Serotonin and norepinephrine

Kosofsky, B.E. Molliver, M.E. Morrison, J.H. and Foote, S.L. The serotonin and norepinephrine innervation of primary visual cortex in the Cynomolgus monkey (Macaca fascicularis). J Comp Neurol 230 168-178, 1984. 

MAOI, monoamine oxidase inhibitor SARI, serotonin antagonist and reuptake inhibitor SNRI, serotonin and norepinephrine reuptake inhibitor SSRI, selective serotonin reuptake inhibitor TCA, tricyclic antidepressant. 

FIGURE 38-1. Primary assessment and initial treatment for complaint of excessive daytime sleepiness. RLS, restless-legs syndrome NPSG, nocturnal polysomnography OSA, obstructive sleep apnea DA, dopamine agonist MSLT, multiple sleep latency test BZDRA, benzodiazepine receptor agonist SNRI, serotonin and norepinephrine reuptake inhibitor TCA, tricyclic antidepressant CPAP, continuous positive airway pressure. 

SSRIs are theorized to reduce the frequency of hot flashes by increasing serotonin in the central nervous system and by decreasing LH. Of the SSRIs, citalopram, paroxetine, and sertraline all have been studied and have demonstrated a reduction in hot flashes while treating other symptomatic complaints such as depression and anxiety.33 Venlafaxine, which blocks the reuptake of serotonin and norepinephrine, has demonstrated a reduction in hot flashes primarily in the oncology population.34 Overall, these antidepressant medications offer a reasonable option for women who are unwilling or cannot take hormonal therapies, particularly those who suffer from depression or anxiety. These agents should be prescribed at the lowest effective dose to treat symptoms and may be titrated based on individual response. 

Enhancing the positive effects of serotonin and norepinephrine in the afferent and efferent pathways of the micturition reflex... 

After neurotransmitter molecules have influenced the firing of a receiving neuron (more technically called a postsynaptic neuron), some of them are destroyed by enzymes in the synaptic cleft (the synapse), some are reabsorbed by the sending presynaptic neuron in a process that is called reuptake , and the rest remain in the space between the two neurons. The chemical-imbalance hypothesis is that there is not enough serotonin, norepinephrine and/or dopamine in the synapses of the brain. This is more specifically termed the monoamine theory of depression, because both serotonin and norepinephrine belong to the class of neurotransmitters called monoamines. 

Different types of antidepressants are supposed to affect different neurotransmitters. Some are supposed to affect only serotonin, others are supposed to affect both serotonin and norepinephrine, and still others are supposed to affect norepinephrine and dopamine. But there is a relatively new antidepressant that has a completely different mode of action. It is a most unlikely medication, and the evidence for its effectiveness puts the last nail in the coffin of the chemical-imbalance theory of depression. 

Preskom, Sheldon H., Tianeptine A Facilitator of the Reuptake of Serotonin and Norepinephrine as an Antidepressant , Journal of Psychiatric Practice, 10, no. 5 (2004) 323-30... 

In the context of preparing benzothienyloxy phenylpropanamines as inhibitors of serotonin and norepinephrine uptake, a group from Eli Lilly and Company has developed a two-step synthesis of benzo[fo]thiophenes (Scheme 6.193) [354]. Thus, a 2-mercapto-3-phenylpropenoic acid derivative was cyclized with iodine in 1,2-dimethoxyethane at 120 °C to give 5-fluoro-4-methoxybenzothiophene-2-carboxylic acid in 67% yield. Decarboxylation under strongly basic conditions involving 1,8-di-azabicyclo[5.4.0]undec-7-ene (DBU) as base in N,N-dimethylacetamide (DMA) as... 

Cases, O., Seif, I., Grimsby, J. et al. Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 268 1763-1766, 1995. 

The goal of treatment of SUI is to improve urethral closure by stimulating a-adrenergic receptors in the smooth muscle of the bladder neck and proximal urethra, enhancing supportive structures underlying the urethral epithelium, or enhancing serotonin and norepinephrine effects in the micturition reflex pathways. 

