Norepinephrine activity

Ethanol also reduces the activity of the noradrenergic system in the locus coeruleus, and alterations in norepinephrine activity may account for some aspects of intoxication and the abstinence syndrome. The 0.2 antagonist clon-idine and the P-receptor antagonist propranolol reduce some symptoms of alcohol withdrawal (Bailly et al. 1992 Carlsson and Fasth 1976 Dobrydnjov et al. 2004 Kahkonen 2003 Petty et al. 1997 Wong et al. 2003). 

Clonidine (Catapres). Like the beta blockers, clonidine acts by reducing norepinephrine activity, though by a different mechanism. Studies show that clonidine can provide early relief from the symptoms of a panic attack, but patients unfortunately relapse with continued treatment. Therefore, clonidine is not used in the treatment of panic disorder. 

Other agents, clonidine and guanfacine, reduce norepinephrine activity by reducing its release. Open label studies suggest these agents might be helpful for the impulsivity that often accompanies PTSD, but the lone controlled study did not find guanfacine to be effective. 

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. 

Tricyclic Antidepressants (TCAs). The TCAs have been nsed to treat ADHD for 30 or more years. Most often used are imipramine (Tofranil) and desipramine (Norpramin), mainly becanse they are the TCAs that most specihcally increase norepinephrine activity. Remember, boosting norepinephrine activity in the brain shonld improve attention. Other TCAs, namely, amitriptyline (Elavil, Endep) and nortriptyline (Pamelor), have been used, though they also increase norepinephrine activity. TCAs do offer a modest benefit for both the inattention and the hyperactivity of ADHD. In addition, they are often effective at doses mnch lower than those required to treat depression. However, their effectiveness nsnally falls short of the stimulant medications. In addition, TCAs have considerable side effects including dry mouth, constipation, drowsiness, weight gain, and adverse cardiac effects. 

Norepinephrine-Blocking Medications. Medications that enhance dopamine activity and to a lesser extent those that enhance norepinephrine activity are believed to be the most successful treatments for ADHD. It may seem counterintuitive to try a medication that reduces norepinephrine turnover. The other ADHD medications... 

Clonidine (Catapres). Clonidine is largely used to treat high blood pressure. Although we don t fully understand how clonidine acts, it appears to reduce norepinephrine activity by stimulating a norepinephrine receptor known as the alpha-2 receptor. When clonidine binds to alpha-2 receptors on norepinephrine neurons, so-called autoreceptors, the cells are tricked into believing that there is already sufficient norepinephrine released and thus decrease any additional release of norepinephrine. As one might anticipate, clonidine is somewhat effective at reducing the hyperactivity and impulsivity of ADHD. It does not, however, provide nearly as much benefit for the inattention of ADHD. 

Norepinephrine-Blocking Medications. There is some evidence that exaggerated norepinephrine activity plays a part in the affective instability, aggression, and impulsivity seen in a variety of psychiatric illnesses including the personality disorders. This may in fact explain why the TCAs, which tend to increase norepinephrine activity, have not proved helpful for BPD. Based on this theory, beta blockers, which interfere with norepinephrine activity at the beta-adrenergic receptor, may help in the treatment of impulsivity and aggression in those with BPD. 

Medications that enhance norepinephrine activity can do so in one of several ways. First, they can block the reuptake of norepinephrine back into the nerve cell once it has been released. This keeps the norepinephrine in the synapse longer and therefore makes it more active. The tricyclic antidepressants (TCAs), duloxetine (Cymbalta), and venlafaxine (Effexor) act in this manner, as does paroxetine (Paxil) at higher doses. Atomoxetine (Strattera), a treatment for ADHD, also works in this way. 

Blocking the norepinephrine alpha-2 receptor can also increase norepinephrine activity. The alpha-2 receptor provides feedback to the neurons to stop releasing norepinephrine and, for that matter, serotonin. By blocking the alpha-2 receptor, norepinephrine and serotonin are more readily released. The atypical antidepressant mirtazapine (Remeron) acts in part in this manner (see Table 13.2). 

TABLE 13.2. Medications that Enhance Norepinephrine Activity... 

A third way of promoting norepinephrine activity is to interfere with the enzyme that inactivates norepinephrine, monoamine oxidase (MAO). The monoamine oxidase inhibitors (MAOIs) work in this way. Incidentally, inhibiting monoamine oxidase also increases serotonin and dopamine activity. 

Finally, you can increase norepinephrine activity by directly stimulating norepinephrine alpha-1 and beta receptors. Some medicines that are used to treat asthma and cardiogenic shock work in this manner, but no psychiatric medications do so. 

