Comparison of the effects of serotonin selective,norepinephrine selective,and dual serotonin and norepinephrine reuptake inhibitors on lower urinary tract function in cats

Previous studies showed that the dual serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitor, duloxetine, increases bladder capacity and urethral sphincter electromyographic (EMG) activity in a cat model of acetic acid-induced bladder irritation. The present study aimed to determine the relative importance of 5-HT versus NE reuptake inhibition for mediating these effects by examining drugs that are selective for either the 5-HT or NE system or both. Similar to duloxetine, venlafaxine (0.1 to 10 mg/kg), also a dual serotonin and norepinephrine reuptake inhibitor, produced marked increases in bladder capacity and EMG activity that were reversed by methiothepin (0.3 mg/kg). S-norfluoxetine (0.01 to 10 mg/kg), a serotonin selective reuptake inhibitor, produced small but significant increases in bladder capacity and EMG activity at doses of 3 and 10 mg/kg. Thionisoxetine (0.01 to 3.0 mg/kg), a NE selective reuptake inhibitor, produced no effects on bladder capacity or sphincter EMG activity. Surprisingly, co-administration of thionisoxetine and s-norfluoxetine up to doses of 1 mg/kg of each compound produced no effect on lower urinary tract function. These doses were the maximum that could be administered in combination due to drug-induced emergence of skeletal muscle activity in chloralose-anesthetized animals. These results indicate that there are unexplained pharmacological differences between the effects of single compounds that exhibit dual NE and 5-HT reuptake inhibition and a combination of compounds that exhibit selective NE and 5-HT reuptake inhibition on lower urinary tract function.     

Antagonism of Serotonin 5-HT1A Receptors Potentiates the Increases in Extracellular Monoamines Induced by Duloxetine in Rat Hypothalamus

Abstract: In the current study we examined the effects of coadministration of a serotonin 5-HT_1A antagonist, (±)-1-(1 H -indol-4-yloxy)-3-(cyclohexylamino)-2-propanol maleate (LY 206130), and a dual 5-HT and norepinephrine (NE) uptake inhibitor, duloxetine, on extracellular levels of NE, 5-HT, dopamine (DA), 5-hydroxyindoleacetic acid, and 3,4-dihydroxyphenylacetic acid in rat hypothalamus microdialysates. LY 206130 (3.0 mg/kg, s.c.) alone significantly increased NE and DA levels by 60 and 34%, respectively, without affecting 5-HT levels. Duloxetine administration at 4.0 mg/kg, i.p. alone produced no significant changes in levels of 5-HT, NE, or DA. In contrast, when LY 206130 and duloxetine were coadministered at 3.0 mg/kg, s.c. and 4.0 mg/kg, i.p., respectively, 5-HT, NE, and DA levels increased to 5.7-, 4.8-, and threefold over their respective basal levels. These data demonstrate that antagonism of somatodendritic 5-HT_1A autoreceptors and concomitant inhibition of 5-HT and NE uptake with duloxetine may promote synergistic increases in levels of extracellular 5-HT, NE, and DA in hypothalamus of conscious, freely moving rats.     

Duloxetine inhibits effects of MDMA ("ecstasy") in vitro and in humans in a randomized placebo-controlled laboratory study

This study assessed the effects of the serotonin (5-HT) and norepinephrine (NE) transporter inhibitor duloxetine on the effects of 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy) in vitro and in 16 healthy subjects. The clinical study used a double-blind, randomized, placebo-controlled, four-session, crossover design. In vitro, duloxetine blocked the release of both 5-HT and NE by MDMA or by its metabolite 3,4-methylenedioxyamphetamine from transmitter-loaded human cells expressing the 5-HT or NE transporter. In humans, duloxetine inhibited the effects of MDMA including elevations in circulating NE, increases in blood pressure and heart rate, and the subjective drug effects. Duloxetine inhibited the pharmacodynamic response to MDMA despite an increase in duloxetine-associated elevations in plasma MDMA levels. The findings confirm the important role of MDMA-induced 5-HT and NE release in the psychotropic effects of MDMA. Duloxetine may be useful in the treatment of psychostimulant dependence. TRIAL REGISTRATION: Clinicaltrials.gov NCT00990067.     

