Review article Open Access Show Are Antidepressants Mood Agents Or Anxiolytic Drugs Neurobiology of anxiety and mood disorders, University of Nantes, France *Corresponding author: Michel Bourin, Neurobiology of anxiety and mood disorders, University of Nantes, France, Email: @Received: May 23, 2018; Accepted: June 29, 2018; Published: July 05, 2018 Citation: Bourin M (2018) Are Antidepressants Mood Agents Or Anxiolytic Drugs? SOJ Pharm Pharm Sci, 5(3) 1-6. DOI: 10.15226/2374-6866/5/3/00185 Abstract Many advances have been made in the treatment of depression with the recent discovery of selective serotonin reuptake inhibitors (SSRIs) and mixed serotonin and norepinephrine reuptake
inhibitors (SNRIs). Behavioral, electrophysiology, and microdialysis studies have shown that serotonin receptors, mainly the 5-HT1A, 5-HT1B, and 5-HT2C subtypes, play a key role in modulating antidepressant activity. The indirect activation of serotonergic receptors by antidepressants could lead, via an increase in 5-HT concentrations in the synapse of certain brain regions, to the activation of G proteins which would cascade the transcription of neurotrophic factor such as “the brainderived
neurotrophic factor “(BDNF). Depression could be considered as an anomaly of transduction mechanisms, this hypothesis needs to be deepened by molecular biology studies. Introduction Although several hypotheses
have been put forward, the aetiology of depression is still poorly defined. The first major theory of depression, i.e., the monoaminergic theory, proposes that this disorder is due in particular to a deficiency of serotonin (5-HT) and norepinephrine (NA) [1, 2, 3, and 4]. Moreover, some molecules that deplete these neurotransmitters, such as reserpine, can induce a depressive state in a small percentage of individuals. However, this simplistic theory cannot explain the pathophysiology of
depression by itself since the efficacy of antidepressants is observed clinically after a few weeks of treatment. A second hypothesis based on neurotransmitter receptors has been issued. According to this hypothesis, the depression is due to an abnormal functioning of the monoamine receptors. This receptor disruption could itself be caused by depletion of monoaminergic neurotransmitters. Advances in molecular and cellular biology suggest the role of neurotrophic factors, such as the
“brain-derived neurotrophic factor” (BDNF) suggesting a neurodegenerative hypothesis to the pathophysiology of depression [4, 5]. Targets for action of antidepressants Serotoninergic receptors Role of 5-HT1A receptors on antidepressant activity Various behavioral, electrophysiological and microdialysis studies have highlighted the role of 5-HT1A receptors in the pharmacological properties of antidepressants. Thus, the effects of the administration of a single dose of antidepressant on an animal model of desperation (forced swimming test) carried out in mice, suggests that the action of imipramine is via the 5-HT1A postsynaptic receptors [6]. Blier and de Montigny [7] in
electrophysiology studies have shown that chronic treatment with a selective serotonin reuptake inhibitor (SSRI) induces functional desensitization of 5-HT1A autoreceptors in nuclei of the dorsal raphe. Moreover, although no down-regulation of 5-HT1A autoreceptors in dorsal raphe nuclei has been observed in binding studies [8], microdialysis studies have been conducted [9, 10]. have shown that chronic treatment with SSRIs causes hypofunction of 5-HT1A autoreceptors. In contrast, postsynaptic
5-HT1A receptors do not react in the same way as 5-HT1A autoreceptors to chronic treatment with SSRIs. Indeed, postsynaptic 5-HT1A receptors, located in the hippocampus, do not undergo desensitization or “down regulation”. Role of 5-HT1B receptors on antidepressant activity Pre-clinical studies have shown that serotonin reuptake inhibitors appear to act indirectly on 5-HT1B receptors [8]. This notion is also found in the fact that in the elderly mice serotonin reuptake inhibitors lose their activity [20, 21], but we know that in these animals age causes a decrease of
this subtype of receivers [22]. The 5-HT1B receptor is present both at the presynaptic level [autoreceptors] where it locally controls the release of serotonin, and at the postsynaptic level where it controls the release of other neurotransmitters [dopamine, glutamate, acetylcholine, GABA]. However, behavioral studies [forced swimming test] and microdialysis carried out in mice have shown that according to the brain structure, the IRSS [paroxetine and fluoxetine] activate either the 5-HT1B
