Antidepressant-like effect of the organoselenium compound ebselen in mice: Evidence for the involvement of the monoaminergic system

Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] is a seleno-organic compound which possesses a potent antioxidant activity and has been shown to exert neuroprotective effects in vitro and in vivo in a variety of pro-oxidative insults. The present study investigates a possible antidepressant activity of ebselen using two predictive tests for antidepressant activity in rodents: the forced swimming test and tail suspension test. Additionally, the mechanisms involved in the antidepressant-like effect of ebselen in mice were also assessed. Ebselen (10 mg/kg, s.c.) decreased the immobility time in the forced swimming test without accompanying changes in ambulation in the open-field test. In contrast, the administration of ebselen (10-30 mg/kg) did not produce any effect in the tail suspension test. The anti-immobility effect of ebselen (10 mg/kg, s.c.) was not prevented by pre-treatment of mice with p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, 4 consecutive days), NAN-190 (0.5 mg/kg, i.p., a serotonin 5-HT_1A receptor antagonist) or ketanserin (5 mg/kg, i.p., a serotonin 5-HT_2A/2C receptor antagonist). On the other hand, the pre-treatment of mice with prazosin (1 mg/kg, i.p., an α₁-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α₂-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) completely blocked the antidepressant-like effect of ebselen (10 mg/kg, s.c.) in the forced swimming test. It may be concluded that ebselen produces an antidepressant-like effect in the forced swimming test that seems to be dependent on its interaction with the noradrenergic and dopaminergic systems, but not with the serotonergic system.     

Evidence for imidazoline receptors involvement in the agmatine antidepressant-like effect in the forced swimming test

This study investigated the involvement of the imidazoline receptors in the antidepressant-like effect of agmatine in the forced swimming test. The antidepressant-like effects of agmatine (10 mg/kg, i.p.) in the forced swimming test was blocked by pretreatment of mice with efaroxan (1 mg/kg, i.p., an imidazoline I1/alpha2-adrenoceptor antagonist), idazoxan (0.06 mg/kg, i.p., an imidazoline I2/alpha2-adrenoceptor antagonist) and antazoline (5 mg/kg, i.p., a ligand with high affinity for the I2 receptor). A subeffective dose of agmatine (0.001 mg/kg, i.p.) produced a synergistic antidepressant-like effect with clonidine (0.06 mg/kg, i.p, an imidazoline I1/alpha2-adrenoceptor agonist), moxonidine (0.5 mg/kg, i.p., an imidazoline I1/alpha2-adrenoceptor agonist), antazoline (1 mg/kg, i.p.) and MK-801 (0.001 mg/kg, i.p., a non-competitive NMDA receptor antagonist), but not with efaroxan (1 mg/kg, i.p.) and idazoxan (0.06 mg/kg, i.p.). Pretreatment of mice with yohimbine (1 mg/kg, i.p., an alpha2-adrenoceptor antagonist) blocked the synergistic antidepressant-like effect of agmatine (0.001 mg/kg, i.p.) with clonidine (0.06 mg/kg, i.p). A subeffective dose of MK-801 (0.001 mg/kg, i.p.) produced a synergistic antidepressant-like effect with antazoline (5 mg/kg, i.p.), but not with efaroxan (1 mg/kg, i.p.) or idazoxan (0.06 mg/kg, i.p.). In conclusion, this study suggests that the anti-immobility effect of agmatine in the forced swimming test is dependent on its interaction with imidazoline I1 and I2 receptors.     

Folic acid administration produces an antidepressant-like effect in mice: evidence for the involvement of the serotonergic and noradrenergic systems