Brain Region-Specific Effects of Short-Term Treatment with Duloxetine,Venlafaxine, Milnacipran and Sertraline on Monoamine Metabolism in Rats

We examined brain region-specific changes in monoamines and metabolites, and their ratios, after short-term administration of antidepressants to rats. Serotonin noradrenaline reuptake inhibitors (SNRIs; duloxetine, venlafaxine, milnacipran) and a serotonin-selective reuptake inhibitor (SSRI; sertraline) elevated serotonin (5-HT) levels in the midbrain (MB). Duloxetine and venlafaxine increased 5-HT levels in the brainstem and 5-HT terminal areas, whereas milnacipran and sertraline increased levels in the brainstem only. Significant reductions in 5-HT turnover were observed in various forebrain regions, including the hippocampus and hypothalamus, after treatment with all of the tested drugs except for milnacipran. In addition, there was reduced 5-HT turnover in the dorsolateral frontal cortex (dlFC), the medial prefrontal cortex (mPFC), and both the dlFC and the mPFC after treatment with duloxetine, sertraline, and venlafaxine, respectively. Venlafaxine significantly increased dopamine (DA) levels in the nucleus accumbens (NAc) and the substantia nigra and decreased DA turnover in the NAc. Similar changes were observed after treatment with duloxetine and sertraline in the NAc, whereas milnacipran increased DA levels in the mPFC. Limited increases in noradrenaline levels were detected after treatment with duloxetine, venlafaxine, or sertraline, but not after treatment with milnacipran. These results show that SNRIs and SSRIs induced region-specific monoaminergic changes after short-term treatment.     

Synthesis of some tropane derivatives of anticipated activity on the reuptake of norepinephrine and/or serotonin

A variety of tropane derivatives 14a–g were prepared via the reaction of the alcohol analogs 12a and 12b with substituted fluorobenzenes 13a–f. The prepared compounds were tested for their activity and selectivity toward the norepinephrine transporter (NET) and serotonin transporter (SERT) using yohimbine-induced mortality and 5-hydroxytryptophan-induced neurotoxicity in mice, respectively. All the tested compounds were found to be NE and 5-HT reuptake inhibitors except 14d which exhibited selective 5-HT reuptake inhibition activity.     

A Generalised Increase in Protein Carbonyls in the Brain in Parkinson''s but Not Incidental Lewy Body Disease

Abstract: A serotonin (5-HT)_1A receptor partial agonist, buspirone, potentiates the clinical antidepressant properties of 5-HT reuptake inhibitors (SSRIs). Herein, we examined the interaction of buspirone with two SSRIs, duloxetine and fluoxetine, on extra-cellular levels of 5-HT, dopamine (DA), and noradrenaline (NAD) in single dialysate samples of freely moving rats. Duloxetine (5.0 mg/kg, s.c.) and fluoxetine (10.0 mg/kg, s.c.) increased dialysate levels of DA (65 and 60% vs. basal values, respectively), NAD (400 and 90%, respectively), and 5-HT (130 and 110%, respectively) in the frontal cortex (FCX). Buspirone (2.5 mg/kg, s.c.) similarly elevated levels of DA (100%) and NAD (160%) but reduced those of 5-HT (−50%). Administered with buspirone, the ability of duloxetine and fluoxetine to increase 5-HT levels was transiently inhibited (over 60 min), although by the end of sampling (180 min) their actions were fully expressed. In contrast, buspirone markedly and synergistically facilitated the elevation in DA levels elicited by duloxetine (550%) and fluoxetine (240%). Furthermore, buspirone potentiated the induction of NAD levels by duloxetine (750%) and fluoxetine (350%). These data suggest that a reinforcement in the influence of SSRIs on DA and, possibly, NAD but not 5-HT release in FCX may contribute to their increased antidepressant activity in the presence of buspirone. More generally, they support the hypothesis that a reinforcement in dopaminergic transmission in the FCX contributes to the actions of SSRIs and other antidepressant drugs.     

