Monoamines neurotransmission

At low doses, both psychostimulants could theoretically stimulate tonic, extracellular levels of monoamines, and the small increase in steady state levels would produce feedback inhibition of further release by stimulating presynaptic autoreceptors. While this mechanism is clearly an important one for the normal regulation of monoamine neurotransmission, there is no direct evidence to support the notion that the doses used clinically to treat ADHD are low enough to have primarily presynaptic effects. However, alterations in phasic dopamine release could produce net reductions in dopamine release under putatively altered tonic dopaminergic conditions that might occur in ADHD and that might explain the beneficial effects of methylphenidate in ADHD. 

A fungus that grows on wheat expends resources to produce ergot alkaloids, which affect vertebrate monoamine neurotransmission. Do ergot alkaloids have an internal plant/fungus purpose or have they evolved as compounds that protect the plant host and, thus, also the fungus from... 

The monoamine hypothesis of depression develops from the finding that drugs reducing monoamine neurotransmission cause depression. Monoamines include serotonin, norepinephrine, and dopamine. 

As previously noted, all currently available antidepressants enhance monoamine neurotransmission by one of several mechanisms. The most common mechanism is inhibition of the activity of SERT, NET, or both monoamine transporters (Table 30-2). Antidepressants that inhibit SERT, NET, or both include the SSRIs and SNRIs (by definition), and the TCAs. Another mechanism for increasing the availability of monoamines is inhibition of their enzymatic degradation (the MAOIs). Additional strategies for enhancing monoamine tone include binding presynaptic autoreceptors (mirtazapine) or specific postsynaptic receptors (5-HT antagonists and mirtazapine). Ultimately, the increased availability of monoamines for... 

Chalon S. (2006). Omega-3 fatty acids and monoamine neurotransmission. Prostaglandins Leukot. Essent. Fatty Acids 75 259-269. 

Serotonin and catecholamine functions in the central nervous system are both diverse and complex, and direct assessment of central neurotransmitters by cfinical laboratory methods is currently limited. The effects, however, of central serotonergic, dopaminergic, and serotonergic systems on metabolic and hormonal function are routinely measured in the clinical laboratory, and many of the therapeutic and illicit drugs that modulate central monoamine neurotransmission are monitored by laboratory techniques in a wide range of clinical settings. 

The action of antidepressants on monoamine neurotransmission does not by itself mean that these systems are abnormal in depression. The main evidence is surtunarised below. 

Most antidepressants have acute effects on monoamine neurotransmission (Fig. 4.3). 

As mentioned above, impaired monoamine neurotransmission has been implicated in causing depression, attention deficit disorder and narcolepsy. 

Smith AD, Weiss F. Ethanol exposure differentially alters central monoamine neurotransmission in alcohol-preferring versus -nonpreferring rats. J Pharmacol Exp Ther... 

Of course, while the identification of these distinct systems may be useful there are many neural pathways that would not fit easily into one of them. Thus some inhibitory pathways, such as that from the caudate nucleus to substantia nigra, utilising GABA, are not intrinsic neurons. The dopamine pathway from the substantia nigra to striatum may start from a small nucleus but unlike other monoamine pathways it shows little ramification beyond its influence on the striatum. The object of the above classification is not to fit all neural pathways and mechanisms into a restricted number of functional categories but again to demonstrate that there are different forms of neurotransmission. 

Typically, neurotoxic effects of drugs on monoamine neurons have been assessed from reductions in brain levels of monoamines and their metabolites, decreases in the maximal activity of synthetic enzymes activity, and decreases in the active uptake carrier. In the present study, the traditional markers described above have been used, including the measurement of the content of monoamines and their metabolites in brain at several different timepoints following drug administration. Since reports in the literature have documented that MDMA and MDA can inhibit the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis (Stone et al. 1986 Stone et al. 1987). it is unclear whether MDMA-induced reductions in the content of serotonin and its metabolite 5-hydroxyin-doleacetic acid (5-HlAA) may be due to suppressed neurotransmission in otherwise structurally intact serotonin neurons or may represent the eonsequenee of the destruction of serotonin neurons and terminals. 

