Adenosine administration produces an antidepressant-like effect in mice: evidence for the involvement of A1 and A2A receptors

This study investigated the effect of adenosine in the forced swimming test (FST) and the tail suspension test (TST) in mice, and the contribution of adenosine A1 and A2A receptors to adenosine's antidepressant-like effect. The immobility time in the FST was reduced by adenosine given either by i.p. (5-10 mg/kg) or i.c.v. (0.01-10 microg/site) route. Adenosine (1-10 mg/kg, i.p.) also produced an antidepressant-like effect in the TST. No treatment affected locomotion in an open-field. The anti-immobility effect of adenosine (10 mg/kg, i.p.) in the FST was prevented by i.p. pretreatment of mice with caffeine (3 mg/kg), DPCPX (2 mg/kg) and ZM241385 (1 mg/kg). CHA (0.05 mg/kg, i.p.) and DPMA (1-5 mg/kg, i.p.) also produced an antidepressant-like effect in the FST. This is the first report of an antidepressant-like effect of adenosine in mice, apparently mediated through an interaction with A1 and A2A receptors.     

Role of 5-HT(1A) and 5-HT(1B) receptors in the antidepressant-like effect of piperine in the forced swim test

Our previous studies have showed that treating mice with piperine significantly decreased the immobility time of the animals in the forced swim test and tail suspension test, which was related to up-regulation of serotonin (5-HT) level in the brain. The purpose of this study is to explore the contribution of 5-HT receptors in the antidepressant-like effect of piperine. The results showed that pre-treating mice with methiothepin (a non-selective 5-HT receptor antagonist, 0.1 mg/kg, intraperitoneally), 4-(2′-methoxy-phenyl)-1-[2′-(n-2″-pyridinyl)-p-iodobenzamino-]ethyl-piperazine (a selective 5-HT_1A receptor antagonist, 1 mg/kg, subcutaneously) or 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol (a 5-HT_1B receptor antagonist, 2.5 mg/kg, intraperitoneally) was found to abolish the anti-immobility effect of piperine (10 mg/kg, intraperitoneally) in the forced swim test. On the other hand, a sub-effective dose of piperine (1 mg/kg, intraperitoneally) produced a synergistic antidepressant-like effect with (+)-8-hydroxy-2-(di-n-propylamino)tetralin (a 5-HT_1A receptor agonist, 1 mg/kg, intraperitoneally) or anpirtoline (a 5-HT_1B receptor agonist, 0.25 mg/kg, intraperitoneally). Taken together, these results suggest that the antidepressant-like effect of piperine in the mouse forced swim test may be mediated, at least in part, by the activation of 5-HT_1A and 5-HT_1B receptors.     

The effect of stimulation and blocking of histamine H2 receptors on the turnover of the serotonin in different parts of the alimentary tract and the brain of the rat

In the experiments performed on Wistar rats it was found that histamine (0.05 and 0.5 mg/kg i.p.) caused an acceleration of the turnover of serotonin (5-HT) in the stomach. After the lowest dose of ranitidine (3 mg/kg i.p.) a decrease in the rate of 5-HT turnover in the stomach was observed, whereas the higher doses (15.0 and 30 mg/kg i.p.) accelerated the turnover of this amine. In the duodenum, both doses of histamine accelerated the turnover of 5-HT, however, ranitidine in all doses induced a reduction in the rate of 5-HT turnover in this part of the alimentary tract. In the intestine, both doses of histamine enhanced the turnover of 5-HT but after all doses of ranitidine a decrease of the turnover was observed.The blockade of histamine H₂ receptors with ranitidine did not completely abolish the effects of histamine on the 5-HT system, in the parts of the rat digestive system studied which suggests also an indirect activity of other receptors in presented observations. In the rat brain, an acceleration of the turnover of 5-HT after both doses of histamine was found. However, ranitidine only reduced the rate of 5-HT turnover at the lowest dose. In animals treated with ranitidine (15 mg/kg i.p.) for three days, histamine did not produce any change in the turnover of 5-HT in rat brain.These experiments show, that in the alimentary tract a relationship exists between histaminergic and serotoninergic systems.     