Duloxetine: a summary of published clinical experience

Effective oral therapy for genuine stress urinary incontinence (SUI) in women has, to date, been an unattainable goal. Although oral pharmacologic agents have been used for this condition, none has ultimately been successful, because of side effects, lack of efficacy, or problematic compliance with drug ingestion. The availability of an effective oral agent for SUI would increase the range of therapeutic options for symptom management and possibly make treatment accessible to more women who otherwise feel that surgical therapy is not an option because of social, personal, or medical reasons. Duloxetine is a selective serotonin (5-HT) and norepinephrine reuptake inhibitor that has been shown to increase rhabdosphincter activity. Rhabdosphincter contractility changes are thought to occur as the result of increased stimulation of alpha(1)-adrenergic and 5-HT(2) receptors in the sacral spinal cord, resulting in increased efferent pudendal nerve activity, producing increased pelvic floor tonus. Two large-scale studies have been completed employing subjective and objective outcomes to assess the therapeutic index of duloxetine as a therapy for SUI.     

Design,synthesis, and biological evaluation of arylpiperazine–benzylpiperidines with dual serotonin and norepinephrine reuptake inhibitory activities

The limitations of established serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitors necessitate the development of safer and more effective therapeutic agents. Based on the structures of 4-benzylpiperidine carboxamides and trazodone, arylpiperazine–benzylpiperidines with chemical scaffolds different from those of marketed drugs were designed, synthesized, and evaluated for their neurotransmitter reuptake inhibitory activities. The majority of the synthesized compounds showed greater NE than 5-HT reuptake inhibition. The activities were even greater than those of the standard drug, venlafaxine hydrochloride were. The derivatives with a three-carbon linker showed better activities than the derivatives with a two-carbon linker. Among the newly synthesized compounds, 2d exhibited the strongest reuptake inhibition of the neurotransmitters (IC₅₀ = 0.38 μM for NE and 1.18 μM for 5-HT). The biological activity data demonstrate that arylpiperazine–benzylpiperidines have the potential to be developed as a new class of therapeutic agents to treat neuropsychiatric and neurodegenerative disorders.     

α2-Adrenergic Receptor Blockade Markedly Potentiates Duloxetine- and Fluoxetine-Induced Increases in Noradrenaline, Dopamine, and Serotonin Levels in the Frontal Cortex of Freely Moving Rats

Abstract: Evidence exists that a reinforcement in monoaminergic transmission in the frontal cortex (FCX) is associated with antidepressant (AD) properties. Herein, we examined whether blockade of α₂-adrenergic receptors modified the influence of monoamine reuptake inhibitors on FCX levels of serotonin (5-HT), noradrenaline (NAD), and dopamine (DA). The selective α₂-adrenergic receptor agonist S 18616 (0.16 mg/kg, s.c.) suppressed extracellular levels of NAD, DA, and 5-HT (by 100, 51, and 63%, respectively) in single dialysates of FCX of freely moving rats. In contrast, the selective α₂-adrenergic receptor antagonists atipamezole (0.16 mg/kg, s.c.) and 1-(2-pyrimidinyl)piperazine (1-PP; 2.5 mg/kg, s.c.) increased levels of NAD (by 180 and 185%, respectively) and DA (by 130 and 90%, respectively), without affecting 5-HT levels. Duloxetine (5.0 mg/kg, s.c.), a mixed inhibitor of 5-HT and NAD reuptake, and fluoxetine (10.0 mg/kg, s.c.), a selective 5-HT reuptake inhibitor, both increased levels of 5-HT (by 150 and 120%, respectively), NAD (by 400 and 100%, respectively), and DA (by 115 and 55%, respectively). Atipamezole (0.16 mg/kg, s.c.) markedly potentiated the influence of duloxetine and fluoxetine on levels of 5-HT (by 250 and 330%, respectively), NAD (by 1,030 and 215%, respectively), and DA (by 370 and 170%, respectively). 1-PP similarly potentiated the influence of duloxetine on 5-HT, NAD, and DA levels (by 290, 1,320, and 600%, respectively). These data demonstrate that α₂-adrenergic receptors tonically inhibit NAD and DA and phasically inhibit 5-HT release in the FCX and that blockade of α₂-adrenergic receptors strikingly potentiates the increase in FCX levels of 5-HT, NAD, and DA elicited by reuptake inhibitors. Concomitant α₂-adrenergic receptor antagonism and inhibition of monoamine uptake may thus provide a mechanism allowing for a marked increase in the efficacy of AD agents.     

