Uptake inhibition

Generic name Trade name Manufacturer Year of introduction Uptake inhibition, IC q, N orepinephrine 10-" M Serotonin... 

Non-n uronaJ uptake inhibiters ( Uptake 1 ) Corticosteroids Normetanephrine (NMN)... 

FIGURE 9. Effect of DA-uptake inhibition on the neostriatal TPH deficit induced by a high single dose of MDMA... 

Nicotine increased DA levels both in vivo11,193 and in vitro. 94 196 Nicotine197 and its metabolites198 were found to both release and inhibit the reuptake of DA in rat brain slices, with uptake inhibition occurring at a lower concentration than that required for DA release. In addition, the (-) isomer was more potent than the (+) isomer.197 However, the effects of nicotine upon DA release and uptake were only apparent when brain slices were utilized because nicotine was unable to affect DA when a synaptosomal preparation was utilized.197 These results indicate that nicotine exerts its effects upon the DAT indirectly, most likely via nicotine acetylcholine receptors. This finding was supported by the results of Yamashita et al.199 in which the effect of nicotine on DA uptake was examined in PC 12 and COS cells transfected with rat DAT cDNA. Nicotine inhibited DA uptake in PC 12 cells that possess a nicotine acetylcholine receptor. This effect was blocked by the nicotinic antagonists hexamethonium and mecamylamine. Additionally, nicotine did not influence DA uptake in COS cells, which lack nicotinic acetylcholine receptors. 

Yim, H.J. and Gonzales, R.A., Ethanol-induced increase in dopamine extracellular concentrations in rat nucleus accumbens are accounted for by increased release and not uptake inhibition, Alcohol, 22, 107, 2000. 

Mateo Y., Budygin E.A., Morgan D., Roberts D.C., Jones S.R. Fast onset of dopamine uptake inhibition by intravenous cocaine. Eur. J. Neurosci. 20 2838, 2004. 

Daily additions of 10 pg/L for 8 days reduced algal growth rate and carbon uptake inhibition persisted for 2 18 h and did not affect community composition 2... 

Doherty, J.D., K. Nishimura, N. Kurihara, and T. Fujita. 1986. Quantitative structure-activity studies of substituted benzyl chrysanthemates. 9. Calcium uptake inhibition in crayfish nerve cord and lobster axon homogenates in vitro by synthetic pyrethroids. Pestic. Biochem. Physiol. 25 295-305. 

Volterra, A., Trotti, D., Tromba, C., Floridi, S., and Racagni, G. (1994) Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes. J. Neurosci. 14,2924-2932. 

Several compounds affecting various 5-HT functional parameters (uptake inhibition (fluoxetine), metabolism (tranylcypromine) or synthesis (5-OH tryptophan, 5-HTP)) had no effect on subemetic doses of cisplatin [110]. In fact, tranylcypromine and 5-HTP antagonized emesis of cisplatin. Thus these results would favour an inhibitory role of 5-HT instead of emetogenic. It is conceivable that an excess of 5-HT may desensitize 5-HT3 receptors that may result in a reduced sensitivity to emetogenic stimuli. 

O, Uptake Inhibition Acetic acid Citric acid... 

Valerian Sesquiterpenes GABA release and reversal of uptake Inhibition of GABA breakdown... 

Seitz U, Schule A, Gleitz J. (1997). [3H]-monoamine uptake inhibition properties of kava pyrones. Planta Med. 63(6) 548-49. 

In our studies, we used flow cytometry to gain quantitative information in terms of uptake kinetics and extent of uptake inhibition after treatment with several inhibitors. 

There is no place anymore for the amphetamines in our therapeutic armamentarium. The only indications for the other stimulants, modaflnil and methylphenidate, are respectively narcolepsy and the attention deflcit disorders (ADHD) and hyperactivity syndromes in children. Their mechanisms of action include enhanced release of dopamine and norepinephrine, re-uptake inhibition of dopamine and norepinephrine and to some extend monoamine oxidase inhibition. 

The delay in onset of anxiolytic and antipanic effects of serotonin reuptake inhibitors and related compounds is still an issue of much speculation. It appears paradoxical that serotonin reuptake inhibitors block serotonin uptake immediately, whereas it takes weeks before their therapeutic effects become apparent. Recently, the idea was advanced that the tentative enhanced serotonin neurotransmission caused by short-term administration of serotonin reuptake inhibitors is offset by negative feedback in the raphe nuclei (Artigas 1993 Blier and de Montigny 1994). The increased level of serotonin in the somatodendritic area, resulting from serotonin uptake inhibition, reduces serotonin neuronal firing through activation of the 5-HTj, autoreceptors. Alterations in the feedback regulation upon repeated administration may... 