Clinical studies have shown that folic acid plays a role in the pathophysiology of depression. However, very few studies have investigated its effect in behavioral models of depression. Hence, this study tested its effect in the forced swimming test (FST) and the tail suspension test (TST), two models predictive of antidepressant activity, in mice. Folic acid administered by oral route (p.o.) produced a reduction in the immobility time in the FST (50-100mg/kg) and in the TST (10-50mg/kg). The administration of folic acid by i.c.v. route also reduced the immobility time in the FST (10nmol/site) and in the TST (1-10nmol/site). Both folic acid administered by oral and i.c.v. route produced no psychostimulant effect, which indicates that its antidepressant-like effect is specific. Pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100mg/kg, i.p., an inhibitor of serotonin (5-HT) synthesis, for 4 consecutive days), ketanserin (5mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), prazosin (1mg/kg, i.p., an alpha(1)-adrenoceptor antagonist) or yohimbine (1mg/kg, i.p., an alpha(2)-adrenoceptor antagonist) prevented the anti-immobility effect of folic acid (50mg/kg, p.o.) in the FST. Moreover, the pretreatment of mice with WAY100635 (0.1mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) blocked the decrease in immobility time in the FST elicited by folic acid (50mg/kg, p.o.), but produced a synergistic effect with a subeffective dose of folic acid (10mg/kg, p.o.). In addition, a subeffective dose of folic acid (10mg/kg, p.o.) produced a synergistic antidepressant-like effect with fluoxetine (10mg/kg, p.o.) in the FST. Overall, the results firstly indicate that folic acid produced an antidepressant-like effect in FST and in TST and that this effect appears to be mediated by an interaction with the serotonergic (5-HT(1A) and 5-HT(2A/2C) receptors) and noradrenergic (alpha(1)- and alpha(2)-adrenoceptors) systems.     

The effect of dopaminergic stimulation and blockade on the nociceptive and antinociceptive responses of mice.

Agents which stimulate dopaminergic receptors directly or indirectly such as apomorphine and L-dopa, increased the reactivity of mice to a nociceptive stimulus. The increased reactivity was pharmacologically quantitated by estimating the hyperalgesic ED50 to be 4.4 and 115 mg/kg for apomorphine and L-dopa, respectively. This hyperalgesia was blocked by the dopamine receptor blocking agents, haloperidol and pimozide, but not by the narcotic antagonist, naloxone. Apomorphine antagonizes morphine analgesia. However the induced hyperalgesia only accounts for part of the antagonistic activity of apomorphine. The majority of the antagonistic activity of apomorphine appears to be by means other than action on dopaminergic receptors.     

Effects of imidazoline derivatives on cholinergic motility in guinea-pig ileum: involvement of presynaptic α2-adrenoceptors or imidazoline receptors?

The present study investigates the possibility that imidazoline receptors mediate modulation of cholinergic motor functions of the guinea-pig ileum. For this purpose, the effects of a series of compounds with known affinity for α₂-adrenoceptors and/or imidazoline recognition sites were examined on the cholinergic twitch contractions evoked by electrical field stimulation (0.1 Hz) of longitudinal muscle-myenteric plexus preparations. Additional experiments were carried out on ileal strips preincubated with [³H]choline, superfused with physiological salt solution containing hemicholinium-3, and subjected to electrical field stimulation (1 Hz). The stimulation-induced outflow of radioactivity was taken as an index of endogenous acetylcholine release. α-Methyl-noradrenaline, noradrenaline, clonidine, medetomidine, oxymetazoline and xylazine caused a concentration-dependent inhibition of twitch responses (IC₅₀ from 0.13 to 1.05 μM; E_max from 85.9 to 92.5%). Rilmenidine and agmatine were less potent in reducing the twitch activity, and the latter compound acted also with low intrinsic activity (IC₅₀=44.9 μM; E_max=35.5%). In interaction experiments, the inhibitory action of clonidine on twitch responses was competitively antagonized by RX 821002 (2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline), idazoxan, rauwolscine, yohimbine and BRL 44408 (2-[2H-(1-methyl-1,3-dihydroisoindole)-methyl]-4,5-dihydroimidazoline), whereas prazosin (10 μM), ARC 239 (2-(2,4-(O-methoxy-phenyl)-piperazin-1-yl)-ethyl-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione; 10 μM) and BRL 41992 (1,2-dimethyl-2,3,9,13b-tetrahydro-1H-dibenzo[c,f]imidazol[1,5-a]azepi-ne; 10 μM) were without effect. Rauwolscine antagonized the inhibitory effects of various agonists on ileal twitch activity in a competitive manner and with similar potency. Agmatine and idazoxan did not significantly modify the twitch contractions when tested in the presence of α₂-adrenoceptor blockade by rauwolscine (3 μM) or RX 821002 (1 μM). Linear regression analysis showed that the affinity values of antagonists correlated with their affinity at the α_2A and α_2D binding sites as well as at previously classified α_2A/D adrenoceptor subtypes, whereas no significant correlation was obtained when comparing the potency estimates of agonists and antagonists with the affinity at I₁ or I₂ binding sites. When tested on the electrically induced outflow of tritium, α-methyl-noradrenaline, noradrenaline, clonidine, medetomidine, oxymetazoline, xylazine and rilmenidine yielded inhibitory concentration-response curves which were shifted rightward to a similar extent in the presence of rauwolscine (3 μM). In the absence of further drugs, agmatine significantly reduced the evoked tritium outflow at the highest concentrations tested (10 and 100 μM), whereas idazoxan (up to 100 μM) was without effect. When RX 821002 (1 μM) was added to the superfusion medium, neither agmatine nor idazoxan modified the evoked outflow of radioactivity. The results argue against modulation by imidazoline receptors of acetylcholine release from myenteric plexus nerve terminals. They provide evidence that compounds endowed with imidazoline-like structures affect the cholinergic motor activity of the guinea-pig ileum by interacting with presynaptic α₂-adrenoceptors belonging to the α_2D subtype. Received: 10 October 1997 / Accepted: 14 March 1998     