A novel class of 3-(phenoxy-phenyl-methyl)-pyrrolidines as potent and balanced norepinephrine and serotonin reuptake inhibitors: Synthesis and structure–activity relationships

A series of 3-(phenoxy-phenyl-methyl)-pyrrolidine analogues were discovered to be potent and balanced norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. Several of these compounds were identified to have suitable in vitro pharmacokinetic properties for an orally dosed and CNS-targeted drug. Compound 39b, in particular, was identified as a potent NET and SERT reuptake inhibitor (NSRI) with minimal off-target activity and demonstrated robust efficacy in the spinal nerve ligation model of pain behavior.     

3,4-Dihydro-2H-benzoxazinones are 5-HT(1A) receptor antagonists with potent 5-HT reuptake inhibitory activity

Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat.     

Neurotransmitter-induced changes in arachidonate incorporation into rat brain phospholipids: pharmacological manipulations of receptors,presynaptic uptake,mao activity and deacylation-reacylation processes

The incorporation of [³H]arachidonic acid ([³H]AA) into phospholipids (PL) of rat brain, was studied in cerebral cortex slices in the presence and absence of norepinephrine (NE), serotonin (5-HT) and carbamylcholine (CCH). Both NE and 5-HT produced a concentration-dependent effect of stimulating [³H]AA incorporation into phosphatidylinositol (PI) while attenuating incorporation into other PL. Addition of CCH had no apparent effect. The β-adrenergic agonist, isoproterenol, had an effect similar to that seen with equimolar concentrations of NE, whereas the α₁ agonist, phenylephrine, or the α₂ agonist, clonidine, did not produce significant changes. However, application of the NE-receptor blockers, propranolol or prazosin, in the presence of NE, did not modify the NE-induced effects. Similarly, the 5-HT-receptor blockers, methysergide or ketanserine, failed to modify the 5-HT-induced effects, indicating that the neurotransmitter-produced changes may not be receptor mediated. Manipulations of the NE or 5-HT reuptake systems by imipramine (IMI) or desipramine (DMI) had a small additive effect on the neurotransmitter-produced changes in [³H]AA incorporation, suggesting that a functional presynaptic reuptake system is not required for the NE or 5-HT-produced effects. The possibility that the NE or 5-HT effects involve the oxidative metabolism of the monoamines by MAO was also investigated. The MAO inhibitors tranylcypromine and pargyline had no appreciable effect on the neurotransmitter-induced changes in [³H]AA incorporation whereas clorgyline clearly reduced the increase in [³H]AA incorporation into PI seen in the presence of NE or 5-HT, but this clorgyline effect may not be related to its activity as MAO inhibitor. The phospholipase A₂ inhibitor mepacrine had no significant effect on the NE-produced increase in [³H]AA incorporation into PI, but it antagonized the NE-produced decrease in [³H]AA incorporation into PC. Delta-9-Tetrahydrocannabinol, which acts as acyltransferase inhibitor, antagonized the NE-produced increase in [³H]AA incorporation into PI without appreciably influencing the NE-produced decrease in [³H]AA incorporation into PC. These findings suggest that the neurotransmitter-produced increase in [³H]AA incorporation into PI is mediated by stimulation of a specific lyso-PI arachidonyl transferase. The neurotransmitter effects on arachidonate incorporation may have physiological significance in view of the importance of processes of deacylation and reacylation of membrane PL in regulating the function of neuronal membranes.     

Acute dopamine/norepinephrine reuptake inhibition increases brain and core temperature in rats.