autoreceptor [at the level of serotoninergic neuronal endings located in the hippocampus but not in the frontal cortex], or the postsynaptic 5-HT1B receptor [23]. Role of other serotonin receptor subtypes on the activity of antidepressants Many antidepressants of different chemical classes have only moderate affinity for 5-HT2-like receptors, so there is no obvious correlation between affinity for these receptors and antidepressant activity. However, the high density of 5-HT2C receptors in the cortical and limbic regions suggests their role in anxiety and / or depressive disorders. Several binding or recognition studies using specific antibodies have focused on the
precise location of 5-HT2C receptors in the brain [26]. Similarly, in untreated, depressed patients, the density of 5-HT2 receptors at the platelet membranes is increased. If we look at the changes that occur in the density of 5-HT2 receptors in the choroid plexus in rats after repeated administration of antidepressants [fluoxetine and citalopram], it is clear that the number of receptors increases [27]. Other results also reinforce the hypothesis that dysregulation of 5-HT2C receptor function
plays an important role in the pathogenesis of anxiety and depressive disorders [28]. Indeed, the mechanisms mediated by the 5-HT2C receptors are hypersensitized in the depression and it is the normalization of this function which could contribute to the antidepressant effect. Is dopamine the common final route? It has been postulated that over 20 years ago dopamine could play a role in depression. In particular, the depression is thought to be due to a decrease in brain concentration of dopamine [30]. Recent studies show that selective serotonin reuptake inhibitors will act on the central dopaminergic system via the D1 and D3 dopamine receptor subtypes. Dopaminergic agonists have been shown to potentiate the antidepressant activity of selective serotonin reuptake inhibitors in the forced swim test [31]. Therefore, three, not two, protagonists [serotonin, norepinephrine, and dopamine] could play a major role in the occurrence of a depressive syndrome. It would therefore be interesting to study the possible mobilization of dopamine during a classic antidepressant treatment, that is to say acting mainly on the two neurotransmitters, serotonin and norepinephrine. Moreover, Gobert et al. [32] showed in microdialysis studies that the concentrations of 5-HT, NA and DA in the same dialysate increased after treatment with fluoxetine. Antidepressant action on second messengers and genes Antidepressants do not only act by inhibiting monoamine reuptake, but also affect neurotransmitter receptors. This stimulation of the receptors causes the activation of transcription factors present inside the nucleus of the cell, via the G proteins. This activation of the transcription factors decreases the synthesis of the receptors: it is the “down regulation”. These successive activations stimulate the release of a trophic factor of neuronal origin: BDNF. Does this stimulation account for the increased size of the hippocampus mentioned above, which is a consequence of the action of antidepressants? This is related to the important notion that antidepressants would not only act on neuromodulators but also on neuronal growth factors [1, 5]. Nibuya et al [35] showed in the rat that chronic administration of antidepressants [desipramine, imipramine, fluoxetine, sertraline] increased the BDNF concentration and the corresponding trkB receptor mRNA expression. The expression “cAMP response element binding protein” [CREB] is also increased in the hippocampus. These results would indicate that the administration of an antidepressant, by increasing CREB synthesis, would regulate certain genes such as that encoding BDNF and its trkB receptor. Recently, other pre-clinical studies have confirmed this hypothesis. Thus, Martin et al, [36] showed that the amount of BDNF mRNA was increased after chronic treatment with an antidepressant. Vollmayr et al. [37] in an animal model of depression, the rat-acquired resignation test, show that chronic treatment with antidepressants or with seismic therapy prevents the reduction of stress-induced BDNF expression. BDNF would exert its neuronal protective action by autocrine activity on hippocampal neurons and paracrine activity on the neurons that innervate this region. The autocrine activity