Antidepressant like effect of selective serotonin reuptake inhibitors involve modulation of imidazoline receptors by agmatine

Recent findings demonstrated the dysregulation of imidazoline receptor binding sites in major depression and their normalization by chronic treatment with antidepressants including selective serotonin reuptake inhibitors (SSRIs). Present study investigated the role of agmatine and imidazoline receptors in antidepressant like effect of SSRIs and imipramine in mouse forced swimming test (FST) paradigm. The antidepressant like effect of fluoxetine or paroxetine was potentiated by imidazoline I₁/I₂ receptor agonist agmatine (5-10 mg/kg, ip), imidazoline I₁ receptor agonists, moxonidine (0.25-0.5 mg/kg, ip) and clonidine (0.015-0.03 mg/kg, ip), imidazoline I₂ receptor agonist, 2-(2-benzofuranyl)-2-imidazoline (5-10 mg/kg, ip) as well as by the drugs known to increase endogenous agmatine levels in brain viz., l-arginine, an agmatine biosynthetic precursor (40 μg/mouse, icv), ornithine decarboxylase inhibitor, difluoromethyl ornithine (12.5 μg/mouse, icv), diamine oxidase inhibitor, aminoguanidine (6.5 μg/mouse, icv) and agmatinase inhibitor, arcaine (50 μg/mouse, icv). Conversely, prior administration of I₁ receptor antagonist, efaroxan (1 mg/kg, ip), I₂ receptor antagonist, idazoxan (0.25 mg/kg, ip) and arginine decarboxylase inhibitor, d-arginine (100 mg/kg, ip) blocked the antidepressant like effect of paroxetine (10 mg/kg, ip) and fluoxetine (20 mg/kg, ip). On the other hand, antidepressant like effect of imipramine was neither augmented nor attenuated by any of the above drugs. Mice pretreated with SSRIs but not imipramine and exposed to FST showed higher concentration of agmatine in brain as compared to saline control. This effect of SSRIs on agmatine levels was completely blocked by arginine decarboxylase inhibitor d-arginine but not by imidazoline receptor antagonists, efaroxan or idazoxan. These results demonstrate that modulation of imidazoline receptors by agmatine are implicated in the antidepressant like effect of SSRIs and may be projected as a potential therapeutic target for the treatment of depressive disorders.     

Cholinergic,dopaminergic, noradrenergic,or glutaminergic stimulation ventral to the anterior septum does not specifically suppress defensive behavior

Three experiments investigated neurotransmitters which might function in the neural system ventral to the anterior septum modulating defensiveness in the rat. In the first experiment, a dose dependent suppression of defensive behavior to the experimenter was produced by intracranial infusion of carbachol or physostigmine but not dopamine, norepinephrine, or glutamate. The suppression of defensiveness did not occur when a carbachol-atropine sulfate mixture was infused. In a second experiment the cholinergic antagonists, atropine methyl nitrate or atropine sulfate, did not increase reactivity when infused ventral to the anterior septum although the nonspecific blocking agent lidocaine was effective. In a final experiment, the infusion of carbachol ventral to the anterior septum which had suppressed defensiveness was found to suppress eating and general activity as well, thus suggesting that the effect of carbachol on defensiveness was the result of a nonspecific suppression of behavior. It is concluded that the specific modulation of defensiveness by the neural system ventral to the anterior septum is not mediated by acetylcholine, dopamine, noradrenaline, or glutamate.     

