Antidepressant-like effects of auraptenol in mice.

Depression is a major psychiatric disorder affecting nearly 21% of the world population and imposes a substantial health burden on society. Current available antidepressants are not adequate to meet the clinical needs. Here we report that auraptenol, an active component of the traditional Chinese medicine, angelicae dahuricae radix, had antidepressant-like effects in mice models of depression. In mouse forced swimming test and tail suspension test, two validated models of depression, auraptenol dose-dependently decreased the immobility duration within the dose range of 0.05-0.4 mg/kg. In addition, the antidepressant-like effects of auraptenol was significantly averted by a selective serotonin 5-HT1A receptor antagonist WAY100635 (1 mg/kg). These doses that affected the immobile response did not affect locomotor activity. In summary, this study for the first time identified an active component from the herbal medicine angelicae dahuricae radix that possesses robust antidepressant-like efficacy in mice. These data support further exploration for the possibility of developing auraptenol as a novel antidepressant agent in the treatment of major depression disorders.

Involvement of NMDA and AMPA receptors in the antidepressant-like activity of antidepressant drugs in the forced swim test.

BACKGROUND: The involvement of glutamate system (particularly the NMDA and AMPA receptors) in the mechanism of antidepressant activity was demonstrated in preclinical and clinical studies. METHODS: In the present study, we investigated the effect of NMDA and AMPA receptors' ligands (agonists and antagonists) on the antidepressant-like activity of escitalopram, milnacipran, imipramine and reboxetine in the forced swim test in mice. RESULTS: Antidepressant activity (reduction in immobility time) of escitalopram and milnacipran but not of imipramine and reboxetine was antagonized by N-methyl-D-aspartate acid. CGP37849 (antagonist of the NMDA receptor) enhanced the antidepressant activity of all examined antidepressants. On the other hand, CX614 (a potentiator/positive allosteric modulator of the AMPA receptor) enhanced the antidepressant activity of imipramine and reboxetine but not of escitalopram and milnacipran in this test. NBQX (the AMPA receptor antagonist) did not influence the antidepressant activity of all tested agents. CONCLUSIONS: The data indicate the complex interactions following the activation or blockade of the NMDA and AMPA receptors with antidepressant drugs. The general phenomenon is the enhancing effect of the NMDA receptor antagonism on the antidepressant activity. Moreover, is can be concluded that the activity of antidepressants with a serotonergic mechanism of action can be inhibited by NMDA activation, while antidepressants with a noradrenergic mechanism of action are dependent on AMPA receptor transmission.

Captodiamine, a putative antidepressant, enhances hypothalamic BDNF expression in vivo by synergistic 5-HT2c receptor antagonism and sigma-1 receptor agonism.

The putative antidepressant captodiamine is a 5-HT2c receptor antagonist and agonist at sigma-1 and D3 dopamine receptors, exerts an anti-immobility action in the forced swim paradigm, and enhances dopamine turnover in the frontal cortex. Captodiamine has also been found to ameliorate stress-induced anhedonia, reduce the associated elevations of hypothalamic corticotrophin-releasing factor (CRF) and restore the reductions in hypothalamic BDNF expression. Here we demonstrate chronic administration of captodiamine to have no significant effect on hypothalamic CRF expression through sigma-1 receptor agonism; however, both sigma-1 receptor agonism or 5-HT2c receptor antagonism were necessary to enhance BDNF expression. Regulation of BDNF expression by captodiamine was associated with increased phosphorylation of transcription factor CREB and mediated through sigma-1 receptor agonism but blocked by 5-HT2c receptor antagonism. The existence of two separate signalling pathways was confirmed by immunolocalisation of each receptor to distinct cell populations in the paraventricular nucleus of the hypothalamus. Increased BDNF induced by captodiamine was also associated with enhanced expression of synapsin, but not PSD-95, suggesting induction of long-term structural plasticity between hypothalamic synapses. These unique features of captodiamine may contribute to its ability to ameliorate stress-induced anhedonia as the hypothalamus plays a prominent role in regulating HPA axis activity.

