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.     

Antidepressant-like activity of methyl jasmonate involves modulation of monoaminergic pathways in mice

Purpose

The efficacy of current antidepressant drugs has been compromised by adverse effects, low remission and delay onset of action necessitating the search for alternative agents. Methyl jasmonate (MJ), a bioactive compound isolated from Jasminum grandiflorum has been shown to demonstrate antidepressant activity but its mechanism of action remains unknown. Thus, the role of monoaminergic systems in the antidepression-like activity of MJ was investigated in this study.

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 stimulatory effects of caffeine with oseltamivir (Tamiflu) on light–dark behavior and open-field behavior in mice

Abnormal behaviors and death associated with the use of oseltamivir (Tamiflu^®) have emerged as a major issue in influenza patients taking the drug. Here, we investigated the mechanisms underlying the effects of oseltamivir on the behavior of mice using light–dark and open-field preference tests. Oseltamivir (75 and 150 mg/kg, intraperitoneally (i.p.)) alone affected neither time spent in the open area in the light–dark preference test nor ambulation in the open-field test at 2 h post-injection. However, a non-selective adenosine A₁/A₂ receptor antagonist, caffeine (10 mg/kg, i.p.) in combination with oseltamivir (150 mg/kg, i.p.) increased time spent in the open area in the light–dark preference test. This enhancement was not inhibited by a benzodiazepine receptor antagonist, flumazenil (10–20 mg/kg, subcutaneously (s.c.)). Enhancement of ambulation in the open-field test was also observed when caffeine (10 mg/kg, i.p.) was combined with oseltamivir (150 mg/kg, i.p.). This enhancement was inhibited by a dopamine D₂ receptor antagonist, haloperidol (0.1 mg/kg, s.c.). Furthermore, an adenosine A₂ receptor antagonist, SCH58261 (3 mg/kg, i.p.) in combination with oseltamivir (150 mg/kg, i.p.) increased ambulation in the open-field test, while an adenosine A₁ receptor antagonist, DPCPX (1–3 mg/kg, i.p.) did not. These findings suggest that the actions of oseltamivir may involve the dopamine and adenosine systems. Our findings suggest that due to the interaction between central blockade of adenosine A₂ receptors by caffeine, and oseltamivir-induced behavioral changes, patients being treated with oseltamivir should be closely monitored.     

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.     

Antidepressant-like effect of Hoodia gordonii in a forced swimming test in mice: evidence for involvement of the monoaminergic system

Hoodia gordonii is a plant species used traditionally in southern Africa to suppress appetite. Recently, it has been associated with a significant increase in blood pressure and pulse rate in women, suggesting sympathomimetic activity. The present study investigated the possible antidepressant-like effects of acute and repeated (15 days) administration of H. gordonii extract (25 and 50 mg/kg, po) to mice exposed to a forced swimming test (FST). Neurochemical analysis of brain monoamines was also carried out to determine the involvement of the monoaminergic system on these effects. Acute administration of H. gordonii decreased the immobility of mice in the FST without accompanying changes in general activity in the open-field test during acute treatment, suggesting an antidepressant-like effect. The anti-immobility effect of H. gordonii was prevented by pretreatment of mice with PCPA [an inhibitor of serotonin (5-HT) synthesis], NAN-190 (a 5-HT_1A antagonist), ritanserin (a 5-HT_2A/2C antagonist), ondansetron (a 5-HT3_A antagonist), prazosin (an α1-adrenoceptor antagonist), {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390 (a D₁ receptor antagonist), yohimbine (an α2-adrenoceptor antagonist), and sulpiride (a D₂ receptor antagonist). A significant increase in 5-HT levels in the striatum was detected after acute administration, while 5-HT, norepinephrine and dopamine were significantly elevated after chronic treatment. Results indicated that H. gordonii possesses antidepressant-like activity in the FST by altering the dopaminergic, serotonergic, and noradrenergic systems.     

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.     

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.     

Central 5-HT3 receptor-induced hypothermia in mice: Interstrain differences and comparison with hypothermia mediated via 5-HT1A receptor