Inhibitory presynaptic imidazoline receptors on sympathetic nerves in the rabbit aorta differ from I1- and I2-imidazoline binding sites

The involvement of imidazoline receptors in modulation of noradrenaline release was investigated in the rabbit aorta preincubated with [³H]noradrenaline and superfused with physiological salt solution containing cocaine, corticosterone and propranolol.After blockade of ₂-autoreceptors by rauwolscine, the electrically evoked tritium overflow was inhibited by various imidazolines and guanidines. The rank order of potency was BDF 7579 (4-chloro-2-isoindolinyl) guanidine) BDF 6143 (4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline] > BDF 6100 [2-(2-imidazolin2-y-lamino)-isoindoline] > clonidine > ST587 (2-(2-chloro-5-trifluoromethylphenylimino) imidazolidine nitrate) cirazoline > tolazoline > idazoxan > phentolamine. Comparison of the potencies of these drugs with those previously found for the presynaptic imidazoline receptors in the rabbit pulmonary artery revealed a very good correlation. In contrast, no positive correlation was found with their affinities for the I₁-and I₂-imidazoline binding sites in bovine adrenal medullary membranes and with their lipophilicity (log P values). The electrically evoked tritium overflow was also inhibited by the recently identified endogenous imidazoline receptor ligand agmatine, but was not affected by amiloride. In further series of experiments, the ability of putative antagonist at presynaptic imidazoline receptors to counteract the inhibitory effect of imidazoline derivatives was determined. Amiloride, imidazole-4-acetic acid and 1-benzylimidazole did not attenuate the inhibitory effect of BDF 6143 on the electrically evoked tritium overflow. In contrast, rauwolscine antagonized the inhibitory effect of various imidazolines; rauwolscine was clearly less potent in antagonizing the effect of clonidine, BDF 6143 and cirazoline (apparent pA₂ 6.48–7.32) than in antagonizing that of oxymetazoline and moxonidine (apparent pA₂ 8.33 and 8.12, respectively). In a final series of experiments, BDF 6143 (under the conditions applied a selective agonist at presynaptic imidazoline receptors) proved to be considerably less potent in inhibiting tritium overflow evoked by high K⁺ than by electrical stimulation, whereas moxonidine (in rabbit aorta a selective agonist at presynaptic ₂-adrenoceptors) exhibited similar potency in inhibiting the overflow evoked by both methods of stimulation.It is concluded that noradrenaline release in the rabbit aorta is inhibited via both ₂-autoceptors and presynaptic imidazoline receptors which can be activated by the endogenous imidazoline receptor ligand agmatine. The occurrence of such an ₂-adrenoceptor-independent mechanism is compatible with the ability of K⁺ ions to attenuate the inhibitory effect of an imidazoline receptor agonist but not of an ₂-adrenoceptor agonist, since susceptibility to K⁺ ions has been suggested to be a typical feature of imidazoline recognition sites. The presynaptic imidazoline receptor in rabbit aorta appears to be identical with the previously characterized presynaptic imidazoline receptor in rabbit pulmonary artery, but differs clearly from the I₁ and I₂ binding sites in the bovine adrenal medulla.     

Acute and chronic effects of the atypical antidepressant,mianserin on brain noradrenergic neurons

