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Antidepressant Action of Tianeptine Is Connected with Acceleration of Serotonin Turnover in the Synapse: a Hypothesis

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Antidepressant Action of Tianeptine Is Connected with Acceleration of Serotonin Turnover in the Synapse: a Hypothesis ÖSSZEFOGLALÓ KÖZLEMÉNY ANTIDEPRESSANT ACTION OF TIANEPTINE IS CONNECTED WITH ACCELERATION OF SEROTONIN TURNOVER IN THE SYNAPSE: A HYPOTHESIS MARAT G. UZBEKOV Department of Brain Pathology, Research Institute of Psychiatry, Moscow ÖSSZEFOGLALÓ KÖZLEMÉNY Neuropsychopharmacologia Hungarica 2009, XI/2, 83-87 ÚJ HIPOTÉZIS A TIANEPTIN SUMMARY ANTIDEPRESSZÁNS HATÁSÁRÓL, A Based on the results of our investigation of pa- SZEROTONIN SZINAPSZISBAN TÖRTÉNÕ tients with anxious depression under the treat- FELSZABADULÁS GYORSÍTÁSÁVAL ment with serotonergic antidepressants with dif- A szerotonerg antidepresszánsokkal kezelt szo- ferent mechanism of action on serotonin reup- rongásos depressziós betegek vizsgálatának take we, the first time in the literature, propose eredményeibõl kiindulva, az irodalomban elsõ- the hypothesis about neurochemical mechanism ként felvetjük, hogy a tianeptin hatás a szero- of tianeptine action. According to this hypothesis tonin visszavétel serkentésén alapul. Eszerint a tianeptine not only activates serotonin reuptake tianeptin nemcsak a szerotonin visszavételt akti- into the synaptic ending but also activates its re- válja a szinapszisban, hanem a felszabadulást is, lease from the ending into the synaptic cleft thus ennélfogva gyorsítja a szerotonin turnovert. Az accelerating serotonin turnover rate in the syn- általunk felvetett fõként a szerotonerg neuro- apse. Proposed mechanism mainly refers the transzmisszió normalizálására irányuló hatás first, acute phase of its action directed to the nor- elsõ, akut fázisára vonatkozik. malization of serotonergic neurotransmission. KULCSSZAVAK: tianptin, neurokémiai hatás- KEYWORDS: tianeptine, neurochemical mecha- mechanizmus, szorongásos depresszió nisms of action, anxious depression Tianeptine is a serotonin (5-hydroxytryptamine, pharmacology” (1999, p. 160) wrote: “Tianeptine 5-HT) reuptake enhancer. It exhibits a mechanism is an example of an agent that allosterically modi- of action totally opposite to selective serotonin fies serotonin reuptake in a manner that is almost reuptake inhibitors (SSRI), such as sertraline, but the opposite to that of the SSRIs. Although this paradoxically both mechanisms of action are asso- might theoretically seem to have the potential to ciated with a therapeutic efficacy in depressive cause depression rather than treat it, tianeptine in disorders, in particular in anxious depressions. In fact appears to be antidepressant.” spite of a numerous experimental and clinical tri- All these prompt us to carry out the compara- als the neurochemical mechanism of tianeptine tive clinical-biochemical investigation of patients action is not enough clear (Ansseau, 1993; Stahl, with anxious depression under the treatment of 1999; Kasper, 2006). Ansseau (1993) had ana- tianeptine and sertraline and on the basis of results lyzed the different effects of tianeptine and dis- of the study develop possible mechanism of tia- cussed the approaches, mainly clinical, which could neptine action. Some clinical and biochemical as- help to understand “the paradoxical activity of pects of this work are described elsewhere (Ma- tianeptine”. But he did not express his views on ximova et al. 2000; Uzbekov et al. 2006). the ways to solve the problem of the neuroche- In this paper we want to stress the attention on mical and therapeutic mechanisms of action of the working hypothesis of the neurochemical mech- this antidepressant. Stahl in his “Essential Psycho- anisms of tianeptine action. Some preliminary as- Neuropsychopharmacologia Hungarica 2009, XI/2, 83-87 83 ÖSSZEFOGLALÓ KÖZLEMÉNY MARAT G. UZBEKOV pects of this hypothesis were published earlier It was earlier shown that in depressed patients (Uzbekov et al., 2002). the capacity (or activity) of the serotonin reuptake Shortly, in 43 patients with anxious depression mechanisms were decreased (Bellivier et al. 2002; we have revealed significant almost twofold in- Slanley et al. 1982; Stahl, 1985). On the other crease of platelet monoamine oxidase (MAO) ac- hand in our study we have established that in tivity as compared with healthy volunteers. These anxious-depressed patients MAO activity was in- disturbances in monoaminergic systems were ac- creased almost twofold (Uzbekov et al. 2006). The companied by the significant twofold decrease of letter specifies that in this case serotonin is taken serum semicarbazide-sensitive amine oxidase up more actively by the glial cells where MAO is (SSAO) activity, significant increase of the level localized. We can assume that the ratio – serotonin of plasma middle-mass endotoxic molecules affinity for receptors on