The effects of mGlu7 receptor modulation in behavioural models sensitive to antidepressant action in two mouse strains.

There is increasing evidence suggesting a role of the neurotransmitter glutamate in depression. The metabotropic glutamate (mGlu) receptors are G-protein coupled receptors, which mediate a slow modulatory response to glutamate signalling. mGlu7 receptor is a presynaptic inhibitory autoreceptor showing great promise as a potential therapeutic target for the treatment of depression. Selective pharmacological modulators of mGlu7 receptor have been developed; the positive allosteric modulator AMN082 and the negative modulator 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one hydrochloride (MMPIP). They remain to be extensively characterized in behavioural models sensitive to antidepressant action. Therefore, we assessed the effects of these compounds on behaviour in two different mouse strains using several preclinical tests sensitive to antidepressant pharmacological action. AMN082 (6 mg/kg) reduced immobility in the forced swim test and tail suspension test (TST) in both C57BL/6j and CD1 mice. In CD1 mice, MMPIP (10 and 30 mg/kg) significantly increased the time spent immobile in the TST, whereas this effect was restricted to a dose of 30 mg/kg in C57BL/6j mice. Administration of MMPIP with AMN082 partially attenuated the antidepressant-like effect of AMN082 in C57BL/6j mice in the forced swim test and the TST. However, this effect was absent from the CD1 strain. This further adds to the growing corpus of data promoting the targeting of mGlu7 receptor with the aim of achieving an antidepressant effect.

Antidepressant-like effect of bis-eugenol in the mice forced swimming test: evidence for the involvement of the monoaminergic system.

Dehydrodieugenol, known as bis-eugenol, is a eugenol ortho dimer, and both compounds were able to exhibit anti-inflammatory and antioxidant activities in previous studies. Furthermore, eugenol showed antidepressant-like effect; however, the biological actions of bis-eugenol on experimental models for screening antidepressant activity are still unknown. The present study investigated a possible antidepressant-like activity of bis-eugenol in the forced swimming test (FST) and tail suspension test (TST) in mice and the involvement in the monoaminergic system in this effect. In addition, a neurochemical analysis on brain monoamines of mice acutely treated with bis-eugenol was also conducted. Bis-eugenol decreased the immobility time in the FST and TST without accompanying changes in ambulation in the open field test at 10 mg/kg, i.p.. Nevertheless, it induced ambulation at 25 and 50 mg/kg doses. The anti-immobility effect of bis-eugenol (10 and 50 mg/kg, i.p.) was prevented by pretreatment of mice with p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, for four consecutive days), yohimbine (1 mg/kg, i.p., an α2-adrenoceptor antagonist), SCH23390 (15 µg/kg, s.c., a dopamine D1 receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist). Monoamines analysis using high-performance liquid chromatograph revealed significant increase in the 5-HT, NE and DA levels in brain striatum. The present study indicates that bis-eugenol possesses antidepressant-like activity in FST and TST by altering dopaminergic, serotonergic and noradrenergic systems function.

Participation of estrogen receptors in the antidepressant-like effect of prolame on the forced swimming test.