Corticotropin-releasing factor (CRF), which may serve as a neurotransmitter in the noradrenergic nucleus, locus coeruleus (LC), has been postulated to be hypersecreted in depression. The present study was designed to test the hypothesis that antidepressants interfere with CRF putative neurotransmission in the LC. The acute and chronic effects of the atypical antidepressant mianserin on LC spontaneous discharge, LC sensory-evoked discharge, LC activation by a stressor which requires endogenous CRF, and LC activation by ICV CRF were characterized in halothane-anesthetized rats. Acute IV administration of mianserin (0.0001–1.0 mg/kg) increased LC spontaneous discharge and decreased LC discharge evoked by repeated sciatic nerve stimulation in a dose-dependent manner. Additionally, mianserin (0.1 mg/kg) inhibited LC activation by hemodynamic stress (IV infusion of nitroprusside) and by ICV administration of CRF (3.0 µg). In rats chronically administered mianserin LC spontaneous and sensory-evoked discharge rates, and LC activation by CRF were similar to those of untreated rats or rats chronically administered saline. Moreover, acute IV administration of mianserin (0.1 mg/kg) to rats chronically treated with mianserin was less effective in altering LC spontaneous and sensory-evoked discharge. In contrast, LC activation by hemodynamic stress was still greatly attenuated in rats chronically administered mianserin. This is similar to the previously reported effect produced by chronic administration of the antidepressant, desmethylimipramine. The present results demonstrate that acute administration of low doses of mianserin attenuates LC activation by a variety of stimuli and suggest that tolerance developes with chronic administration to some of the effects of mianserin on LC discharge characteristics. The finding that LC activation by hemodynamic stress, which requires endogenous CRF, is attenuated after chronic mianserin administration suggests that interference with putative CRF neurotransmission in the LC may be an important common mode of antidepressant action.This work was supported by U.S.P.H.S. Grants MH42796, MH40008, MH00840, and a NARSAD award to A.L.C.     

Evidence for the involvement of imidazoline receptors in the central hypotensive effect of rilmenidine in the rabbit.

1. Rilmenidine has recently been introduced as a new centrally-acting antihypertensive agent. We examined its cardiovascular effects after intracerebral injection to anaesthetized rabbits. Cumulative doses of rilmenidine injected intracisternally (1 to 300 micrograms kg-1) led to dose-dependent decreases in arterial blood pressure and heart rate. The effective doses of rilmenidine were lower when injected centrally than when injected intravenously. 2. Pretreatment with the same dose of yohimbine or idazoxan shifted the rilmenidine dose-response curves for its hypotensive and bradycardic effects to the right. Idazoxan, which has an imidazoline structure, proved to be a more active antagonist than yohimbine of rilmenidine centrally-mediated cardiovascular effects. 3. The dose-response curve for the central hypotensive effect of rilmenidine was also shifted to the right after pretreatment with a bovine brain extract. This extract contains the endogenous ligand of the imidazoline-preferring receptors which is not a catecholamine. 4. Rilmenidine, like clonidine, proved to be active when micro-injected into the rabbit nucleus reticularis lateralis region. 5. In conclusion, rilmenidine exhibited in the rabbit a central hypotensive effect which originated in the same area as where clonidine acts. Specific imidazoline-preferring receptors appear to be involved in this hypotensive effect.     

Potentiating effect of tramadol on methamphetamine-induced behavioral sensitization in mice

Rationale Polydrug abuse is a common phenomenon in human drug addicts. Previous studies have shown that both tramadol (TRAM) and methamphetamine (METH) share the ability to modulate brain monoaminergic (dopamine, 5-hydroxytryptamine, and noradrenaline) systems that may be involved in behavioral sensitization to METH. Therefore, we hypothesized that there would be an interaction between TRAM and METH on behavioral sensitization induced by METH. Objectives To investigate whether TRAM affects METH-induced behavioral sensitization. Methods Male Kunming mice were subjected to two regimens of drugs: (1) Mice were injected with TRAM (1–16 mg/kg, i.p.) alone or a combination of TRAM and METH (1 mg/kg, i.p.) once daily for 7 days. After 7 drug-free days (on day 15), animals were challenged with the corresponding TRAM dose or METH (1 mg/kg, i.p.). On days 1, 7, and 15, locomotion was monitored in the open field test after the last injection. (2) Mice received METH (1 mg/kg, i.p.) once daily for 7 days, followed by 7 drug-free days. On day 15, a challenge of TRAM (1–16 mg/kg, i.p.) or TRAM plus METH (1 mg/kg, i.p.) was given and then locomotor activity was quantified. Results TRAM or METH challenge did not induce hyperlocomotion in mice chronically treated with TRAM, and TRAM challenge was insufficient to induce subsequent hyperlocomotion in METH-sensitized mice. However, TRAM significantly increased METH-induced hyperlocomotion. TRAM plus METH-sensitized mice showed a significantly greater hyperlocomotor response to METH challenge than METH-sensitized mice. Furthermore, TRAM (16 mg/kg, i.p.) plus METH (1 mg/kg, i.p.) challenge enhanced the sensitized locomotor response compared to METH-alone (1 mg/kg, i.p.) challenge in METH-sensitized mice. Conclusions TRAM fails to produce behavioral sensitization, and there is no apparent cross-sensitization between TRAM and METH. However, TRAM can increase METH-induced hyperlocomotion and potentiate the development and expression of behavioral sensitization to METH.     

