, Eur J Pharmacol 264 99-102... 

Stolerman IP, Chamberlain S, Bizarro L, Fernandes C, Schalkwyk L (2004) The role of nicotinic receptor alpha7 subunits in nicotine discrimination. Neuropharmacology 46 363-371 Summers KL, Giacobini E (1995) Effects of local and repeated systemic administration of (—) nicotine on extracellular levels of acetylcholine, norepinephrine, dopamine, and serotonin in rat cortex. Neurochem Res 20 753-759... 

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. 

As previously mentioned, many of the effects of nicotine in the brain are likely to be mediated through neuromodulation, in which nicotine potentiates the release of dopamine, norepinephrine, and serotonin (Picciotto 1998). By selectively activating these neurotransmitters, one might be able to mimic some of the reinforcing effects of nicotine. 

Bupropion is an atypical antidepressant drug that is the only nonnicotine-based prescription medicine approved for smoking cessation by the FDA. Its mechanism of action is presumed to be mediated by its capacity to block neuronal reuptake of dopamine and/or norepinephrine (Fiore et al. 2000). Relative to other antidepressants, bupropion has a relatively high affinity for the dopamine transporter (Baldessarini 2001). There is also evidence that bupropion acts as a functional nicotine antagonist, suggesting another potential mechanism by which bupropion could reduce smoking rates (Slemmer et al. 2000). 

Granberg NE, Popp KA, Bowen DJ, Nespor SM, Winders SE, Eury SE (1988) Effects of chronic nicotine administration on insulin, glucose, epinephrine, and norepinephrine. Life Sci 42 161-170... 

Bupropion (Weiibutrin, Zyban). Bupropion is an antidepressant that is also FDA approved as a treatment for smoking cessation. It is marketed as an antidepressant as Weiibutrin and for the treatment of nicotine dependence as Zyban. Its mechanism of action in this regard is obscure, but it may act on dopamine and/or norepinephrine systems. 

Nortriptyline (Pamelor). A recent study suggested that the tricyclic antidepressant nortriptyline, like bupropion, is effective in the treatment of smoking cessation. Nortriptyline does not have any significant effect on dopamine reuptake activity, but it does increase norepinephrine availability. Like bupropion, nortriptyline may therefore reduce the physical symptoms of nicotine withdrawal. Because nortriptyline carries the danger of lethality in overdose and has the unfavorable side effect profile of the tricyclics, we do not recommend its use for smoking cessation. However, it does raise the question as to whether other newer antidepressants that increase norepinephrine activity (e.g., venlafaxine, mirtazapine, duloxetine) may also prove to be effective treatments for nicotine withdrawal. 

Bupropion belongs to the chemical class of aminoketones. It is an atypical antidepressant that acts as a norepinephrine and dopamine reuptake inhibitor, and nicotinic antagonist. Initially developed and marketed as an antidepressant, bupropion was subsequently found to be effective as a smoking cessation aid. If given to lactating women it can trigger convulsions in the newborn. 

Bupropion and also varenicline are mentioned in Chapter 21, Section I.c.4. Bupropion is a norepinephrine and dopamine reuptake inhibitor de-veoped as an antidepressant. It is now used on a large scale as a smoking cessation aid. Varenicline is the first nicotinic receptor partial agonist approved to treat smoking addiction. 

In addition to autonomic ganglia, nicotinic receptors are found in a variety of organs, and their stimulation will produce quite different results in these different tissues. Activation of nicotinic receptors on the plasma membrane of the cells of the adrenal medulla leads to the exo-cytotic release of epinephrine and norepinephrine stimulation of nicotinic receptors at the neuromuscular junction results in the contraction of skeletal muscle (see... 

Chapter 28). Stimulation of nicotinic receptors in adrenergic nerve terminals leads to the release of norepinephrine and activation of nicotinic chemoreceptors in the aortic arch and carotid bodies causes nausea and vomiting. Nicotinic receptors in the central nervous system mediate a complex range of excitatory and inhibitory effects. 

The effects of nicotine on the cardiovascular system mimic those seen after activation of the sympathoadrenal system, and they are principally the result of a release of epinephrine and norepinephrine from the adrenal medulla and adrenergic nerve terminals. These effects include a positive inotropic and chronotropic effect on the myocardium as well as an increase in cardiac output. In addition, both systohc and diastolic blood pressures are increased secondary to stimulation of the sympathoadrenal system. These effects are the end result of a summation of adrenergic and chohnergic stimulation. 

L E. The principal neurotransmitter released from preganglionic nerve terminals in all autonomic ganglia is acetylcholine. It acts on the postganglionic cell body to activate a nicotinic-cholinergic receptor resulting in a fast EPSP. Dopamine or norepinephrine or both are the mediators released from SIF cells or intemeurons. Neuropeptide Y is a peptide neurotransmitter. Angiotensin and serotonin are modulatory mediators. These last three contribute to the late very slow EPSP. 

Sympathetic arc involved in blood pressure regulation and sites where drugs may act to influence the system. A. Receptors on effector cell. 6. Adrenergic varicosity. C. Nicotinic receptors (postganglionic fibers). D. Brainstem nuclei. NTS, nucleus of the tractus solitarii VMC, vasomotor center ACh, acetylcholine NE, norepinephrine a, a-adrenoceptors (3, 13-adrenoceptors P2, P2-purinoceptors ATR adenosine triphosphate. 

Mechanism of Action An aminoketone that blocks the reuptake of dopamine and norepinephrine at CNS presynaptic membranes, increasing their availability at postsynaptic receptor sites. Therapeutic Effect Relieves depression and nicotine withdrawal symptoms. 

Dogs given norepinephrine by infusion at 0.185-2.04 Ug/kg per minute for long periods (9-35 h) until their blood pressures became approximately the same as they had been before the Infusions began were then given intravenous Injections of I at 20 or 40 mg/kg, tyra-mlne at 0.1 or 0.5 mg/kg, or nicotine at 0.5 mg/kg.The concentration of norepinephrine In carotid arterial blood was estimated before and at intervals after the Injection of one of the test compounds. Except after the lower dose of tyramlne, when the maximal Increase In the concentration of norepinephrine in the blood appeared at 5 min after the injection, the peak concentration of norepinephrine in carotid arterial blood occurred at 3 min after Injection. 

The release of norepinephrine induced by I at 40 mg/kg was about 1.35 times that produced by the lower dose. The release of norepinephrine induced by tyramlne at 0.5 mg/kg was 1.47 times that by I at 40 mg/kg. The release by nicotine at 0.5 mg/kg was 1.59 times that by the larger dose of I. The action of I In Inducing release of norepinephrine from tissues In which it has been stored, although it Is slightly more prolonged (20 min vs. 15 min) than those of the classical releasers of norepinephrine, Is much weaker than those of tyramlne and nicotine. 

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