The selective agonist of serotonin 5-HT₃ receptor 1-(3-chlorophenyl)biguanide hydrochloride (m-CPBG) administered intracerebroventricularly (40, 80 or 160 nmol) produced long-lasting dose-dependent hypothermic response in AKR/2J mice. m-CPBG (160 nmol i.c.v.) induced profound hypothermia (delta t = −4 °C) that lasted up to 7 h. m-CPBG (40 nmol i.c.v.)-induced hypothermia was attenuated by 5-HT₃ receptor antagonist ondansetron pretreatment. At the same time, intraperitoneal administration of m-CPBG in a wide range of doses (0.5, 1.0, 5.0 or 10.0 mg/kg) did not affect the body temperature. These findings indicate: (1) the implication of central, rather than peripheral 5-HT₃ receptor in the thermoregulation; (2) the inability of m-CPBG to cross blood–brain barrier in mice. The comparison of brain 5-HT₃-induced hypothermic reaction in six inbred mouse strains (DBA/2J, CBA/Lac, C57BL/6, BALB/c, ICR, AKR/J) was performed and two highly sensitive to m-CPBG strains (CBA/Lac and C57BL/6) were found. In the same six mouse strains the functional activity of 5-HT_1A receptor was studied. The comparison of hypothermic reactions produced by 5-HT_1A receptor agonist 8-OH-DPAT (1.0 mg/kg i.p.) and m-CPBG revealed significant correlation between 5-HT₃ and 5-HT_1A-induced hypothermia in five out of six investigated mouse strains. 5-HT_1A receptor antagonist p-MPPI pretreatment (1 mg/kg i.p.) diminished hypothermia produced by centrally administered m-CPBG (40 nmol i.c.v.). The data suggest the cross-talk between 5-HT_1A and 5-HT₃ receptors in the mechanism of 5-HT-related hypothermia.     

Activation of α2-adrenoceptors in the lateral hypothalamus reduces pilocarpine-induced salivation in rats

Anti-hypertensive drugs that act on central α₂-adrenoceptors and imidazoline receptors usually cause dry mouth in patients. A central area important for the control of salivary secretion and also for the effects of α₂-adrenoceptor activation is the lateral hypothalamus (LH). Therefore, in the present study we investigated the effects of the injections of moxonidine (an α₂-adrenoceptor and imidazoline agonist) alone or combined with RX 821002 (α₂-adrenoceptor antagonist) into the LH on the salivation induced by intraperitoneal (i.p.) pilocarpine (cholinergic muscarinic agonist). Male Holtzman rats with stainless steel cannula implanted into the LH were used. Saliva was collected using pre-weighted small cotton balls inserted into the animal’s mouth under ketamine anesthesia. Salivation induced by i.p. pilorcarpine (4 μmol/kg of body weight) was reduced by the injection of moxonidine (10 and 20 nmol/0.5 μl) into the LH (222 ± 46 and 183 ± 19 mg/7 min, vs. vehicle: 480 ± 30 mg/7 min). The inhibitory effect of moxonidine on pilocarpine-induced salivation was abolished by prior injections of RX 821002 (160 and 320 nmol/0.5 μl) into the LH (357 ± 25 and 446 ± 38 mg/7 min). Injections of the α₁-adrenoceptor antagonist prazosin (320 nmol/0.5 μl) into the LH did not change the effects of moxonidine. The results show that activation of α₂-adrenoceptors in the LH inhibits pilocarpine-induced salivation, suggesting that LH is one of the possible central sites involved in the anti-salivatory effects produced by the treatment with α₂-adrenoceptor agonists.     

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.     

Sub-chronic administration of rimonabant causes loss of antidepressive activity and decreases doublecortin immunoreactivity in the mouse hippocampus

Rimonabant is a cannabinoid receptor 1 antagonist, and is used to treat anorexia and obesity. However, it has been suggested that rimonabant may act as a depressant. In the present study, we investigated the depressive effects of rimonabant using behavioral and biochemical methods. A single treatment with rimonabant (10 mg/kg, p.o.) reduced immobility duration in the forced swimming test (FST) to a level similar to that observed for the tricyclic antidepressant, imipramine (15 mg/kg, i.p.). However, mice treated with rimonabant for 2 weeks did not show any significant reductions in immobility duration versus vehicle-treated controls. To investigate why the antidepressant effect of rimonabant disappeared after extended treatment, we carried out 5-bromo-2-deoxyuridine (BrdU) and doublecortin (DCX) immunohistochemistry assay. Numbers of BrdU-immunoreactive cells were not significantly changed after administering rimonabant (10 mg/kg, p.o.) for 2 weeks in the hippocampal dentate gyrus (DG), but interestingly, numbers of DCX-immunopositive cells in the DG were significantly reduced after 2 weeks of rimonabant treatment at doses of 1 or 10 mg/(kg day) compared with vehicle-treated controls (P < 0.05). These results suggest that sub-chronic treatments with rimonabant inhibit cell proliferation in DG, and that a lack of antidepressive activity may be related to a reduction in cell proliferation in this region.     

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.     

