Neurotransmitter re-uptake

A.P. Kozikowski etal, US Patent 6,150,376 (November 21, 2000) Assignee Georgetown University Utility Neurotransmitter Re-Uptake Inhibitors... 

At the pharmacological level, for example, because bioactivation is necessary to create the active species, these compounds cannot be submitted to preliminary in vitro screening tests, namely, binding studies, neurotransmitter re-uptake, measurements of enzymatic inhibition and activity on isolated organs. 

Histamine is synthesized from the amino acid histidine via the action of the specific enzyme histidine decarboxylase and can be metabolized by histamine-TV-methyl transferase or diamine oxidase. Interesting, in its role as a neurotransmitter the actions of histamine are terminated by metabolism rather than re-uptake into the pre-synaptic nerve terminals. 

Receptors can mediate the action of endogenous signalling compounds and may therefore be viewed as regulatory proteins. Such receptors are the physiological targets for neurotransmitters and hormones. Other types of receptors include enzyme proteins, transport proteins and structural proteins. For example, statins inhibit an enzyme catalysing the synthesis of cholesterol and loop diuretics inhibit an enzyme that facilitates the re-uptake of salt in primary urine. 

The neurochemical effects of the tricyclic antidepressants are blockade of the re-uptake of norepinephrine and for some drugs also serotonin by nerve terminals in the CNS and peripherally. This reuptake inhibition results in higher concentrations of the neurotransmitters at their receptors sites. There is little or no effect on DA neurotransmission. The tricyclic antidepressants have varying affinities for U2... 

Mechanism of Action A mood stabilizer that affects the storage, release, and reuptake of neurotransmitters. Antimanic effect may result from increased norepinephrine re-uptake and serotonin receptor sensitivity. Therapeutic Effect Produces antimanicand antidepressant effects. 

Fig. 3. Schematic representation of the neurochemical events associated with neurotransmitter synthesis, release, re-uptake and metabolism in axons of diencephalic DA neurons terminating in classical synapses (Top Panel), and TIDA neurosecretory neurons terminating in close proximity to the hypophysial portal system (Botton Panel). Arrows with dashed lines represent end-product inhibition of TH activiy by DA (Top + Bottom Panels) or DA presynaptic autoreceptor-mediated inhibition of DA synthesis and release (Top Panel). Abbreviations COMT, Catechol-O-methyltransferase D, dopamine DDC, DOPA decarboxylase DOPA, 3,4-dihydrophenylalanine DOPAC, 3,4-dihydroxyphenylacetic acid HVA, homovanillic acid MAO, monoamine oxidase 3MT, 3-methoxytyramine TH, tyrosine hydroxylase.

Re-uptake of neurotransmitters into neurons and synaptic vesicles... 

Duloxetine has recently been marketed as an antidepressant in Europe. It inhibits the re-uptake of serotonin and noradrenaline, with minimal effects on other neurotransmitter mechanisms. It is therefore classified as a serotonin and noradrenaline re-uptake inhibitor (SNRI) and is grouped with venlafaxine. The adverse effect profile of duloxetine appears to be similar to that of the SSRIs and venlafaxine. In placebo-controlled trials the most common adverse effects were nausea (37%), dry mouth (32%), dizziness (22%), somnolence (20%), insomnia (20%), and diarrhea (14%). Sexual dysfunction has also been reported. Current data suggest that, unlike venlafaxine, duloxetine does not increase the blood pressure, but further post-marketing surveillance studies will be needed to confirm this (1). 

Nerve cells practice a sort of recycling, in which neurotransmitters already released are reabsorbed into the presynaptic cell this process is referred to as re-uptake (see figure 3-D). Physiologic malfunctions and certain medications can either overstimulate or retard re-uptake. 

Decades of research have yet to provide a clear understanding of the exact mechanism of action of lithium. Multiple sites of action within the CNS have been identified, none of which fully explain lithium s action on both mania and depression. Since neurotransmitter production, release, and re-uptake rely on various ions (sodium, calcium, potassium, and magnesium), lithium s ionic properties may affect neurotransmitter-mediated depression and mania. Another potential mechanism of... 

Numerous substances target mechanisms involved in neurotransmitter (NT) synthesis, transport, synaptic release, re-uptake, the interaction between NT and postsynaptic receptor, or the removal of NT from the synaptic gap. Neurotoxicity occurs when the agent reduces or increases NT release, alters NT concentration or resident time, or acts as an agonist or antagonist at a postsynaptic receptor. 

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