Antidepressant-like effect of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol, a putative trace amine receptor ligand involves l-arginine-nitric oxide-cyclic guanosine monophosphate pathway

1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol is a novel putative trace amine receptor modulator hypothesized to be useful for treatment-resistant depression. In our previous study, we have demonstrated the antidepressant-like effect of this molecule in mouse forced swim and tail suspension tests and shown to act via modulating the levels of norepinephrine, serotonin and dopamine. The present study attempts to explore the involvement of l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol in the mouse forced swim test. The antidepressant-like action of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol (8 mg/kg, i.p) was reversed by pretreatment with L-arginine (750 mg/kg, i.p.), a nitric oxide precursor. In contrast, pretreatment with methylene blue (a soluble guanlyate cyclase inhibitor and nitric oxide synthase (NOS) inhibitor) or 7-nitroindazole (a specific neuronal NOS inhibitor) potentiated the antidepressant-like effect of sub-effective dose of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol (2 mg/kg, i.p.) in this test model. Furthermore, the antidepressant-like effect of this molecule (8 mg/kg, i.p.) was reversed by sildenafil (5 mg/kg, i.p.), a phosphodiesterase inhibitor. In conclusion, the antidepressant-like action of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol involved L-arginine-nitric oxide-cyclic guanosine monophospate signaling pathway.     

Involvement of PKA, MAPK/ERK and CaMKII, but not PKC in the acute antidepressant-like effect of memantine in mice

This study investigated the cellular signaling pathways involved in the acute antidepressant-like action of memantine in the forced swimming test (FST) in mice. The immobility time in the FST was reduced by memantine (3-10 mg/kg, i.p.). The anti-immobility effect of memantine (3 mg/kg, i.p.) was prevented by pretreatment with H-89 (1 microg/site, i.c.v., an inhibitor of PKA), PD098059 (5 microg/site, i.c.v., an inhibitor of MAPK/ERK), KN-62 (1 microg/site, i.c.v., an inhibitor of CaMKII), but not with chelerythrine (1 microg/site, i.c.v., an inhibitor of PKC). Taken together, these results firstly demonstrate that the acute antidepressant-like effect of memantine seems to be dependent on the cellular signaling modulated by PKA, CaMKII and MAPK/ERK, but not by PKC.     

Evidence for the involvement of the opioid system in the agmatine antidepressant-like effect in the forced swimming test

This study investigated the involvement of the opioid system in the antidepressant-like effect of agmatine in the mouse forced swimming test (FST). The antidepressant-like effects of agmatine (10 mg/kg, i.p.), as well as those of fluoxetine (32 mg/kg, i.p, a selective serotonin reuptake inhibitor, SSRI) or morphine (5 mg/kg, s.c., a nonselective opioid receptor agonist) in the FST was completely blocked by pretreatment of mice with naloxone (1 mg/kg, i.p., a nonselective opioid receptor antagonist). Pretreatment of mice with naltrindole (3 mg/kg, i.p., a selective delta-opioid receptor antagonist), clocinnamox (1 mg/kg, i.p., an irreversible mu-opioid receptor antagonist), but not with 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide (DIPPA; 1 mg/kg, i.p., a selective kappa-opioid receptor antagonist) completely blocked the anti-immobility effect of agmatine (10 mg/kg, i.p.) in the FST. These results firstly demonstrate that the antidepressant-like effects of agmatine in the FST seem to be mediated, at least in part, by an interaction with the opioid system, that involves an activation of delta- and mu-opioid receptors.     