Caffeine and a selective adenosine A(2B) receptor antagonist but not imidazoline receptor antagonists modulate antinociception induced by diphenyl diselenide in mice

The present study examined the antinociceptive effect of diphenyl diselenide (PhSe)2, given orally (p.o.), in the hot-plate test in mice. The administration of diphenyl diselenide (10-100 mg/kg, p.o.) caused a significant inhibition of thermal nociception induced by hot-plate test in mice. Pretreatment of animals by intraperitoneal route (i.p.) with caffeine (10 mg/kg; a non-specific adenosine receptor antagonist) and PSB1115 (1 mg/kg; an adenosine A(2B) receptor antagonist), but not DPCPX (2 mg/kg; an adenosine A(1) receptor antagonist) and SCH5826 (3 mg/kg; an adenosine A(2A) receptor antagonist) significantly blockaded the antinociceptive effect caused by diphenyl diselenide (10 mg/kg, p.o.) in the hot-plate test. Moreover, the pretreatment of animals with efaroxan (1 mg/kg, i.p.; a mixed I(1) imidazoline/alpha(2)-adrenoceptor antagonist) and idazoxan (3 mg/kg, i.p.; a mixed I(2) imidazoline/alpha(2)-adrenoceptor antagonist) did not significantly reverse the antinociception caused by oral administration of diphenyl diselenide (10 mg/kg, p.o.) in the hot-plate test. These results indicate that diphenyl diselenide produced antinociception in a thermal model of pain in mice and its effect was prevented by caffeine and by a selective adenosine A(2B) receptor, but not by imidazoline receptor antagonists in mice.     

Antidepressant-like effect of diphenyl diselenide on rats exposed to malathion: Involvement of NaK ATPase activity

The antidepressant-like effect of repeated administration of diphenyl diselenide (PhSe)₂ in rats exposed to malathion is reported. The role of Na⁺K⁺ ATPase, acetylcholinesterase (AChE) and monoamine oxidase (MAO) activities and oxidative stress in antidepressant behavior were investigated in cerebral cortex of rats. Rats were exposed once a day for 3 consecutive days to malathion (50 mg/kg, intraperitoneal) and (PhSe)₂ (50 mg/kg, oral). To investigate the antidepressant-like behavior rats were submitted to the forced swimming test (FST) and open-field test (OFT). Thiobarbituric acid reactive species (TBARS) levels, enzymatic and non-enzymatic antioxidant defenses were carried out in cerebral cortex of rats. The results confirmed that malathion increased immobility time in the FST without altering the locomotor performance in the OFT. Treatment with (PhSe)₂ ameliorated performance in the FST without altering the crossing numbers in the OFT. The inhibition of Na⁺K⁺ ATPase activity caused by malathion was prevented by treatment with (PhSe)₂. Exposure to malathion did not alter parameters of oxidative stress as well as AChE and MAO activities in cerebral cortex of rats. In conclusion, (PhSe)₂ exerted antidepressant-like effect in rats exposed to malathion. Na⁺K⁺ ATPase activity is, at least in part, involved in (PhSe)₂ antidepressant-like behavior.     

Role of different types of potassium channels and peroxisome proliferator-activated receptors γ in the antidepressant-like activity of bis selenide in the mouse tail suspension test

In the present study we investigated the role of potassium (K(+)) channels and peroxisome proliferator-activated receptor gamma (PPARγ) in the antidepressant-like effect of bis selenide in the mouse tail suspension test (TST). Intracerebroventricular (i.c.v.) pretreatment with tetraethyl ammonium (TEA, a non-specific inhibitor of K(+) channels, 25 pg/site), glibenclamide (an ATP-sensitive K(+) channel inhibitor, 0.5 pg/site), charybdotoxin (a large and intermediate conductance calcium-activated K(+) channel inhibitor, 25 pg/site) or apamin (a small-conductance calcium-activated K(+) channel inhibitor, 10 pg/site) produced a synergistic action with a sub effective dose of bis selenide (0.1 mg/kg, per oral--p.o.). Picrotoxin (1 mg/kg, intraperitoneally--i.p.) pretreatment did not prevent the reduction in immobility time elicited by bis selenide (1 mg/kg, p.o.) in the TST. The reduction in the immobility time elicited by an effective dose of bis selenide (1 mg/kg, p.o.) was prevented by the pretreatment of mice with cromakalim, minoxidil (K(+) channel openers, 10 μg/site, i.c.v.) and GW 9662 (a PPARγ antagonist, 10 μg/site, i.c.v.). The findings clearly suggest that an acute oral dose of bis selenide produced an antidepressant-like effect in the mouse TST by a mechanism that involves the K(+) channels and PPARγ receptors.     