is very important in depressions associated with severe chronic stress, in which there is a decrease in the concentration of BDNF, leading to atrophy of the hippocampus and, in the worst case, to a reduction in the number of hippocampal neurons [38]. Paracrine activity of BDNF may increase the functions of neurons [serotonergic and noradrenergic] innervating the hippocampus. Indeed, Sklair-Tavron and Nestler [39] have shown that BDNF increases the survival and growth of hippocampal neurons. Animal studies have shown that imipramine antidepressants and their derivatives can behave as compounds that interact with G proteins [40]. Thus, it is plausible to hypothesize that depression could be considered a disorder of the super family of G-proteins coupled to a receptor. This disorder, determined by a genetic defect in some cases, could be expressed at the level of the receptor or alternatively in the G proteins thus leading to a faulty coupling between the receptor and the G protein and thus leading to abnormal transduction mechanisms. This hypothesis is to be studied mainly because the 5-HT1A receptors do not react in the same way to a chronic treatment of antidepressant according to their localization. Indeed, presynaptic 5-HT1A receptors are desensitized after chronic antidepressant treatment, whereas postsynaptic 5-HT1A receptors are not desensitized. The receiver, whatever its location, is nevertheless coded by one and the same gene. Therefore, the differences in antidepressant response would not be due to the receptor protein itself. It is possible that the presynaptic 5-HT1A receptor is coupled to a different G protein [Gi, GB] from that to which the postsynaptic 5-HT1A receptor is coupled. This suggests that the nature of G-protein coupled to the 5-HT1A receptor might be different from one brain region [dorsal raphe nucleus] to another [frontal cortex, ventral hippocampus]. The use of molecular biology and cell cultures, for example, should shed light on this issue. The pathophysiology of depression should be better studied anyway. What molecular perturbations [receptors, protein G, BDNF and other transcription factors] does it cause? A good experimental model remains to be defined and identified by Knock-Out or transgenic mice. Therapeutic problems related to antidepressant treatment Are there more specific targets for antidepressants? At the end of the 1970s, the decrease in the number or sensitivity of beta-adrenergic receptors in the brain appeared to be implicated in antidepressant activity [41]. And since the clinical effect of antidepressants was felt after 15 days, it was thought that there was a rational explanation for antidepressant activity. This decrease also occurs in rats almost three weeks after the start of treatment. Unfortunately, at the moment there are antidepressants that do not lead to “down regulation” of beta receptors and that are clinically active in depression. This is particularly the case of the new antidepressants, that is to say the inhibitors of serotonin retreading. Although “down-regulation” of beta receptors is observed with fluvoxamine, fluoxetine and sertraline, it has not been observed for citalopram and paroxetine. The dose / effect relationship of antidepressants The existence of effect / dose relationships has long been lacking in psychiatry, depriving patients of significant potential benefits. Phase II drug development involves establishing this relationship but it was relatively erratic. With tricyclics in particular, a significant increase in the dose leads to inefficiency following a U-shaped effect / dose curve. Today, the proof of an effect / dose relationship has been established for two molecules: paroxetine and venlafaxine. . Like paroxetine [42], venlafaxine is expected to have a low serotonin reuptake inhibitory dose and a norepinephrine reuptake inhibitor [43]. It is thus considered that starting at 150 mg and above, venlafaxine mainly inhibits the reuptake of norepinephrine [6]. Thus, for paroxetine, increasing