Estrogen therapy may produce antidepressant-like actions, but the side effects, such as thromboembolic events, may restrict its use among women. The 17ß-aminoestrogens (AEs) [prolame [17ß-(3-hidroxy-1-propylamino)-1,3,5(10)-estratrien-3-ol)], butolame [17ß-(3-hidroxy-1-butylamino)-1,3,5(10)-estratrien-3-ol)], and pentolame [17ß-(5-hidroxy-1-pentylamino)-1,3,5(10)-estratrien-3-ol)] induce estrogenic and anticoagulant actions, effects that could prove advantageous in an estrogen therapy; however, their antidepressant-like effects have not been described. The objective of this study was to determine the effect of these 17ß-AEs (prolame, butolame and pentolame) in the forced swimming test (FST), an animal model sensitive to antidepressant drugs, and to establish the role of estrogen receptors in such actions. Ovariectomized female rats treated with prolame (10-200 µg/rat) showed a reduction in immobility and an increase in active behaviors in the FST, while this effect was not produced by butolame and pentolame (10-200 µg/rat). The antidepressant-like effect of prolame was similar to that of 17ß-estradiol (E2, 5-20 µg/rat), sharing with it a biphasic profile but at higher doses. Antidepressant-like actions of prolame and E2 were not associated with changes in locomotor activity. With respect to a control group tamoxifen (15 mg/kg) by itself produced no changes in all behavioral evaluations, but canceled the antidepressant-like effect of prolame and E2. It is concluded that estrogen receptors participate in antidepressant-like effect of both estrogens in the FST. Antidepressant-like activity of different AEs is discussed considering their differences in chemical structure and the schedule used. Our results show additional central actions of prolame besides its pro-sexual, anti-coagulant, estrogenic and anxiolytic activity.

Antidepressant-like effect of the novel MAO inhibitor 2-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in mice.

Monoamine oxidase (MAO) inhibitors were the first antidepressant drugs to be prescribed and are still used today with great success, especially in patients resistant to other antidepressants. In this study, we evaluated the MAO inhibitory properties and the potential antidepressant action of 2-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in mice. We found that 2-DMPI inhibited both MAO isoforms (K(i) values were 1.53 (1.3-1.8) µM and 46.67 (31.8-68.4) µM for MAO-A and MAO-B, respectively) with 30-fold higher selectivity toward MAO-A. In relation to the nature of MAO-A inhibition, 2-DMPI showed to be a mixed and reversible inhibitor. The treatment with 2-DMPI (100-1000 µmol/kg, s.c.) caused a significant decrease in immobility time in the tail suspension test (TST) without affecting locomotor activity, motor coordination or anxiety-related activities. Conversely, moclobemide (1000 µmol/kg, s.c.) caused a significant increase in immobility time in the TST, which appeared to be mediated by a nonspecific effect on motor coordination function. 2-DMPI (300 µmol/kg, s.c.) decreased serotonin turnover in the cerebral cortex, hippocampus and striatum, whereas dopamine turnover was diminished only in the striatum, and norepinephrine turnover was not changed. The antidepressant-like effect of 2-DMPI was inhibited by the pretreatment of mice with methysergide (2 mg/kg, s.c., a non-selective serotonin receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) or haloperidol (0.05 mg/kg, i.p., a non-selective dopamine receptor antagonist). These results suggest that 2-DMPI is a prototype reversible and preferential MAO-A inhibitor with potential antidepressant activity, due to its modulatory effect on serotonergic and dopaminergic systems.

AMPA glutamate receptors mediate the antidepressant-like effects of N-acetylcysteine in the mouse tail suspension test.

The aim of this study was to investigate the involvement of noradrenaline, serotonin, and subtypes of glutamate receptors in the antidepressant-like effects of N-acetylcysteine (NAC). The tail suspension test was used with male CF1 albino mice. D,L-α-methyl-ρ-tyrosine and ρ-chlorophenylalanine methyl ester hydrochloride were used as synthesis inhibitors of noradrenaline and serotonin, respectively. N-methyl-D-aspartate (NMDA) and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione were used as an NMDA receptor agonist and an α-amino acid-3-hydroxy-5-methyl-4-isoxazol propionic acid (AMPA) receptor antagonist, respectively. NAC (10, 25, and 50 mg/kg intraperitoneally) significantly (P<0.05) decreased tail suspension test immobility time, whereas pretreatment with D,L-α-methyl-ρ-tyrosine, ρ-chlorophenylalanine methyl ester hydrochloride, and NMDA partially prevented (P<0.05) the effects of NAC (25 mg/kg), and pretreatment with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione completely abolished (P<0.01) this effect. The study corroborates the antidepressant-like effects of NAC in the TST, a model with a well-established predictive value. The results point to the key role of AMPA receptors in the mechanism of the antidepressant-like action of NAC. Like other AMPA potentiators, NAC indirectly modulates noradrenaline and serotonin pathways. It is suggested that the value of NAC as an antidepressant arises from combined and intertwined effects on a variety of pathways.