Involvement of monoaminergic systems in the antidepressant-like effect of nobiletin

Nobiletin isolated from citrus peels up-regulates synaptic transmission and improves memory impairment in rodents. This study investigated the antidepressant-like effect of nobiletin in the forced swimming test (FST) and tail suspension test (TST) in mice. Additionally, the monoaminergic mechanisms involved in the antidepressant-like effect of nobiletin in mice were also assessed. Nobiletin (25, 50 and 100 mg/kg, p.o.) decreased the immobility time in both the FST and TST without locomotor alterations in the open-field test (OFT). The anti-immobility effect of nobiletin (50 mg/kg, p.o.) was completely prevented by the pretreatment of mice with WAY 100635 (0.1 mg/kg, s.c., a serotonin 5-HT_1A receptor antagonist), cyproheptadine (3 mg/kg, i.p., a serotonin 5-HT₂ receptor antagonist), prazosin (62.5 μg/kg, i.p., an α₁-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist) or sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist). On the other hand, the pretreatment of mice with yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist) or propranolol (5 mg/kg, i.p., a β-adrenoceptor antagonist) did not block the antidepressant-like effect of nobiletin in the TST. Taken together, the data demonstrated that nobiletin produced an antidepressant-like effect that seems to be dependent on its interaction with the serotonergic, noradrenergic and dopaminergic systems. Thus, the present study suggests the therapeutic potential of this dietary flavonoid for the treatment of depression.     

Antidepressant-like effect of centrally acting non-narcotic antitussive caramiphen in a forced swimming test

Recently, we reported that a centrally acting non-narcotic antitussive (cough suppressant drug), tipepidine produces an antidepressant-like effect in the forced swimming test in rats. Because pharmacological properties of tipepidine apparently differ from those of typical antidepressants developed to date, we speculated that caramiphen, another centrally acting antitussive, has an antidepressant-like effect. That effect of caramiphen was studied in rats using the forced swimming test. Caramiphen at 20 and 40 mg/kg i.p. significantly reduced immobility. At 40 mg/kg i.p., it increased climbing behavior. Even at 40 mg/kg, this drug had no effect on locomotor activity. Results suggest that a centrally acting antitussive possessing inhibition of GIRK channels has an antidepressant-like effect.     

Antidepressant-like effect of genipin in mice

The present study aimed to investigate the antidepressant potential of genipin and its possible mechanisms. Mouse models of depression including the forced swimming test (FST) and the tail suspension test (TST) were used to evaluate the effects of genipin. A possible mechanism was explored in the test of antagonism of reserpine-induced ptosis and hypothermia in mice. The contents of monoamine neurotransmitters and their metabolites including epinephrine (NE), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in mice hippocampi were determined by HPLC–ECD. The results showed that intra-gastric administration of genipin at 50, 100, 200 mg/kg or fluoxetine at 7.5 mg/kg for 7 days significantly reduced the duration of immobility in FST and TST, while it did not affect the locomotor activity in the open field test (OFT). However, the effect was not dose-dependent. When the mice were treated with genipin or fluoxetine for 7 days, both of them could antagonize reserpine-induced ptosis and hypothermia. The 5-HT and NE contents in mice hippocampi were decreased after the peritoneal injection of reserpine at 2.0 mg/kg. The pre-treatment with genipin at 50, 100, 200 mg/kg or fluoxetine at 7.5 mg/kg for 7 days could elevate the contents of NE and 5-HT in mice hippocampi significantly. The results suggest that compared with fluoxetine, genipin exerts antidepressant-like effects significantly. A possible mechanism, at least in part, is the regulation of the 5-HT and NE levels in the hippocampus.     

Involvement of sigma-1 receptor modulation in the antidepressant action of venlafaxine