Inhibition of monoamine oxidase has been proposed as a possible mechanism underlying the hydrogen sulfide-mediated disruption of neurotransmission in brain stem nuclei controlling respiration (Warenycia et al. 1989a). Administration of sodium hydrosulfide, an alkali salt of hydrogen sulfide, has been shown to increase brain catecholamine and serotonin levels in rats. It has also been suggested that persulfide formation resulting from sulfide interaction with tissue cystine and cystinyl peptides may underlie some... 

Virtually all types of drug that have been shown to be effective in major depression exert profound effects on the functioning of the serotoninergic or noradrenergic systems, or both. Although some treatments have been shown to decrease the sensitivity of certain postsynaptic 5-HT and NE receptors, it is generally believed that it is an enhancement of neurotransmission in these systems that is responsible for the improvement of the core symptoms of depression. For instance, long-term administration of tricyclic antidepressants (TCAs) or monoamine oxidase inhibitors (MAOIs) decreases the density of (3-adrenoceptors and cortical 5-HT2 receptors (Blier and Abbott 2003). 

The primary catabolic pathway for 5-HT is oxidative deamination by the enzyme monoamine oxidase 237 In addition to classical synaptic transmission, 5-HT may relay information by volume transmission or paracrine neurotransmission 238 5 -HT may be involved in a wide variety of behaviors by setting the tone of brain activity in relationship to the state of behavioral arousal/activity 238... 

A number of medications used in the treatment of anxiety have effects on serotonin neurotransmission (Ch. 13). These medications include tricyclic antidepressant medications, SSRIs, and monoamine oxidase inhibitors (MAOIs). However, because these medications take weeks to exert their full anxiolytic effects, it is unlikely that blocking the reuptake (and thus increasing synaptic levels) of either serotonin or norepinephrine selectively is responsible for their anxiolytic properties — rather it is suspected that the therapeutic effects are due to changes in gene expression, protein levels, and eventually changes in synaptic connections between neurons. 

Blocking Enzymes. Remember that there are enzymes both in the synapse and in the cytoplasm of the nerve cells that metabolize and thereby inactivate neurotransmitter molecules. One way to promote neurotransmission is to increase the supply of available neurotransmitter. Blocking (or inhibiting) the enzymes that destroy neurotransmitter will do just that. Certain antidepressants known as monoamine oxidase inhibitors (MAOIs) and some medications used to treat Alzheimer s disease act in this manner. 

Monoamine Oxidase Inhibitors (MAOIs). As mentioned earlier, the MAOIs are excellent treatments for both depression and anxiety. They act by increasing neurotransmission of three neurotransmitter systems serotonin, norepinephrine. 

Ultimately, the effects of virtually aU existing antidepressants can be traced to the improvement of neurotransmission in the brain by one or more monoamine neurotransmitters, that is serotonin (5-HT, 4), norepinephrine (NE, 5), and dopamine (DA, 6). By blocking monoamine transporters, which remove the neurotransmitter from the synapse and extracellular space by uptake processes, the drugs increase extracellular levels of the transmitter and cause a cascade of intracellular events leading to the desired CNS effect. 

Hashimoto S, Inoue T, Koyama T (1999) Effects of conditioned fear stress on serotonin neurotransmission and freezing behavior in rats. Eur J Pharmacol 378 23-30 Hayley S, Borowski T, Merali Z, Anisman H (2001) Central monoamine activity in genetically distinct strains of mice following a psychogenic stressor effects of predator exposure. Brain Res 892 293-300... 

The involvement of dopaminergic neurotransmission in AD has led to the use of agonists such as bromocriptine, lisuride, and pergolide, with poor results. A selective monoamine oxidase B inhibitor (MAO-B) such as deprenyl has also been employed. Little solid information exists on the effects of deprenyl on AD. Unfortunately, all information available comes from small studies. In a double-blind study, Tariot et al. (1987) observed that, with a daily dose of 10 mg in 17 patients with AD, a significant reduction in the scores for anxiety, depression, tension, and excitement was achieved. Burke et al. (1993), in a study of more than 20 patients with AD during a period of 15 months, found no behavioral changes in the progression of the illness nor in its scores. 

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