Risperidone, an atypical antipsychotic enhances the antidepressant-like effect of venlafaxine or fluoxetine: possible involvement of alpha-2 adrenergic receptors

Clinical studies have reported the beneficial outcome of addition of lower doses of risperidone to antidepressant therapy specifically with selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depression. The present study, therefore, examined the beneficial effect, if any, of addition of risperidone (an atypical antipsychotic) to the antidepressant-like effect of venlafaxine (dual reuptake inhibitors of both serotonin and norepinephrine, SNRI) or fluoxetine (SSRI) in Porsolt's Forced Swim Test (FST) using male laca mice. Attempts have been made to study the involvement of alpha-2 adrenergic receptors in the mechanism of action. Immobility period was recorded for a period of 6 min. Venlafaxine (4 and 8 mg/kg, i.p.) or fluoxetine (10 and 20 mg/kg, i.p.) inhibited the immobility period in mice. Addition of risperidone (0.1 mg/kg, i.p.) potentiated the anti-immobility effect of either venlafaxine (4 and 8 mg/kg, i.p.) or fluoxetine (10 and 20 mg/kg, i.p.) in mouse FST. Furthermore, the anti-immobility effect of combination of risperidone (0.1 mg/kg, i.p) plus venlafaxine (4 mg/kg, i.p.) or fluoxetine (10 mg/kg, i.p.) was potentiated by the addition of yohimbine (2 mg/kg, i.p.), an alpha-2 adrenoceptors antagonist. The results of the present study suggest that the beneficial consequences of addition of risperidone with venlafaxine or fluoxetine in mouse forced swim test may involve alpha-2 adrenergic receptors.     

Orchiectomy modifies the antidepressant-like response of nicotine in the forced swimming test

Several studies have demonstrated that nicotine (NIC) exhibits antidepressant-like effects. In addition, it has been suggested that sexual hormones participate in the antidepressant actions of antidepressives. The present study was designed to analyze the effect of orchiectomy and the supplementation of testosterone propionate (TP) or 17β-estradiol (E₂) on the antidepressant properties of NIC using the forced swimming test (FST), as well as to determine possible changes in the FST during different time periods after orchiectomy. In order to evaluate the influences of orchiectomy on the effects of NIC, the study first evaluated the effects of different time periods on orchiectomized rats (15, 21, 30, 45 and 60 days) that were subjected to the FST. Then, different doses of NIC (0.2, 0.4, 0.8, 1.6 mg/kg, sc) were administered for 14 days to both intact and orchiectomized rats (after 21 day) which were then also subjected to the FST. Finally, the influence of the TP or E₂ supplementation on the antidepressant-like effect of NIC on orchiectomized rats (after 21 days) was also analyzed. Results reveal that orchiectomy significantly increased immobility behavior and decreased swimming and climbing up to 60 days after castration. In contrast, NIC decreased immobility behavior and increased swimming in intact rats; whereas orchiectomy suppressed this antidepressant effect of NIC. Only with E₂ supplementation was it possible to restore the sensitivity of the castrated rats to NIC. These results suggest that E₂ was able to facilitate the antidepressant response of NIC in orchiectomized rats.     

Further antinociceptive effects of myricitrin in chemical models of overt nociception in mice

The present work explored the antinociceptive effects of the flavonoid myricitrin in models of overt nociception triggered by intraplantar injection of chemical algogens into the hind paw of mice. The nociception induced by bradykinin (3 nmol/paw i.pl.) was abolished by prior treatment with myricitrin (10–100 mg/kg, i.p.) with ID₅₀ of 12.4 (8.5–18.1) mg/kg. In sharp contrast, myricitrin failed to affect the nociception elicited by prostaglandin E₂ (3 nmol/paw i.pl.). Cinnamaldehyde (10 nmol/paw i.pl.)-induced nociception was reduced by myricitrin (100 mg/kg, i.p.) and camphor (7.6 mg/kg, s.c.) in 43 ± 10% and 57 ± 8%, respectively. Myricitrin (30–100 mg/kg, i.p.) and amiloride (100 mg/kg, i.p.) inhibited nociceptive responses induced by acidified saline (pH 5/paw i.pl.), with ID₅₀ of 22.0 (16.1–30.0) mg/kg and inhibition of 71 ± 6% and 64 ± 5%, respectively. Moreover, myricitrin (10–30 mg/kg, i.p.) and ruthenium red (3 mg/kg, i.p.) significantly reduced the nociception induced by menthol (1.2 μmol/paw i.pl.) with the mean ID₅₀ of 2.4 (1.5–3.7) mg/kg and inhibition of 95 ± 3% and 51 ± 7%, respectively. In addition, myricitrin administration (30 and 100 mg/kg, i.p.) markedly reduced menthol-induced mechanical allodynia. However, myricitrin (100 mg/kg, i.p.) prevented (only in time of 60 min) cold allodynia induced by menthol. Collectively, the present results extend prior data and show that myricitrin promotes potent antinociception, an action that is likely mediated by an inhibition of the activation of nociceptors by bradykinin and TRPs agonist (i.e. cinnamaldehyde, acidified saline and menthol), probably via inhibition of PKC pathways. Thus, myricitrin could constitute an attractive molecule of interest for the development of new analgesic drugs.