Figure 1: Mutual interactions between dorsal Raphe serotoninergic neurons and Locus Coeruleus noradrenergic neurons and their respective projections across the brain. the daily dosage from 20 to 40 mg / day significantly increases the proportion of responders. Although this dose increase is limited by the occurrence of side effects, the dose / effect relationship allows the patient to be offered a dose increase rather than an interruption of treatment and the change by another molecule. The establishment of a dose-response relationship for some antidepressants is a significant contribution to the treatment of depression. Inter-relationships between brain structures / neurotransmitters Knowledge of interrelationships between neurotransmission systems is very important. Activation or inhibition of one system is not without effect on others. For example, the noradrenergic and serotoninergic system interacts with each other. Indeed, serotoninergic cell bodies [present in raphe nuclei] and noradrenergic cell bodies [present in the region of the locus coeruleus] emit mutually projections from one to the other [Figure 1]. Thus, we find serotoninergic heteroreceptors [5- HT2A] on the endings of noradrenergic neurons as well as noradrenergic heteroreceptors [alpha 1] on the cell bodies of serotoninergic neurons. The alpha 2 noradrenergic receptor can itself be an autoreceptor or a heteroreceptor. Thus, activation of the alpha 2 noradrenergic autoreceptors of the locus coeruleus contributes to the reduction of the concentration of noradrenaline and serotonin in the frontal cortex via a decrease in excitatory noradrenergic fiber activity, mediated by postsynaptic alpha 1 noradrenergic receptors. Localized in the cell bodies of the neurons of the raphe nuclei. In addition, the activation of alpha 2 adrenergic autoreceptors present at the end of adrenergic neurons in the raphe nuclei may also inhibit the activity of serotoninergic cell bodies [32]. Evolution of the antidepressant concept The concept of antidepressant is evolving gradually since these molecules are used successfully to treat other mental pathologies than depression. Clomipramine was the first to prove an activity in the treatment of obsessive compulsive disorder [OCD] while other imipramines
and derivatives are not effective. In fact, its desmethyl-clomipramine metabolite is a potent inhibitor of serotonin reuptake but also norepinephrine. The combined results of clomipramine and desmethylclomipramine on the inhibition of serotonin reuptake are much greater than those of other tricyclics. Other selective serotonin reuptake inhibitors, such as fluoxetine, fluvoxamine, sertraline and paroxetine, have also been shown to be effective in the treatment of OCD. Their effectiveness in
treating this condition is clearly not related to their antidepressant properties as these drugs reduce obsessivecompulsive symptoms in patients who are not depressed. Conclusion It is important to recall a now admitted fact that depression must be conceptualized as a recurrent illness that requires treatment at the time of the episode and in the long run to avoid relapse. Indeed, all
antidepressants are effective in the acute phase of the disease and the prevention of relapses requires continuation of long-term treatment and the same dosage. Finally, the neurobiological bases of relapses and recurrences are, to date, unknown. Relapses and recurrences likely involve complex mechanisms of pre- and post-synaptic regulation. While considerable progress has been made recently, the treatment of depression needs to be further improved. ReferencesTop
Which anxiolytic drug promotes agonist activity at both the serotonin and dopamine?Cariprazine is a partial agonist at both dopamine D2 and D3 receptors as well as serotonin 5-HT1A receptors and in this regard is relatively similar to the currently available atypical antipsychotics, aripiprazole, and brexpiprazole.
Which drug may cause serotonin syndrome if given together with an antidepressant medication?The drugs and supplements that could potentially cause serotonin syndrome include: Selective serotonin reuptake inhibitors (SSRIs), antidepressants such as citalopram (Celexa), fluoxetine (Prozac), fluvoxamine (Luvox), escitalopram (Lexapro), paroxetine (Paxil, Pexeva, Brisdelle) and sertraline (Zoloft)
Is Buspirone a serotonin?Buspirone is an anxiolytic drug and is a partial agonist for the serotonin 5-HT(1A) receptors as well as possessing low affinity and is an antagonist for the dopamine D(2) autoreceptors, with some evidence of a weak affinity to 5-HT(2) receptors.
Which Antiparkinson drug causes an increase in the levels of dopaminergic stimulation?Stimulation of the receptors increases dopaminergic activity in the brain, thereby lessening the severity of parkinsonism symptoms. Examples of dopamine-receptor agonists include pergolide, ropinirole, pramipexole, and bromocriptine.
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