The purpose of the present study was to examine the effects of an acute dose of the dual dopamine (DA) and norepinephrine (NE) reuptake inhibitor bupropion (Bup) on brain (T(brain)), body core (T(core)), and tail skin (T(tail)) temperature in freely moving rats and to simultaneously monitor the extracellular neurotransmitter concentrations in the preoptic area and anterior hypothalamus (PO/AH). A microdialysis probe was inserted in the PO/AH, and samples for NE, DA, and serotonin (5-HT) were collected every 20 min before and after the injection of 17 mg/kg of Bup, for a total sampling time of 180 min. T(core) was monitored using a biotelemetry system. T(brain) and T(tail), an index of heat loss response, were also measured. Both NE and DA levels in the PO/AH significantly increased after Bup injection compared with the baseline levels, reaching approximately 450 and 230%, respectively, 40 min after injection. There was no effect on 5-HT release. The neurotransmitter changes were accompanied by a significant decrease in T(tail) and an increase in both T(brain) and T(core) compared with the baseline levels. The present results demonstrate that inhibition of NE and DA reuptake suppresses heat loss mechanisms and elevates T(brain) and T(core) in freely moving rats.     

Effect of cholecystokinin octapeptide sulphate ester on brain monoamines in the rat

The effect of different doses of intracerebro-ventricularly administered cholecystokinin octapeptide sulphate ester (CCK-8-SE) was studied on dopamine (DA), norepinephrine (NE) and serotonin (5-HT) contents in the hypothalamus, mesencephalon, amygdala, septum and striatum, 10, 20 and 60 min following administration. The DA and NE content increased and the 5-HT content decreased in the hypothalamus and mesencephalon. A biphasic action was observed in the amygdala of DA, NE and 5-HT depending upon the time and doses used. Similar action was seen on DA and NE in the septum. In the striatum, the DA and 5-HT content decreased while the NE level first increased and then decreased. The data indicate that the CCK-8-SE is able to modify the activity of DA, NE and 5-HT in different brain regions in a time and dose-dependent manner, with a local specific action.     

Effects of systemically administered monoamine reuptake blocking agents on patterns of buspirone-induced analgesia in rats

We have recently shown the serotonin 5-HT1A receptor agonist buspirone to produce analgesia in several pain tests in rats. As a 5-HT1A agonist, buspirone may change serotonergic (5-HT) tone to alter the balance of central monoaminergic (MA) systems that function in analgesia. MA-reuptake blocking drugs have been shown to produce analgesia, both when given alone and in combination with a variety of other agents, presumably via their action upon MA neurochemistry. The present study was undertaken to examine the effect of systemic administration of the 5-HT-reuptake blocker amitriptyline (AMI: 10 mg/kg), NE-reuptake blocker desipramine (DMI: 10 mg/kg) or DA-reuptake blocker GBR-12909 (7.5 mg/kg) on patterns of analgesia produced by buspirone (1-5 mg/kg) in thermal and mechanical pain tests in rats. Neither reuptake blocking agents or buspirone, when administered alone or in combination, produced overt changes in motor activity at the doses tested. AMI alone was not analgesic in either thermal or mechanical pain tests. In both assays, AMI reduced the analgesic action of buspirone, with greater effects seen in the thermal test. When administered alone, DMI produced significant analgesia against thermal and mechanical pain. DMI significantly attenuated the analgesic action of all doses of buspirone in both pain tests. Alone, GBR-12909 did not affect nociception in thermal or mechanical tests. GBR-12909 decreased buspirone-induced analgesia at all doses in the thermal test, while having no effect on buspirone-induced analgesia against mechanical pain. These results demonstrate that facilitation of 5-HT, NE and DA function with reuptake blocking drugs did not enhance the analgesic action of buspirone. These data indicate against the adjuvant use of reuptake blocking compounds and buspirone as analgesics. Furthermore, such findings may suggest other possible non-MA substrates of buspirone-induced analgesia.     

Age-related changes in 24-hour rhythms of norepinephrine content and serotonin turnover in rat pineal gland: effect of melatonin treatment