the presynaptic ending (MMEM) and significant decrease of albumin and the same on the glial cells in patients with functional properties (Uzbekov et al. 2006). There anxious depression changes. The left part of the were found significant changes in blood serum ratio is decreasing and the right part – is increas- concentrations of cortisol, estradiole and testos- ing, i.e. the ratio becomes, for example, 2 to 2 terone (Uzbekov et al. 2003). All these disturbed instead of 3 to 1 (as in norm). On the functional parameters indicate on the pronounced endoge- level it means that in anxious depression serotonin nous intoxication (Uzbekov and Misionzhnik, 2000; is taken up by glial cells in larger quantity where it Uzbekov et al. 2006). chemically inactivated by MAO. Owing to this Anxious depression is characterized by the de- serotonin concentration in the synaptic cleft is crease in serotonergic activity (Kasper, 2001) and reduced and as a result less quantity of serotonin is possibly by the decrease in serotonin concent- returned in the presynaptic ending. All this events ration in the synapses. Twofold increased platelet lead to the disturbances in serotonergic activity MAO activity in anxious patients indirectly sup- and in particular serotonergic neurotransmission. ported this view. It is thought that the platelet The therapeutic effects under tianeptine treat- MAO activity in some instances reflects the simi- ment (37,5 mg/day) is manifested after two weeks lar enzyme activity in the brain (Stahl, 1985). of therapy (Maximova et al. 2000; Uzbekov 2006) According to the literature (Avakjan, 1976; that is supported by literature data (Quitkin et al. Hughes, 1972) it is supposed that at normal 1984; Kato and Weitsch, 1988; Ansseau, 1993). condition about 75% of serotonin released in the At that time we have found changes in activity or synaptic cleft undergoes functional inactivation levels of all investigated biochemical parameters. by the reuptake in the presynaptic ending (neuron) These changes were not very pronounced although by the reuptake mechanisms (reuptake receptor or they were significant (Uzbekov, 2006). serotonin transporter). Serotonin is accumulated Elucidation of the antidepressive mechanism of in the synaptic vesicles and thus it becomes un- tianeptine action is one of the most difficult prob- available to the action of MAO localized in mito- lems. The analysis of available data has shown the chondria of presynaptic ending. The remaining lack of any information that could explain neuro- serotonin (approximately 25%) undergoes chemi- chemical mechanism of action of this antidepres- cal (irreversible) inactivation by MAO localized sant. It is well known that tianeptine activates in mitochondria of glial cells (astrocytes and/or serotonin reuptake in the presynaptic ending. microglial cells) that close the synaptic cleft and Thus promoting for the more “energetic with- where the neurotransmitter is taken up (Hughes, drawal” of serotonin from the synaptic cleft. In 1972; Avakjan, 1976; Whitaker et al. 1983). As spite of all existing theories tianeptine on the clini- serotonin uptake in neuronal and glial cells pro- cal level reveals antidepressive, anxiolytic effects. ceeds through the receptors (or transporters) it is Ansseau writes about this situation in such words: possible to suppose that serotonin affinity for the “The paradoxical finding that both tianeptine and receptors on presynaptic ending (neuron) and on selective 5-HT reuptake inhibitors exhibit antide- glial cells correlates as 3 to 1 (75% and 25%, see pressant activity despite clearly antagonistic me- above). It is necessary to note that receptors for chanisms is rather puzzling” (1993). serotonin on astrocytes differ from those on the We think that the problem of tianeptine action neurons (Hertz and Tamir, 1981). is necessary to consider from the point of view of structural-functional unity of the synapse. Based 84 Neuropsychopharmacologia Hungarica 2009, XI/2, 83-87 ANTIDEPRESSANT ACTION OF TIANEPTINE IS CONNECTED WITH… ÖSSZEFOGLALÓ KÖZLEMÉNY on this thesis the synapse has to be considered as a conclude that under tianeptine action serotonin complex, multiple biological system but not only turnover rate in the synapse is increased that pro- as a structure with “reuptake receptor”. motes the increase in the unit of time serotonin According to our working hypothesis tianep- concentration on postsynaptic receptors. Decreas- tine, enhancing serotonin reuptake, decreases se- ing MAO activity supports serotonin concentra- rotonin level in the synaptic cleft. Simultaneously tion in the synaptic cleft on the minimally allow- with this process in responders we have estab- able level to display its neurotransmitter func- lished that a very high MAO activity starts to tions. decrease. It is possible to suppose that tianeptine Proceeding from the offered neurochemical decreasing affinity of
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