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 100mg/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 (50mg/kg, p.o.) was completely prevented by the pretreatment of mice with WAY 100635 (0.1mg/kg, s.c., a serotonin 5-HT(1A) receptor antagonist), cyproheptadine (3mg/kg, i.p., a serotonin 5-HT(2) receptor antagonist), prazosin (62.5µg/kg, i.p., an α(1)-adrenoceptor antagonist), SCH23390 (0.05mg/kg, s.c., a dopamine D(1) receptor antagonist) or sulpiride (50mg/kg, i.p., a dopamine D(2) receptor antagonist). On the other hand, the pretreatment of mice with yohimbine (1mg/kg, i.p., an α(2)-adrenoceptor antagonist) or propranolol (5mg/kg, i.p., a ß-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.

Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis.

There is a well-established connection between smoking and depression. Depressed individuals are over-represented among smokers, and ex-smokers often experience increased depressive symptoms immediately after stopping smoking. Nicotine in tobacco binds, activates and desensitizes nicotinic acetylcholine receptors (nAChRs), but it is not known whether activation or desensitization is more important for the effects of nicotine on depressive symptoms. Here we review, based on clinical and preclinical studies of nicotinic drugs, the hypothesis that blockade (rather than activation) of neuronal nAChRs might be important for the effects of nicotinic agents on depressive symptoms. The endogenous neurotransmitter for nAChRs is acetylcholine, and the effects of nicotine on depression-like behaviors support the idea that dysregulation of the cholinergic system might contribute to the etiology of major depressive disorder. Thus, pharmacological agents that limit acetylcholine signaling through neuronal nAChRs might be promising for the development of novel antidepressant medications.

Antidepressant-like effects of neferine in the forced swimming test involve the serotonin1A (5-HT1A) receptor in mice.

The effects of neferine, an alkaloid of Nelumbo nucifera Gaertner embryos, on immobility in the forced swimming test, which is used to evaluate antidepressants, were investigated in mice. The administration of neferine from 25 to 100 mg/kg i.p. elicited anti-immobility effects in mice. The molecular dose effects of neferine in the forced swimming test were almost equal to those of the typical antidepressants maprotiline and imipramine. The involvement of the 5-HT receptor subtypes was also studied using 5-HT receptor antagonists. Anti-immobility effects of neferine are antagonized by the serotonin1A (5-HT1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY 100635). However, the 5-HT1B receptor antagonist, 3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl] benzamide dihydrochloride (GR 55562), the 5-HT2 receptor antagonist, 6-methyl-1-(methylethyl)-ergoline-8beta-carboxylic acid 2-hydroxy-1-methylpropyl ester (LY 53857), the 5-HT3 receptor antagonist, ondansetron and the 5-HT4 receptor antagonist, 4-amino-5-chloro-2-methoxy-benzoic acid 2-(diethylamino)ethyl ester (SDZ 205,557) did not affect the anti-immobility effects of neferine. The anti-immobility effect of the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetaralin (8-OH-DPAT) was also antagonized by WAY 100635. Furthermore, co-administration of subactive doses of neferine (10 mg/kg) and 8-OH-DPAT (0.1 mg/kg) produced synergistic antidepressant-like effects. These results suggest that neferine shows antidepressant-like effects in mice similar to typical antidepressants and that these effects are mediated by the 5-HT1A receptor. Therefore, the central effects of neferine are likely to be linked to serotonergic neurotransmission.

Dopamine is involved in the antidepressant-like effect of allopregnanolone in the forced swimming test in female rats.