The 24-hour rhythms of pineal norepinephrine (NE) content and serotonin (5-HT) turnover [estimated from the ratio of 5-hydroxyindoleacetic acid (5-HIAA) to 5-HT] were studied in young (2 months) and aged (18-20 months) Wistar rats killed at 6 different time points throughout a 24-hour cycle. In the first study, significant changes dependent on the time of day were identified, with acrophases in the first half of the activity span for both parameters. Old rats showed significantly smaller mesor and amplitude of the 24-hour rhythm of pineal NE content. They also showed decreased amplitude of the pineal 5-HT turnover rhythm, in the absence of changes in mesor. In old rats, pineal 5-HT and 5-HIAA concentrations were 41-47% of those found in young rats. In a second study, young and old rats received daily intraperitoneal injections of melatonin (30 microg) or vehicle for 11 days at 19.00 h (i.e. 11 h after light on). Analyzed as a main factor in a factorial analysis of variance, both pineal NE content and 5-HT turnover decreased in old rats while pineal 5-HT turnover increased after melatonin treatment. Melatonin treatment augmented the amplitude of the 24-hour rhythm of pineal NE content by 120 and 52% in young and old rats, respectively. The amplitude of the 24-hour rhythm of pineal 5-HT turnover almost doubled after melatonin treatment in young rats and did not change in old rats. Melatonin injection did not modify the rhythm's acrophase. The results indicate that old rats had lower amplitude and lower mesor values of 24-hour variations in pineal NE content and 5-HT turnover. Melatonin treatment only partly restored pineal NE content and was devoid of activity on pineal 5-HT turnover and 5-HT and 5-HIAA concentration in old rats. Impairment of pineal melatonin synthesizing capacity and intrapineal responses to melatonin may underlie pineal aging in rats.     

Cytochemical localization of Na+/K+-ATPase activity in cochlear strial marginal cells after various catecholamine administrations

Sodium/potassium-activated adenosine triphosphatase (Na+/K+-ATPase) activity in the kidney and brain is high, and is regulated by catecholamines. Na+/K+-ATPase activity is also high in the basolateral infoldings of the strial marginal cells, where it aids in maintaining the characteristic electrolyte composition of the endolymph. To clarify the involvement of humoral control in strial function, particularly the role of catecholamines, the K+-dependent p-nitrophenylphosphatase (K+-NPPase) activity of strial marginal cells was investigated in guinea pigs using a cerium-based cytochemical method. The effects of reserpine, serotonin (5-HT), norepinephrine (NE), epinephrine (EP), both alone and in combination, were studied. High doses of reserpine cause depletion of sympathetic substances. Strial K+-NPPase activity was decreased after reserpine or dopamine treatment, and was increased after 5-HT, NE, and EP treatment. After reserpinization, repeated treatment with 5-HT, NE, or EP led to detectable strial enzyme activity. Thus, exogenous 5-HT, NE, and EP were able to restore strial K+-NPPase activity in the reserpine-treated animals. These results suggested that biogenic amines regulate strial K+-NPPase activity. Thus, the function of the stria vascularis may be regulated by the opposing actions of these catecholamines, and 5-HT.     

Studies toward the discovery of the next generation of antidepressants. Part 2: incorporating a 5-HT(1A) antagonist component into a class of serotonin reuptake inhibitors

The design and synthesis of a novel series of indole derivatives (9) having dual 5-HT transporter reuptake and 5-HT(1A) antagonist activity are described.     

Effect of pharmacologically selective antidepressants on serotonin uptake in rat platelets

We tested a hypothesis that a long-term administration of antidepressants acting through different primary biochemical mechanisms is associated with changes in the platelet serotonin (5-hydroxytryptamine, 5-HT) transport. Laboratory rats were administered norepinephrine reuptake inhibitors (desipramine, maprotiline), selective 5-HT reuptake inhibitor (citalopram), reversible monoamine oxidase inhibitor (moclobemide), and lithium (inositol monophosphatase inhibitor among others) during a 4-week period. Apparent kinetic parameters of platelet 5-HT transport were analyzed. Significant decrease in apparent Michaelis constant (K(M)) was found after the administration of all tested antidepressants except for desipramine. There was certain increase in maximal velocity (V(max)) values following the administration of desipramine, maprotiline, and citalopram; however, the all V(max) changes were not significant. V(max)/K(M) ratio representing limiting permeability at low extracellular concentrations of 5-HT was systematically increased in all the tested drugs, but significant changes were occurred only in maprotiline- and citalopram-treated rats. Adaptive changes in platelet 5-HT transport induced by citalopram were opposite to the acute inhibitory effect of this drug on 5-HT transporter activity. An increase in limiting membrane permeability for 5-HT could be included in the common adaptive effect of the long-term administration of antidepressants that differ in pharmacologic selectivity.