Evidence for the involvement of the monoaminergic system, but not the opioid system in the antidepressant-like activity of ellagic acid in mice

Dietary flavonoids possess a multiplicity of neuroprotective actions in various central nervous pathophysiological conditions including depression. Ellagic acid is a polyphenolic compound that occurs in plants such as raspberries, nuts and eucalyptus species. The present study was designed to investigate the antidepressant-like effect of ellagic acid in mice using forced swimming test (FST) and tail suspension test (TST). The involvement of the monoaminergic and opioid systems in the antidepressant-like activity of ellagic acid was also studied. Our results showed that ellagic acid when administered acutely or chronically to mice (25, 50 and 100mg/kg, p.o.), produced a significant reduction in the duration of immobility, with a profile comparable to that of fluoxetine (20mg/kg, p.o.). However, ellagic acid treatment had no effect on the locomotor activity of mice when tested in actophotometer. The reduction in immobility time observed with ellagic acid treatment (50mg/kg, p.o.) was prevented by pretreatment with p-chlorophenylalanine (100mg/kg, i.p., a serotonin synthesis inhibitor), pindolol (10mg/kg, i.p., a β-adrenoceptors blocker/5HT(1A/1B) receptor antagonist), ketanserin (5mg/kg, i.p., a 5HT(2A/2B) receptor antagonist), ondansetron (1mg/kg, i.p., a 5HT(3) receptor antagonist), prazosin (1mg/kg, i.p., an α(1)-adrenoceptor antagonist) and yohimbine (1mg/kg, i.p., an α(2)-adrenoceptor antagonist), but not with naloxone (1mg/kg, i.p., an opioid receptor antagonist). Our results suggest that ellagic acid produced an antidepressant-like effect which was unrelated to its locomotor activity. Furthermore, this anti-immobility effect seems most likely to be mediated through an interaction with the monoaminergic system (serotonergic and noradrenergic systems) and not through the opioid system.     

Vagotomy reveals the importance of the imidazoline receptors in the cardiovascular effects of marsanidine and 7-ME-marsanidine in rats

BackgroundThe recently synthesized novel benzazole derivates – marsanidine (1-[(imidazolidin-2-yl)imino]indazole) and 7-Me-marsanidine (1-[(imidazolidin-2-yl)imino]-7-methylindazole) display promising effects on the circulatory system. We previously indicated that i.v. administration of both compounds decreased the mean arterial blood pressure (MAP) and heart rate (HR) in rats. The cardiovascular effect of the tested compounds may consist not only in inhibiting the sympathetic, but also in activating the parasympathetic pathways related to vagal nerves. Present experiments were performed to determine how vagotomy, with or without an α₂ adrenoreceptor blockade, may affect hypotensive and HR limiting actions of marsanidine and 7-Me-marsanidine.MethodsBoth compounds were infused i.v. (10 μg/kg b.w.) to anesthetized rats, half of which underwent vagotomy. Half the intact, and half the vagotomised rats received RX821002, an α₂ adrenorereceptor inhibitor. MAP and HR were monitored directly throughout the experiment.ResultsVagotomy enhanced hypotension observed after marsanidine administration. The α₂ adrenergic blockade abolished the action of marsanidine in both the intact and vagotomised rats. Vagotomy did not affect the 7-Me-marsanidine-induced decrease of MAP or HR. However, it abolished the reducing effect of the α₂ adrenergic receptor blockade on the hypotension triggered by 7-Me-marsanidine.ConclusionThe results show that although cardiovascular effects of marsanidine and 7-Me-marsanidine are not mediated by the vagal nerves, vagotomy enhanced sensitivity of the sympathetic pathways for the tested compounds. While the action of marsanidine in vagotomised and intact rats may be explained by activation of the α₂ adrenoreceptors, the effects of 7-Me-marsanidine seem to be α₂ adrenoreceptor-independent. It seems likely that activation of I₁ imidazoline receptors could mediate the observed effects.     