Multiple lines of investigation have explored the role of sigma receptors in mental depression. Sigma receptors particularly, sigma-1 subtype is known to modulate the release of various catecholamines in the brain and may play, in some way, a role in the mechanism of action of various antidepressants. The present study investigated the possible involvement of sigma receptors in modulating the antidepressant-like effect of venlafaxine (dual serotonin and norepinephrine reuptake inhibitor) in the mouse forced swim test (FST). Immobility period in the forced swim test was registered for a total period of 6 min. Venlafaxine produced dose-dependent (4–16 mg/kg, i.p.) reduction in immobility period. Pretreatment of mice with (+)-pentazocine (2.5 mg/kg, i.p.), a high-affinity sigma-1 receptor agonist, produced synergism with subeffective dose of venlafaxine (2 mg/kg, i.p.). On the contrary, pretreatment with progesterone (10 mg/kg, s.c.), a sigma-1 receptor antagonist neurosteroid, rimcazole (5 mg/kg, i.p.), another sigma-1 receptor antagonist, or BD 1047 (1 mg/kg, i.p.), a novel sigma-1 receptor antagonist, reversed the anti-immobility effects of venlafaxine (8 mg/kg i.p.). The various modulators used in the study did not produce any changes in locomotor activity per se except venlafaxine which at higher dose (16 mg/kg, i.p.) significantly increased the locomotor activity in mice. The results for the first time demonstrated that the anti-immobility effects of venlafaxine in the FST possibly involve an interaction with sigma-1 receptors.     

Nicotine-induced increases of noradrenaline turnover in discrete noradrenaline nerve terminal systems of the hypothalamus and the median eminence of the rat and their relationship to changes in the secretion of adenohypophyseal hormones

The effects of acute single doses (0.3 and 1 mg/kg) of nicotine on various hypothalamic catecholamine nerve terminal systems and on the secretion of adenohypophyseal hormones in the rat were studied. Nicotine, in a dose of 1.0 mg/kg, increased noradrenaline turnover in the median eminence and in the peri- and paraventricular hypothalamic regions. The dopamine and noradrenaline nerve terminal systems in the median eminence and the dorsomedial hypothalamic nucleus respectively were unaffected. Serum GH levels were decreased and serum prolactin levels increased after a dose of 1 mg/kg. In the presence of tyrosine hydroxylase inhibition, nicotine in a dose of 1 mg/kg, instead increased GH and also LH secretion. It is suggested that the preferential increases of noradrenaline turnover in various hypothalamic noradrenaline nerve terminal systems by nicotine may be partly responsible for the nicotine induced increases of serum prolactin, GH and LH levels observed.     

Serotonergic mediation of the antidepressant-like effect of the green leaves odor in mice

The green odor (GO) that emanates from green leaves has been observed to have many physiological actions in mammals and may be associated with a healing effect in humans. This study examined the effect of GO (we used a mixture of cis-3-hexenol and trans-2-hexenal) on behavior in the forced swim test (FST) of depression in mice. Exposure of GO showed the antidepressant-like effect in the FST, i.e., a significant decrease in immobility time and increase in swimming time, but no change in climbing time. The behavioral responses of GO-exposed animals to FST were similar to those observed for animals given citalopram, which is a selective serotonin reuptake inhibitor. In contrast, desipramine, which is a selective noradrenaline reuptake inhibitor, decreased immobility time and increased climbing time without affecting swimming time. To examine the involvement of the serotonergic system in mediating the antidepressant-like action of GO, we performed further FST examinations in which GO-exposed mice were treated with p-chlorophenylalanine (PCPA). Prior PCPA administration induced depletion of central 5-HT in the brain and completely diminished the GO effect on the behavioral responses seen during the FST. No changes in locomotor activity after GO inhalation were observed. These results indicate that acute exposure to GO has an antidepressant-like effect that may involve the serotonergic system.     

安神方对大鼠抑郁模型行为学及单胺类神经递质的影响

目的探讨中药复方安神方抗抑郁作用的机制。方法以慢性中等强度应激刺激建立大鼠抑郁模型,用强迫游泳试验进行行为学评分,用高效液相电化学检测方法检测大鼠脑干内单胺类神经递质的含量,观察模型大鼠给药前后的变化。结果抑郁模型大鼠第7天与第28天水中强迫游泳不动时间分别为（133.4±24.0）s、（179.7±35.3）s,正常组则为（127.9±31.3）s、（131.8±29.3）s,模型组显著高于正常组（P〈0.05）;脑干内5-HT、NE含量显著降低,模型组为（0.093±0.031）ng/mg、（0.146±0.038）ng/mg,正常组为（0.160±0.023）ng/mg、（0.237±0.049）ng/mg（P〈0.05）;安神方高剂量组第7天与第28天水中强迫游泳不动时间分别为（121.5±27.8）s、（145.1±24.2）s,与模型组比较显著降低（P〈0.05）,大鼠脑干内5-HT、NE含量分别为（0.151±0.021）ng/mg、（0.208±0.057）ng/mg,较正常组显著提高（P〈0.05）。结论安神方具有抗抑郁作用,对中枢单胺类神经递质的调节作用是其疗效机制之一。     