Evidence from both animal and human studies suggests a role for dopamine in the therapeutic effect of antidepressant drugs. Consistently, dopamine receptor antagonists antagonize the effect of antidepressant drugs in different experimental models of depression. Neurosteroids, and in particular allopregnanolone, seem to be involved both in the pathophysiology of depression and in the mechanism of action of antidepressant drugs, and their role seems to be particularly important in the understanding of mood disturbances related to the different phases of the reproductive life in women. The aim of this study was to investigate the possible role of dopamine on the antidepressant-like effect of allopregnanolone in a model of depression. Thus, we examined (i) the behaviour of female Sprague-Dawley rats in the forced swimming test during estrus and diestrus and their response to allopregnanolone treatment (0.5, 1 and 2 mg/kg), and (ii) the effect of the dopamine D1-like and D2-like receptor antagonists SCH 23390 (0.01 and 0.025 mg/kg) and raclopride (0.05 and 0.2 mg/kg) on the antidepressant-like effect of allopregnanolone (2 mg/kg) in the same experimental model. We failed to observe differences in depressive-like behaviour between estrous phases, and allopregnanolone administration in both estrus and diestrus resulted in an antidepressant-like effect consisting in an increase of swimming behaviour. The allopregnanolone effect was unaffected by a dose of the dopamine D1-like receptor antagonist SCH 23390 displaying a marked inhibitory effect on basal activity, while it was turned into a potentiation of the depressive-like behaviour of the forced swimming condition by treatment with the higher dose of raclopride. The present results indicate an involvement of dopamine transmission in the allopregnanolone antidepressant-like effect in the forced swimming model of depression, and suggest that this effect depends mainly on stimulation of dopamine D2-like receptors.

Eficacia comparada de los antidepresivos actuales: el papel de bupropión / Efficacy of the current antidepressants: the role of bupropion

El hallazgo fortuito de los precursores de dos de las familias más importantes de sustancias antidepresivas a finales de la década de 1950, iproniazida (inhibidores de la monoaminooxidasa, IMAO) e imipramina (antidepresivos tricíclicos, ATC), sirvieron como base al desarrollo de numerosos fármacos antidepresivos. Durante décadas, las diferencias conocidas entre los distintos agentes se han limitado, por lo general, a aspectos de seguridad y tolerabilidad. Este hecho se ha debido en gran medida a que la mayoría de los estudios comparativos sobre eficacia con antidepresivos estaban diseñados para detectar diferencias comparativamente grandes, de manera que las diferencias más sutiles que existen entre las diferentes clases de fármacos empleados habitualmente como fármacos de primera elección en el tratamiento de la depresión, como los inhibidores selectivos de la recaptación de serotonina(ISRS), inhibidores de la recaptación de noradrenalina y serotonina (IRNS) y el inhibidor de la recaptación de dopamina y noradrenalina (IRDN) bupropión, no se exploraban de forma adecuada. Teóricamente esta limitación puede superarse a través de la utilización simultánea de datos procedentes de diferentes ensayos mediante técnicas de análisis combinado y metaanálisis. De hecho, la acumulación de datos procedentes de ensayos clínicos aleatorizados, doble ciego, comparando la eficacia de distintas sustancias antidepresivas en el tratamiento del trastorno depresivo mayor (TDM) ha hecho posible la búsqueda de diferencias entre fármacos. En la revisión que presentamos a continuación se efectuará una descripción de los estudios combinados y de metaanálisis con antidepresivos en el TDM más recientes, junto con una valoración más detallada de los estudios que evalúan la eficacia comparativa de bupropión, un IRDN recientemente introducido en España, frente a otros fármacos antidepresivos para el tratamiento de la depresión mayor (AU)