Duloxetine, a dual inhibitor of serotonin and norepinephrine reuptake indicated for depression and painful diabetic neuropathy, is expected to become first-line therapy for SUI. Duloxetine is thought to facilitate the bladder-to-sympathetic reflex pathway, increasing urethral and external urethral sphincter muscle tone during the storage phase. 

McCall, R. B., and Aghajanian, G. K. (1980) Hallucinogens potentiate responses to serotonin and norepinephrine in the facial motor nucleus. Life Sci.. 26 1149-1156. 

The biogenic amines are the preferred substrates of MAO. The enzyme comes in two flavors, MAO-A and MAO-B, both of which, like FMO, rely on the redox properties of FAD for their oxidative machinery. The two isoforms share a sequence homology of approximately 70% (81) and are found in the outer mitochondrial membrane, but they differ in substrate selectivity and tissue distribution. In mammalian tissues MAO-A is located primarily in the placenta, gut, and liver, while MAO-B is predominant in the brain, liver, and platelets. MAO-A is selective for serotonin and norepinephrine and is selectively inhibited by the mechanism-based inhibitor clorgyline (82). MAO-B is selective for /1-phcncthylaminc and tryptamine, and it is selectively inhibited by the mechanism-based inhibitors, deprenyl and pargyline (82) (Fig. 4.32). Recently, both MAO-A (83) and MAO-B (84) were structurally characterized by x-ray crystallography. 

Belej T, Manji D, Sioutis S, Barros HM, Nobrega JN. (1996). Changes in serotonin and norepinephrine uptake sites after chronic cocaine pre- vs. post-withdrawai effects. Brain Res. 736(1-2) 287-96. Bennett TL. (1973). The effects of centraiiy biocking hippocampai theta activity on iearning and retention. Behav Biol. 9(5) 541-52. 

Methods and devices for transdermal delivery of lithium (US6,375,990 Bl) Methods to estimate serotonin and norepinephrine transporter occupancy after drug treatment using patient or animal serum (provisional filing April 2001)... 

Venlafaxine (Effexor, Effexor XR). Venlafaxine works by blocking the reuptake of both serotonin and norepinephrine. Because of this dual action, some believe that venlafaxine may be more effective than the SSRIs when treating severe depression. Its side effects and toxicity are similar to the SSRIs with abdominal discomfort, sexual dysfunction, and anxiety being commonly reported. At higher doses, it may mildly elevate blood pressure therefore, blood pressure should be checked periodically. When stopping venlafaxine, serotonin discontinuation symptoms may be especially problematic. Therefore, gradually tapering of the dose every 2-4 weeks is recommended. 

It appears that SSRls and bnpropion are less likely than TCAs to indnce mania. Venlafaxine, perhaps becanse of its dnal effects on serotonin and norepinephrine like the TCAs, also appears to increase the likelihood of switching into mania. Rarely, if ever, shonld an antidepressant be nsed in bipolar patients withont concomitant treatment with a mood stabilizer. 

The newest appetite suppressant, sibutramine (Meridia), works by blocking the reuptake of both serotonin and norepinephrine. It does not stimulate nerve cells to release serotonin, as do fenfluramine and dexfenfluramine. Administered at 20 mg/ day, sibutramine effectively reduces weight in obese patients, but its use has not been assessed in eating disorder patients. The most common side effects of this medication are insomnia, dry mouth, and constipation. It has not been associated with the more serious heart and lung complications observed with fenfluramine and dexfenfluramine. Because sibutramine acts in part through modulation of norepinephrine, there is no rational basis for coadministering phentermine, which acts via this same mechanism. 

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. 

Pharmacology Bupropion is a weak blocker of the neuronal uptake of serotonin and norepinephrine. 

Pharmacology Venlafaxine and its active metabolite, 0-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. 

Pharmacoiogy Nefazodone is an antidepressant with a chemical structure unrelated to available antidepressant agents. The mechanism of action is unknown. Nefazodone inhibits neuronal uptake of serotonin and norepinephrine. Pharmacokinetics ... 

MAOis- Because nefazodone is an inhibitor of both serotonin and norepinephrine reuptake, it is recommended that nefazodone not be used in combination with an MAOl, or within 14 days of discontinuing treatment with an MAOI. Allow at least 1 week after stopping nefazodone before starting an MAOl. 

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