Serotonin type 3 receptors modulate the aggression-stimulating effects of adolescent cocaine exposure in Syrian hamsters (Mesocricetus auratus)

Repeated cocaine (0.5 mg/kg) exposure throughout adolescence stimulates offensive aggression in hamsters. These studies examined whether the cocaine-induced aggressive response was regulated by serotonin Type 3 (5-HT(3)) receptor activity and correlated with altered 5-HT(3) receptor expression. Cocaine-treated Syrian hamsters (Mesocricetus auratus) were tested for aggression after the administration of either the 5-HT(3) antagonist 3-tropanylindole-3-carboxylate methiodide (tropisetron; 0.01-1.20 mg/kg) or the 5-HT(3) agonist l-(m-chlorophenyl)-biguanide hydrochloride (mCPBG; 5.0-15.0 mg/kg), alone or in combination. Tropisetron alone dose dependently reduced cocaine-induced aggression, with a significant reduction at 0.3 mg/kg, whereas mCPBG was ineffective. mCPBG administered prior to tropisetron required a higher dose (1.2 mg/kg) of antagonist to block aggression, indicating a selective 5-HT(3) effect. Cocaine-treated hamsters showed altered 5-HT-sub-3 immunoreactivity in several brain areas implicated in aggression control. These data support a role for 5-HT(3) receptors in adolescent cocaine-induced aggression.     

雌激素对抑郁症小鼠行为学和脑组织单胺类递质的作用

目的:探讨雌激素低下对抑郁症模型小鼠行为学影响及神经生化机制。方法:清洁级昆明小鼠随机分为假手术组(Sham)、卵巢切除组(OVX)、慢性应激组(CUMS)、卵巢切除+慢性应激组(OVX+CUMS)和雌激素治疗组(E组,0.15 mg/kg),每组10只。给药组于每日应激前1 h,ig给药,其余各组给予等体积生理盐水,共计21 d。采用卵巢切除法(OVX)制备雌激素低下动物模型,采用CUMS法制备抑郁症小鼠模型。观察各组小鼠一般体征,行阴道上皮角化实验,通过旷场实验(OFT)、强迫游泳实验(FST)及体重测试(BWM)观察其行为学变化,采用ELISA法检测脑组织单胺类递质五羟色胺(5-HT)及多巴胺(DA)含量变化。结果:OVX小鼠,阴道细胞涂片未见动情周期变化连续7 d。模型小鼠在第21 d,与Sham组比较,(1)OVX和CUMS小鼠体重增加(P﹤0.01),而OVX+CUMS则体重下降(P﹤0.01);(2)在OVX和CUMS小鼠,OFT水平和垂直运动得分减少(P﹤0.01),而在E组小鼠,OFT水平和垂直运动得分增加(P﹤0.05);(3)在OVX和CUMS小鼠,FST不动时间减少(P﹤0.01),但在E组小鼠,FST不动时间增加(P﹤0.01)。(4)在OVX组小鼠,阴道脱落细胞呈现大量白细胞和少量上皮细胞。在CUMS和OVX小鼠,脑组织5-HT和DA含量减少(P﹤0.01),但在E组小鼠,脑组织中5-HT、DA含量增加(P﹤0.05,P﹤0.01)。结论:小鼠抑郁行为可以由于雌激素低下诱发,并且与脑组织5-HT和DA含量下调有关。补充雌激素可能通过增加单胺类递质5-HT和DA含量在脑组织,从而改善小鼠抑郁行为。     

Single or repeated administrations of SCH 23390 fail to affect serotonergic neurotransmission