The serendipitous discovery of the precursors of two of the major contemporary antidepressant families during the late 1950's, iproniazid for the monoamine oxidase inhibitors (MAOI) and imipramine for the tricyclic antidepressants (TCA), has guided the subsequent development of numerous antidepressant drugs. For decades, known differences among these agents have, generally, been limited to aspects of safety and tolerability. This, in part, has been due to the fact that most antidepressant comparator trials, while adequately powered to show large efficacy differences, are not large enough to detect more subtle differences in efficacy that may exist among common, first-line antidepressant drugs including the selective serotonin reuptake inhibitors (SSRIs), serotonin- norepinephrine reuptake inhibitors (SNRIs), and the norepinephrine-dopamine reuptake inhibitor (NDRI) bupropion. This limitation could be overcome by combining data from individual trials with the use of pooled analyses and meta-analyses. In fact, the progressive accumulation of data from randomized, double-blind, antidepressant-comparator trials in major depressive disorder (MDD) has now made it possible to examine for potential differences among antidepressant agents. In the following review, we will briefly present an overview of such meta and pooled analyses of antidepressants in MDD, followed by a more focused description of studies focusing on describing the relative (to other newer antidepressants) efficacy of the NDRI bupropion in MDD which as recently approved in Spain for the treatment of MDD (AU)

The neuropeptide VGF produces antidepressant-like behavioral effects and enhances proliferation in the hippocampus.

Brain-derived neurotrophic factor (BDNF) is upregulated in the hippocampus by antidepressant treatments, and BDNF produces antidepressant-like effects in behavioral models of depression. In our previous work, we identified genes induced by BDNF and defined their specific roles in hippocampal neuronal development and plasticity. To identify genes downstream of BDNF that may play roles in psychiatric disorders, we examined a subset of BDNF-induced genes also regulated by 5-HT (serotonin), which includes the neuropeptide VGF (nonacronymic). To explore the function of VGF in depression, we first investigated the expression of the neuropeptide in animal models of depression. VGF was downregulated in the hippocampus after both the learned helplessness and forced swim test (FST) paradigms. Conversely, VGF infusion in the hippocampus of mice subjected to FST reduced the time spent immobile for up to 6 d, thus demonstrating a novel role for VGF as an antidepressant-like agent. Recent evidence indicates that chronic treatment of rodents with antidepressants increases neurogenesis in the adult dentate gyrus and that neurogenesis is required for the behavioral effects of antidepressants. Our studies using [(3)H]thymidine and bromodeoxyuridine as markers of DNA synthesis indicate that chronic VGF treatment enhances proliferation of hippocampal progenitor cells both in vitro and in vivo with survival up to 21 d. By double immunocytochemical analysis of hippocampal neurons, we demonstrate that VGF increases the number of dividing cells that express neuronal markers in vitro. Thus, VGF may act downstream of BDNF and exert its effects as an antidepressant-like agent by enhancing neurogenesis in the hippocampus.

Prevention of pro-depressant effect of L-arginine in the forced swim test by NG-nitro-L-arginine and [1H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one].

Previous studies have shown that l-arginine, the precursor of nitric oxide, has a dual effect (antidepressant and pro-depressant) in the forced swim test. The aim of the present study was to investigate whether nitric oxide-cGMP pathway was involved in this dual effect. Porsolt swim test was conducted to resemble the symptomatology of major depressive disorder. An open field locomotor activity test was also used. L-arginine exerted a U-shape effect in the forced swim test: doses of 30, 100, 300, and 1000 mg/kg caused no alteration, statistically significant reduction, no alteration, and non-significant enhancement, respectively. Neither N(G)-nitro-L-arginine (NNA) nor [1H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one] (ODQ) at doses of 3 mg/kg was found to be effective in the forced swim test, whereas 10 mg/kg ODQ significantly reduced the immobility time. In the presence of NNA, the antidepressant and pro-depressant effects of L-arginine disappeared, however, only the pro-depressant component of l-arginine effect was prevented by ODQ (3 and 10 mg/kg). Saline, the solvent of L-arginine and NNA, and dimethyl sulfoxide (15% in saline), the solvent of ODQ, had no effect on the duration of immobility. None of the drugs or solvents used in the present study had any effect on locomotor activity over the dose range applied. The results show that L-arginine exerts its paradoxical effects by producing nitric oxide and that cGMP seems to have a role only in the pro-depressant component.

Biphasic effects of losartan potassium on immobility in mice.

