5-HT reuptake inhibitor

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Sharp, T, Umbers, V and Gartside, SE (1997) Effect of a selective 5-HT reuptake inhibitor in combination with 5-HTlA and 5-HTlB receptor antagonists on extracellular 5-HT in rat frontal cortex in vivo. Br. J. Pharmacol. 121 941-946. 

Figure 20.6 Schematic representation of the effects of 5-HT reuptake inhibitors on serotonergic neurons, (a) 5-HT is released at the somatodendritic level and by proximal segments of serotonergic axons within the Raphe nuclei and taken up by the 5-HT transporter. In these conditions there is little tonic activation of somatodendritic 5-HTia autoreceptors. At nerve terminals 5-HTib receptors control the 5-HT synthesis and release in a local manner, (b) The blockade of the 5-HT transporter at the level of the Raphe nuclei elevates the concentration of extraneuronal 5-HT to an extent that activates somatodendritic autoreceptors (5-HTia). This leads to neuronal hyperpolarisation, reduction of the discharge rate and reduction of 5-HT release by forebrain terminals, (c) The exposure to an enhanced extracellular 5-HT concentration produced by continuous treatment with SSRIs desensitises Raphe 5-HTia autoreceptors. The reduced 5-HTia function enables serotonergic neurons to recover cell firing and terminal release. Under these conditions, the SSRI-induced blockade of the 5-HT transporter in forebrain nerve terminals results in extracellular 5-HT increases larger than those observed after a single treatment with SSRIs. (Figure and legend taken from Hervas et al. 1999 with permission)...

The combination of antidepressants is a common clinical practice. The most usual pharmacological profile is serotoninergic-noradrenergic (96%) and the most popular combinations are selective 5-HT reuptake inhibitor (SSRI) + mir-tazapine, SSRI + reboxetine, and SSRI + TCAs (De la Gandara et al. 2005). 

MAOI non-selective monoamine oxidase (A/B) inhibitors RIMA reversible inhibitor of monamine oxidase type A SSRI selective serotonin (5-HT) reuptake inhibitors SNRI serotonin/noradrenaline reuptake inhibitor SNARI selective noradrenaline (NA) reuptake inhibitor NA = 5-HT — DA potency of the drug is very similar in raising the level of both (or all three) monamines NA > 5-HT more selective for NA 5-HT>NA more selective for 5-HT NA increases the release of NA. 

Figure 7.3. Structural formulae of the noradrenaline (norepinephrine)/dopamine reuptake inhibitor amfebutamone (bupropion) and some nonselective noradrenaline and serotonin (5-hydroxytr3 tamine 5-HT) reuptake inhibitors (venlafaxine, and...

Serotonin has an effect on the hypothalamic control of pituitary function (see chapter 5), in central thermoregulation (attributed to the 5-HTj receptor), and in pain perception (probably the S-HTj receptor), where increased serotonergic function potentiates opiate analgesia. The administration of 5-HT reuptake inhibitors like fluoxetine increases the anorectic effect of 5-hydroxytryptamine and induces a selective suppression of nonprotein caloric intake in rats. The involvement of serotonin in endogenous psychiatric depression has been mentioned. 

Dufour H, Bouchacourt M, Thermoz P, et al. Citalopram —a highly selective 5-HT reuptake inhibitor—in the treatment of depressed patients. Int Clin Psychopharmacol 1987 2 225-237. 

Rollema H, Clarke T, Sprouse JS, Schulz DW. Combined administration of a 5-hydroxytryptamine (5-HT1D) antagonist and a 5-HT reuptake inhibitor syneigis-tically increases 5-HT release in guinea pig hypothalamus in vivo. J Neurochem 1996 67 2204-2207. 

Sorbera, L.A. Leeson, P.A. Castaner, J. Castaner, R.M. Escitalopram Oxalate. Antidepressamt 5-HT Reuptake Inhibitor. Drugs Future 2001, 26, 133-140. 

Other selective DAT inhibitors have been proposed for the treatment of the withdrawal phase of CNS drug abuse. On the other hand, the structure of cocaine (30) has been modified in such a manner [e.g., (31)and (32)] that the resulting agents behave primarily as selective 5-HT reuptake inhibitors (113,114). 

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