Differential role of 5-HT1A and 5-HT1B receptors on the antinociceptive and antidepressant effect of tramadol in mice

Rationale Tramadol, (1RS,2RS)-2-[(dimethylamine)-methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride, is an atypical analgesic which binds weakly to ì-opioid receptors and enhances the extra-neuronal concentration of noradrenaline and serotonin by interference with both the uptake and release mechanisms.Objectives The present study was undertaken to evaluate the potential role of 5-HT_1A and 5-HT_1B receptors on the analgesic and antidepressant-like effect of tramadol.Methods The effect of either a selective 5-HT_1A receptor antagonist (WAY 100635; N-2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane carboxamide; 0.2–0.8, 8 mg/kg) or a selective 5-HT_1B receptor antagonist (SB 216641; N-[3-(3-dimethylamino) ethoxy-4-methoxyphenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1′-biphenyl)-4-carboxamide; 0.2–0.8, 8 mg/kg) was investigated in mice in combination with tramadol by means of the hot-plate test, a phasic nociceptive model, and the forced swimming test, a paradigm aimed at screening potential antidepressants.Results The results showed that WAY 100635 enhanced the antinociceptive effect and produced a large decrease in the antidepressant-like effect of tramadol. In contrast, SB 216641 did not significantly modify either the analgesic or the antidepressant-like effects of tramadol.Conclusions These findings suggest that 5-HT_1A receptors modulate the analgesic and the antidepressant-like effects of tramadol in differing ways. The results suggest the involvement of the 5-HT_1A autoreceptors from the raphe nuclei and spinal 5-HT_1A receptors in the antinociceptive effect. In contrast, the 5-HT_1A receptors located in the forebrain may be responsible for the blockade of the antidepressant-like effect of tramadol. 5-HT_1B receptors seem not to modify these effects in the models investigated.     

Antidepressant-like effect of tramadol in the unpredictable chronic mild stress procedure: possible involvement of the noradrenergic system

Tramadol, which inhibits the reuptake of noradrenaline and serotonin, is effective in animal models of depression. Its antidepressant-like effects may be mediated mainly by the noradrenergic system. This study investigated the role of the noradrenergic system in the antidepressant-like effects of tramadol and desipramine in the unpredictable chronic mild stress model. We assessed the involvement of beta-adrenoreceptors, particularly beta2-receptors in the activity of these drugs. In addition, we measured the level of noradrenaline and its metabolite 3-methoxy-4-hydroxy-phenylglycol (MHPG) in the locus coeruleus, hypothalamus, hippocampus and cerebellum in stressed mice. Unpredictable chronic mild stress induced a degradation of coat state and decreased grooming behaviour in the splash test, which was reversed by the chronic administration of tramadol (20 mg/kg) and desipramine (10 mg/kg). The nonselective beta-adrenoreceptor antagonist propranolol (5 mg/kg, intraperitoneally) and the selective beta2-receptor antagonist ICI 118,551 (2 mg/kg, intraperitoneally) reversed the antidepressant-like effects of tramadol and desipramine. Moreover, chronic tramadol and desipramine treatment increased the level of noradrenaline (NA) and MHPG in the locus coeruleus but not in the cerebellum, whereas only MHPG level was increased in the hypothalamus. Tramadol, however, increased the levels of MHPG and NA in the hippocampus, whereas desipramine only increased NA level. These data support the view that the noradrenergic system plays an important role in the antidepressant-like action of tramadol.     

Involvement of PKA,PKC, CAMK-II and MEK1/2 in the acute antidepressant-like effect of creatine in mice

BackgroundThe aim of this study was to investigate the involvement of signaling pathways on the creatine antidepressant-like effect in the tail suspension test (TST) in mice.MethodsThe TST was used to assess the antidepressant-like properties of creatine.ResultsThe anti-immobility effect of creatine (1 mg/kg, p.o.) in the TST was blocked by i.c.v. pretreatment with H-89 (1 μg/site, PKA inhibitor), KN-62 (1 μg/site, CAMK-II inhibitor), chelerythrine (1 μg/site, PKC inhibitor), U0126 (5 μg/site, MEK1/2 inhibitor) or PD09058 (5 μg/site, MEK1/2 inhibitor).ConclusionThese results suggest that the antidepressant-like effect of creatine is dependent on PKA, CaMK-II, PKC and MEK 1/2 activation.     