In synaptic membrane preparations from the frontal cortex of rats treated with single or repeated administration of mianserin or methysergide (10 mg/kg i.p.) the number of 5-HT2 receptors was reduced. In contrast, single (0.1 mg/kg or 5 mg/kg i.p.) or repeated administration of SCH 23390 (0.05 mg/kg i.p. twice daily for 3 weeks) failed to change the kinetic characteristics of 5-HT2 receptors. Moreover, in several cerebral areas, 5-HT levels and turnover were not modified by any treatment. Although SCH 23390 has a high affinity for cerebral 5-HT2 receptors, and there are conflicting data on the antagonistic activity in the periphery, our data show that doses which selectively affect dopaminergic transmission are devoid of serotonergic effects.     

Facilitation of enkephalins-induced delta-opioid behavioral responses by chronic amisulpride treatment

The endogenous opioid system is known to have a great influence on the dopaminergic system. Conversely, blockade of the dopaminergic system in D2 receptor knock-out mice triggers an increase in enkephalin supporting the important physiological relationship between both systems. Therefore, the aim of this study was to investigate whether or not chronic treatment with the specific D2 antagonist amisulpride (20mg/kg, i.p., twice daily for 5 days) could lead to a facilitation of behavioral effects of enkephalins, protected from their enzymatic degradation by the dual inhibitor N-[(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-oxopropyl]-l-phenylalanine benzyl ester (RB101) (5mg/kg, i.v.) in mice. RB101 induced an increase in locomotor activity, antidepressant-like effects in the forced swim test, and antinociceptive effects in the hot-plate test. Chronic treatment with amisulpride potentiated the action of RB101 and this effect seemed to be restricted to behavioral responses induced by opioids acting on delta-opioid receptors (locomotor activity and forced swim test). This was confirmed by the use of the selective delta-opioid receptor agonist, (+)-4-[alpha-R*)-alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80; 2.5mg/kg, i.p.), and antagonist, naltrindole (5mg/kg, i.p.). Considering the involvement of delta-opioid receptors in mood regulation, the interaction between amisulpride and RB101 could lead to a new therapeutic approach in the treatment of some mood disorders.     

Sertraline behavioral response associates closer and dose-dependently with cortical rather than hippocampal serotonergic activity in the rat forced swim stress

The rat Forced Swim Test (FST) is widely used to investigate the response to antidepressant treatment. Selective serotonin reuptake inhibitors (SSRIs) elongate swimming duration during the FST, while climbing duration is unaffected. In the present study, we aimed to correlate behavioral effects of the SSRI sertraline in the FST with respective changes in the serotonergic activity of the hippocampus and the prefrontal cortex. Male rats were subjected to the standard FST (two swim sessions in two consecutive days) and between the two sessions they received three i.p. injections of sertraline (10mg/kg or 40mg/kg) or vehicle. All rats were killed immediately after the second FST session. Unstressed animals received the same administration schemes and were killed in equivalent time-points. Serotonin and its metabolite 5-HIAA were assayed in the hippocampus and the prefrontal cortex with the use of high-performance liquid chromatography (HPLC-ED) and their ratio 5-HIAA/5-HT was calculated. Sertraline enhanced swimming and decreased immobility duration at both doses. Serotonergic activity was not altered by the 2-day swim stress in either brain region, while subchronic sertraline treatment enhanced 5-HT levels and decreased 5-HIAA/5-HT in the hippocampus and the prefrontal cortex. The serotonin turnover rate (5-HIAA/5-HT ratio) decrease is probably indicative of reduced 5-HT metabolism, as a result of 5-HT reuptake inhibition. This effect was significant in the prefrontal cortex of unstressed rats only after a higher dose of sertraline. In the prefrontal cortex, but not in the hippocampus, immobility duration was negatively correlated with 5-HT tissue levels, whereas swimming duration was positively correlated with 5-HT. These results indicate that after antidepressant treatment, behavior during the FST can be predictive of respective serotonergic changes, especially in the prefrontal cortex.