Nicholson AN, Pascoe PA 5-Hydroxytryptamine and noradrenaline uptake inhibition studies on sleep in man. Neuropharmacology 25 1079-1083, 1986 Nicholson AN, Pascoe PA Studies on the modulation of the sleep-wakefulness continuum in man by fluoxetine, a 5-HT uptake inhibitor. Neuropharmacology 27 597-602, 1988... 

Randrup A, Braestrup C Uptake inhibition of biogenic amines by newer antidepressant drugs relevance to the dopamine hypothesis of depression. Psychopharmacology 53 309-314, 1977... 

The effect of antidepressants on this system was believed to subserve their efficacy. Whereas various agents may enhance, inhibit, or modulate NE activity, the heterocyclics (FICAs) and MAOIs increase the activity of this transmitter by two different mechanisms. FICAs generally block the uptake pump that recovers NE from the synaptic cleft shortly after its release from the presynaptic neuron. Thus, uptake inhibition is occurring during both the acute and the chronic phases of therapy. Interestingly, antidepressant response usually occurs during the chronic phase. MAOIs, by contrast, interfere with enzymatic deamination. In either case, the outcome is increased NE concentrations. 

Among FICAs, clomipramine is one of the more selective reuptake inhibitors of serotonin. Because plasma levels of its demethylated metabolite (which primarily works through the NE system) can in some patients exceed those of the parent compound, its therapeutic action cannot be solely attributed to serotonin uptake inhibition. 

Amoxapine has been found to be effective in several double-blind studies (Table 7-4 and Table 7-6). It is a dibenzoxazepine derivative that has both NE and serotonin uptake inhibiting properties. Amoxapine is converted into 8-hydroxyamoxapine, which has considerable dopamine receptor binding properties (i.e., radioreceptor bioassays on patients given amoxapine have found activity levels similar to those of patients on typical antipsychotics), a chemical structure similar to loxapine, and effects similar to antipsychotics (1Q3). As a result of this metabolite, amoxapine theoretically may have unique beneficial effects in psychotically depressed patients. However, this possibility has never been adequately tested. Nevertheless, this metabolite is likely responsible for some of the antidopamine effects reported in patients taking amoxapine, including acute and chronic extrapyramidal side effects and elevated prolactin levels ( 104). Like TCAs, amoxapine can be lethal in... 

The overall efficacy among the SSRIs for major depressive disorder is remarkably similar, consistent with the hypothesis that they have the same mechanism of action (i.e., serotonin uptake inhibition). 

All of the SSRIs also show a flat dose-response curve, meaning that there is usually no advantage to increasing the dose above that which is the usually effective minimum dose. Of interest, the four SSRIs marketed as antidepressants in the United States at their usual effective therapeutic dose (i.e., 40 mg per day for citalopram, 20 mg per day for paroxetine and fluoxetine, and 50 mg per day for sertraline) produce comparable effects on either plasma serotonin levels or the serotonin uptake pump in platelets (25). These results are consistent with the conclusion that serotonin uptake inhibition is the mechanism responsible for the antidepressant efficacy of these agents. 

Its adverse effect profile suggests that hypericum may produce physiologically relevant serotonin uptake inhibition comparable with that seen with SSRIs. Photosensitivity has also been rarely reported ( 237). 

Bupropion, the only marketed aminoketone antidepressant, also has a side-effect profile different from the other classes of antidepressants. It is essentially devoid of anticholinergic, antihistaminic, and orthostatic hypotensive effects. Its principal adverse effects are consistent with its indirect agonism of dopamine and NE via uptake inhibition and include the following ... 

This antidepressant can interact with other drugs via its two mechanisms of action serotonin and NE uptake inhibition. The former action means that the same pharmacodynamic interactions will occur with venlafaxine as with SSRIs, including the serotonin syndrome. At higher doses, venlafaxine is also prone to the same pharmacodynamic interactions as NSRIs such as secondary amine TCAs like desipramine and with newer NSRIs such reboxetine. Thus, the combination of high-dose venlafaxine plus an MAOl could produce a hypertensive crisis as well as the serotonin syndrome. 

Because nefazodone does inhibit the 5-HT uptake pump, it has the same class warning against combined use with an MAOl. Nevertheless, there are several reasons to suspect that there may be less risk of this interaction with nefazodone than other serotonin uptake pump inhibitors. First, trazodone, an analogue of nefazodone, is one of the few antidepressants that can be used in combination with an MOAI with minimal risk of an adverse interaction. Second, the most potent action of nefazodone is 5-HT2a receptor blockade, rather than 5-HT uptake inhibition. Nonetheless, we recommend the conservative approach of avoiding this combination, particularly when using high doses (i.e., > 450 mg per day), at which appreciable serotonin uptake inhibition is produced by nefazodone. 

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