Effect of extracellular dopamine on the release of dopamine in the rabbit caudate nucleus: Evidence for a dopaminergic feedback inhibition

Summary Slices of the head of the rabbit caudate nucleus were preincubated with 10^–7 M ³H-dopamine and then superfused, and the effect of unlabeled dopamine on the outflow of tritium was investigated. In most experiments, nomifensine was added throughout superfusion in order to block uptake of the unlabeled amine. Nomifensine was a potent inhibitor of the uptake of ³H-dopamine into rabbit caudate synaptosomes, with an IC₅₀ of 5·10^–8 M at a ³H-dopamine concentration of 4·10^–8 M.In the absence of nomifensine, unlabeled dopamine (10^–7 M and higher concentrations) accelerated the basal outflow of tritium from preincubated slices. 10^–5 M nomifensine strongly counteracted the acceleration. In the presence of nomifensine, unlabeled dopamine (10^–7 to 10^–6 M) caused a concentrationdependent decrease of the overflow of tritium evoked by electrical stimulation at 0.1 Hz. Chlorpromazine and haloperidol (in the presence of nomifensine) increased the stimulation evoked overflow and antagonized the inhibitory effect of dopamine.It is concluded that extracellular dopamine shares with other dopaminergic agonists the ability to inhibit action potential-evoked release of intraneuronal dopamine. The inhibition is mediated by specific receptors. The results support the hypothesis that previously released dopamine, by an action on these receptors, can inhibit further release of dopamine.     

Evidence for the involvement of glutamatergic receptors in the antinociception caused in mice by the sesquiterpene drimanial

Drimanial, a new sesquiterpene isolated from the barks of the plant Drimys winteri (Winteraceae), given systemically, intraplantarly, or by spinal or supraspinal routes, produced pronounced antinociception against both phases of formalin-induced licking. The systemic injection of drimanial also inhibited, in a graded manner, the pain-related behaviours induced by intraplantar or intrathecal (i.t.) administration of glutamate. Moreover, drimanial also caused marked inhibition of the nociception induced by i.t. administration of a metabotropic glutamate agonist (1S,3R)-ACPD, without affecting nociceptive responses induced by ionotropic agonists (NMDA, kainate, AMPA) or by substance P. The antinociception caused by drimanial was not influenced by naloxone, nor did it interfere with the motor coordination of animals in the rota-rod test. Furthermore, drimanial caused graded inhibition of [(3)H]glutamate binding in cerebral cortical membranes from mice, with an IC(50) value of 4.39 micro M. Together, these results provide strong evidence indicating that the sesquiterpene drimanial produces antinociception in mice at peripheral, spinal and supraspinal sites. An interaction with metabotropic glutamate receptors seems to contribute to the mechanisms underlying its antinociceptive action.     

The antidepressant-like effect of Hedyosmum brasiliense and its sesquiterpene lactone, podoandin in mice: evidence for the involvement of adrenergic, dopaminergic and serotonergic systems

We have recently shown that the ethanol extract of the leaves of Hedyosmum brasiliense exhibits an antidepressant-like effect in the tail suspension and forced swimming tests in mice. The present study investigates the mechanisms involved in the antidepressant-like effect of H. brasiliense extract, together with the antidepressant potential of podoandin, an isolated sesquiterpenoid. H. brasiliense (50mg/kg, i.p.) and podoandin (10mg/kg, i.p.) decreased the immobility time in the forced swimming test, without any accompanying changes in ambulation in the open-field test. The anti-immobility effect of the H. brasiliense extract was prevented by pre-treating the mice with ondansetron, NAN 190, pindolol, prazosin, yohimbine, haloperidol, SCH23390, and sulpiride. On the other hand, pre-treating the mice with: p-chlorophenylalanine (4 consecutive days), ketanserin, naloxone, naltrindole, bicuculline, phaclofen, or l-arginine did not block the antidepressant-like effect of H. brasiliense. In addition, pre-treatment of the animals with methylene blue, NG-nitro-l-arginine or 7-nitroindazole, at subeffective doses, did not cause a synergistic effect with H. brasiliense extract at an effective dose in the forced swimming test. The anti-immobility effect of podoandin was also prevented by pre-treating the mice with NAN-190, ondansetron, prazosin, yohimbine, sulpiride and haloperidol. The results indicate that the antidepressant-like effect of H. brasiliense (and podoandin) is dependent on the serotonergic, noradrenergic and dopaminergic systems, but not on the GABAergic, opioid and oxidonitrergic systems.