The effects of losartan potassium, an angiotensin AT(1) receptor blocker on immobility in forced swim test have been studied. Effect of losartan potassium, nortriptyline HCl, fluoxetine HCl and reserpine per se and in combination on forced swimming-induced immobility in mice have also been studied. In mice, losartan potassium elicits biphasic responses i.e. positive responses at lower doses (0.1, 1.0 and 5 mg/kg, i.p.) in the forced swim test, a test of potential antidepressant activity and vice versa at higher dose (20 and 100 mg/kg, i.p.). In chronic studies, enhancement in immobility was observed for losartan potassium (3 and 30 mg/kg, p.o., 21 days). In acute combination studies, losartan potassium (1 and 5 mg/kg) significantly reversed the reserpine-induced immobility, but vice versa at 100 mg/kg. Losartan potassium (0.1 and 5 mg/kg) potentiate antidepressant activity of nortriptyline (30 mg/kg, i.p.) in mice, but vice versa at 100 mg/kg. Likewise, Losartan potassium (100 mg/kg), significantly reversed antidepressant activity of fluoxetine HCl, but at 0.1 and 5 mg/kg, failed to modify fluoxetine HCl induced immobility. The obtained biphasic effect of losartan potassium on immobility in mice might be due to inhibitory effect on AT(1) receptor at lower dose and pronounced effect on AT(2) receptor at higher dose (large concentrations of losartan potassium can displace Angiotensin II (Ang II) from its AT(1) receptor to AT(2) receptor.

Gender differences in clinical presentation and response to sertraline treatment of generalized anxiety disorder.

OBJECTIVE: To evaluate gender differences in the clinical presentation of generalized anxiety disorder (GAD) and response to sertraline treatment. METHODS: Adult outpatients who met DSM-IV criteria for GAD with a minimum Hamilton rating scale for anxiety (HAM-A) total score>or=18 were randomized to 12 weeks of double-blind treatment with flexible doses (50-150 mg) of sertraline (n=182; female, 59%) or placebo (n=188; female, 51%). RESULTS: Clinical presentation of GAD was very similar in men and women in terms of the severity of the HAM-A psychic factor, severity of concomitant depression symptoms, duration of GAD, quality of life and impairment in physical health. Women had an earlier age of onset and higher HAM-A somatic factor scores compared with men. For both men and women, treatment with sertraline resulted in greater change from baseline to endpoint on the HAM-A compared with placebo (adjusted change+/-SE: men:-12.1+/-0.9 vs -8.8+/-0.9; women: -11.4+/-0.8 vs -7.1+/-0.9, p<0.001); the interaction between gender and treatment group was not significant, nor was there a significant difference between the average change from baseline for men compared with women. Similarly, responder rates based upon clinical global impression-improvement (CGI-I) scores at endpoint showed no significant interaction between gender and treatment, nor was there a significant difference in the response rates by gender; however, the response rate of sertraline compared with placebo was significantly different (p<0.0001) (men: 64% vs 40%; women: 62% vs 34%). Similar findings were evident at week 4 assessment and for completers (week 12). Overall, sertraline was well tolerated by both men and women. DISCUSSION: Women and men with GAD showed similar clinical presentations, with the exception that women had an earlier age of onset and reported more somatic anxiety symptoms. Sertraline was an effective and well tolerated treatment for GAD in both men and women.

Corticosterone attenuates the antidepressant-like effects elicited by melatonin in the forced swim test in both male and female rats.

Melatonin has been demonstrated to increase activity in the forced swim test (FST), a putative model of antidepressant efficacy, indicating that it may possess antidepressant-like qualities. It has been suggested that corticosterone can interfere with the efficacy of antidepressants, an effect that has previously been demonstrated in the FST. This experiment examined the effects of melatonin and corticosterone, independently and in combination, on the behaviours of both male and female rats in the FST. Corticosterone, melatonin, combined vehicles or a combined melatonin/corticosterone regimen were administered for 20 days, after which the animals were observed in the FST. As seen in previous research, melatonin elicited an antidepressant-like effect in the FST by reducing immobile behaviour (P<.01) and increasing active behaviour (P<.01). Corticosterone was found to reduce activity (P<.01) and increase immobility (P<.01), as well as attenuate the anti-immobility effects of melatonin (P=.03). These findings suggest that while melatonin may possess antidepressant-like qualities, high levels of corticosterone seem capable of attenuating these effects.