Medications that enhance norepinephrine activity are used to treat depression and ADHD. Boosting norepinephrine can also produce numerous side effects including nervousness and anxiety, insomnia, and loss of appetite. With mirtazapine and the TCAs, these side effects are usually not a problem because these antidepressants also block histamine receptors. Their antihistamine effects promote increased appetite and drowsiness that tend to offset the side effects that might be experienced from increased norepinephrine activity. 

Blocking the Alpha-1 Receptor. Blocking the alpha-I receptor can also reduce norepinephrine activity. There is no apparent psychiatric benefit to blocking alpha-1 receptors, and unfortunately, many psychiatric medications do just that, resulting in side effects. 

A host of medications have been nsed to treat TD including medications that block norepinephrine activity (clonidine and propranolol), dopamine-activating medications (bromocriptine), benzodiazepines, acetylcholine-activating medications, calcium channel blockers, and monoamine oxidase inhibitors. In addition, vitamin E supplementation and atypical antipsychotics including clozapine have been used to treat TD. 

When we talk about serotonin-blocking medications, a point of clarification must be made. In most cases, medications do not block overall serotonin activity but instead block the activity at one of the many serotonin receptor types. For example, the antidepressants trazodone, nefazodone, and mirtazapine increase total serotonin activity yet they block certain of the serotonin receptors. Mirtazapine increases both serotonin and norepinephrine activity by interfering with the alpha-2 receptor. By also blocking the serotonin-2 and serotonin-3 receptors, mirtazapine avoids the sexual dysfunction and GI side effects commonly experienced with other serotoninboosting medications. We cannot truly call these serotonin-blocking medications, because they are serotonin-boosting medications that selectively block certain serotonin receptors. 

Dopamine, the immediate metabolic precursor of norepinephrine, activates Di receptors in several vascular beds, which leads to vasodilation. The effect this has on renal blood flow may be of clinical value, though this is uncertain. The activation of presynaptic D2 receptors, which suppress norepinephrine release, contributes to these effects to an unknown extent. In addition, dopamine activates Bi receptors in the heart. At low doses, peripheral resistance may decrease. At higher rates of infusion, dopamine activates vascular a receptors, leading to vasoconstriction, including in the renal vascular bed. Consequently, high rates of infusion of dopamine may mimic the actions of epinephrine. 

Harmer, C.J., Hill, S.A., Taylor, M.J., Cowen, P.J., and Goodwin, G.M. (2003). Toward a neuropsychological theory of antidepressant drug action increase in positive emotional bias after potentiation of norepinephrine activity. American Journal of Psychiatry, 160, 990-992. 

Estes KS, Simpkins JW (1984) Age-related alterations in dopamine and norepinephrine activity within microdissected brain regions of ovariectomized Long Evans rats. Brain Res 298 209-218. 

Smooth muscle is unstriated with innervations from 2 both sympathetic (flight or fight) and parasympathetic (more relaxed) nerves of the autonomic nervous system. E. Smooth muscle appears unstriated under a polarized light microscope, because the myofilaments inside are less or-ganized. Smooth muscle fibers contain actin and myosin myofilaments which are more haphazardly arranged than they are in skeletal muscles. The sympathetic neurotransmitter, Ach, and parasympathetic neurotransmitter, norepinephrine, activate this type of muscle tissue. 

Answer A. Norepinephrine activates a( and pr receptors, causing increases in PVR and CO. The increase in mean BP can elicit reflex bradycardia (vagal outflow leads to stimulation of cardiac M receptors), which may overcome the direct stimulatory effects of NE on the heart. However, reflex bradycardia is not possible following pretreatment with an M blocker. Thus, HR increases because of the direct activation of cardiac p, receptors by NE. 

The transcription of UCP mRNA is upregulated by norepinephrine activation of adrenoreceptors and by increased cAMP. This upregulation can be enhanced by the presence of triiodothyronine and abolished if the deiodinase activity of the cell is inhibited. BAT has a nuclear receptor for triiodothyronine that functions as a transcription factor and probably binds upstream of the UCP gene to activate transcription. The presence of both thyroid response elements and cAMP response elements is likely to be required. 

When compared with the selective serotonin reuptake inhibitors (SSRIs), mirtazapine may show an earlier onset of action (although data are currently not well established). Mirtazapine has also been found to be efficacious in the treatment of elderly patients with depression. Mirtazapine has been shown to be effective in the treatment of panic disorder, social phobia, and post-traumatic stress disorder. In one study, mirtazapine combined with citalopram in obsessive-compulsive patients induced an earlier response when compared with citalopram plus placebo. It was suggested that antagonism of presynaptic a2-adrenergic receptors does not enhance serotonin neurotransmission directly, but rather disinhibits the norepinephrine activation of serotonergic neurons and thereby increases serotonergic neurotransmission by a mechanism that may not require a time-dependent desensitization of receptors. 

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