Galanin attenuates basal and antidepressant drug-induced increase of extracellular serotonin and noradrenaline levels in the rat hippocampus.

Galanin is co-localized with classical neurotransmitters, such as acetylcholine, serotonin (5-HT) and noradrenaline (NA) in neurons or in brain regions implicated in cognitive and affective behaviour. In the present study, the effects of galanin on extracellular 5-HT and NA levels in the rat hippocampus were measured by in vivo microdialysis under basal conditions and following systemic administration of antidepressant drugs. Galanin (1.5 nmol i.c.v.) reduced basal 5-HT and NA levels to 65% and 86% of controls, respectively. Galanin (0.5 and 1.5 nmol i.c.v.) dose-dependently attenuated the elevation of 5-HT concentrations induced by imipramine and citalopram (10 mg/kg i.p., each) from 350% to 312% and from 230% to 160%, respectively. Galanin at 1.5 nmol transiently attenuated the effect of desipramine-induced (10 mg/kg i.p.) increase in extracellular NA levels from a maximal increase of 389-296% of the predrug levels. It is concluded that intraventricularly administered galanin attenuated both basal 5-HT and NA release and antidepressant drug-induced accumulation of extracellular 5-HT and NA levels most likely via a predominant inhibitory action on serotonergic and noradrenergic neurons in the raphe and locus coeruleus, respectively. These results further emphasize a possible role of galanin in regulation of 5-HT and NA neurotransmission in depressive states and during the course of antidepressant therapy.

An investigation of monoamine receptors involved in antinociceptive effects of antidepressants.

UNLABELLED: We attempted to determine which monoamine receptor subtypes are predominantly involved in antidepressant-induced antinociception. Antinociceptive effects were evaluated by using formalin tests with rats. Antidepressants acting as potent inhibitors of norepinephrine reuptake (nisoxetine, nortriptyline, and maprotiline) or inhibiting reuptake of both norepinephrine and serotonin (5-HT) (imipramine and milnacipran) induced dose-dependent antinociception. Simultaneous intraperitoneal administration of antidepressants and either prazosin (alpha(1) antagonist) or ketanserin (5-HT(2) antagonist) significantly antagonized antinociceptive effects. Fluvoxamine (selective serotonin reuptake inhibitor) induced antinociception less potently than other antidepressants and was significantly antagonized by ketanserin, but not prazosin. Ondansetron (5-HT(3) antagonist) significantly antagonized antinociception by 10 mg/kg of imipramine. In contrast, SDZ-205,557 (5-HT(4) antagonist) markedly enhanced antinociception by small-dose (2.5 mg/kg) imipramine. Imipramine-induced antinociception was significantly antagonized by intracerebroventricular administration of prazosin or ketanserin, but not by yohimbine (alpha(2) antagonist) or ondansetron, and was significantly enhanced by intracerebroventricularly administered SDZ-205,557. These findings suggest that alpha(1) adrenoceptors and 5-HT(2) receptors in the brain are involved in antidepressant-induced antinociception. In addition, the results suggested functional interactions between noradrenergic and serotonergic neurons as mechanisms for antidepressant-induced antinociception. IMPLICATIONS: Formalin tests of rats treated with antidepressants and antagonists of monoamine receptors indicate that alpha(1) adrenoceptors, serotonin (5-HT)(2) receptors, and 5-HT(3) receptors are involved in antidepressant-induced antinociception, suggesting functional interactions between noradrenergic and serotonergic neurons as mechanisms of antidepressant-induced antinociception.