The effect of l-arginine and l-NAME on pentylenetetrazole induced seizures in ovariectomized rats,an in vivo study

The role of ovarian hormones and nitric oxide (NO) on seizure and their interaction have been widely investigated. The present study carried out to evaluate the effect of chronic administration of l-arginine (lA) and l-NAME (lN) on pentylenetetrazole (PTZ) induced epilepsy in ovariectomized (OVX) and naïve female rats.Fourty-eight female rats were randomly divided into six groups (n = 8) as follows: (1) sham, (2) ovarectomized (OVX), (3) sham-lA, (4) sham-lN, (5) OVX-lA, and (6) OVX-lN.The animals of sham-lA and OVX-lA received daily injection of 500 mg/kg l-arginine (i.p.) during 4 weeks. Sham-lN and OVX-lN were treated by 10 mg/kg l-NAME (i.p.) daily for 4 weeks. The animals of sham and OVX groups received 1 ml/kg saline (i.p.) instead of l-arginine and l-NAME. The latencies to minimal clonic seizures (MCS) and generalized tonic–clonic seizures (GTCS) after intraperitoneal injection of penetylenetetrazole (PTZ, 90 mg/kg) was recorded and compared between groups.A significant increase in the GTCS, but not MCS, latency was seen in OVX rats in comparison with sham-operated animals. Pretreatment of animals with l-NAME resulted in a significant increase in the GTCS and MCS latencies in sham group while no significant effects were seen in OVX rats. On the contrary, while pretreatment with l-arginine had no effects on MCS and GTCS latencies in sham group, a significant decrease in GTCS latency was observed in OVX rats.It is concluded that ovarian sex hormones affect seizure thresholds induced by PTZ and NO has a role on seizures susceptibility following PTZ administration. This NO effect might be differing in the presence or absence of ovarian hormones, but further investigations need to be done.     

Evidence for the involvement of 5-HT1A receptor in the acute antidepressant-like effect of creatine in mice

Creatine was previously shown to produce an antidepressant-like effect in the tail suspension test through a modulation of the dopaminergic system. In this study, the mechanisms underlying its antidepressant-like effect were further evaluated by investigating the involvement of the serotonergic system in its effect. The anti-immobility effect of creatine (1 mg/kg) was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., for 4 consecutive days, an inhibitor of serotonin (5-HT) synthesis). Creatine (0.01 mg/kg, sub-effective dose) in combination with sub-effective doses of WAY100635 (0.1 mg/kg, s.c., a 5-HT_1A receptor antagonist), 8-OH-DPAT (0.1 mg/kg, i.p., a 5-HT_1A receptor agonist) or selective serotonin reuptake inhibitors fluoxetine (5 mg/kg, p.o.), paroxetine (0.1 mg/kg, p.o.), citalopram (0.1 mg/kg, p.o.) and sertraline (3 mg/kg, p.o.) reduced the immobility time in the tail suspension test as compared with either drug alone. These results indicate that the antidepressant-like effect of creatine is likely mediated by an interaction with 5-HT_1A receptors. Of note, the present results also indicate that creatine improves the effectiveness of the selective serotonin reuptake inhibitors, a finding that may have therapeutic implications for the treatment of depressive disorders.     

The neuroprotective effect of tropisetron on vincristine-induced neurotoxicity

Vincristine (VCR) peripheral neuropathy is a dose-limiting side effect. Several studies have shown that tropisetron, a 5-HT₃ receptor antagonist, exerts anti-inflammatory and immunomodulatory properties. Current study was designed to investigate a suppressive effect of tropisetron on VCR-induced neuropathy and whether this effect exerts through the 5-HT₃ receptor or not.Neuropathy was induced in rats by administration of vincristine (0.5 mg/kg, 3 intraperitoneal injections on alternate days) and in treatment group, tropisetron (3 mg/kg); m-chlorophenylbiguanide (mCPBG), a selective 5-HT₃ receptor agonist (15 mg/kg); tropisetron (3 mg/kg) plus mCPBG (15 mg/kg); granisetron, another selective 5-HT₃ receptor antagonist (3 mg/kg) were administered intraperitoneally 1 h prior to vincristine injection. Hot plate, open field tests (total distance moved, mean velocity and percentage of total duration of the movement) and motor nerve conduction velocity (MNCV) were performed to evaluate the sensory and motor neuropathy. Further, plasma levels of tumor necrosis factor-alpha (TNF-α) and interleukin-2 (IL-2) and the level of TNF-α in sciatic nerve were assessed as well as histological examination.In only VCR-treated rats hot plate latencies were significantly increased, total distance moved, mean velocity, total duration of the movement and sciatic MNCV significantly decreased compared with control. In tropisetron and tropisetron plus mCPBG groups, one injection of tropisetron prior to each VCR injection robustly diminished TNF-α and IL-2 levels, and also prevented mixed sensory-motor neuropathy, as indicated by less mortality rate, better general conditions, behavioral and electrophysiological studies. Moreover, pathological evidence confirmed the results obtained from other findings. But granisetron and mCPBG had no significant effect on the mentioned parameters.In conclusion, these studies demonstrate that tropisetron significantly suppressed VCR-induced neuropathy and could be a neuroprotective agent for prevention of VCR-induced neuropathy via a receptor-independent pathway.     

Endothelial nitric oxide synthase activity involves in the protective effect of ascorbic acid against penicillin-induced epileptiform activity

Ascorbic acid and nitric oxide are known to play important roles in epilepsy. The aim of present study was to identify the involvement of nitric oxide (NO) in the anticonvulsant effects of ascorbic acid on penicillin-induced epileptiform activity in rats. Intracortical injection of penicillin (500, International Units (IU)) into the left sensorimotor cortex induced epileptiform activity within 2–5 min. Thirty minutes after penicillin injection, nitric oxide synthase (NOS) inhibitor, N^G-nitro-l-arginine methyl ester (l-NAME, 100 mg/kg), neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI, 40 mg/kg), NO substrate, l-arginine (500 mg/kg) were administered with the most effective dose of ascorbic acid (100 mg/kg) intraperitoneally (i.p.). The administration of l-arginine significantly decreased the frequency of epileptiform activity while administration of l-NAME did not influence the mean frequency of epileptiform activity. Injection of 7-NI decreased the mean frequency of epileptiform activity but did not influence amplitude. Ascorbic acid decreased both the mean frequency and amplitude of penicillin-induced epileptiform activity in rats. The application of l-NAME partially and temporarily reversed the anticonvulsant effects of ascorbic acid. The results support the hypothesis of neuro-protective role for NO and ascorbic acid. The protective effect of ascorbic acid against epileptiform activity was partially and temporarily reversed by nonspecific nitric oxide synthase inhibitor l-NAME, but not selective neuronal nitric oxide synthase inhibitor 7-NI, indicating that ascorbic acid needs endothelial-NOS/NO route to decrease penicillin-induced epileptiform activity.     

Nitric oxide mediates the anticonvulsant effects of thalidomide on pentylenetetrazole-induced clonic seizures in mice

Thalidomide is an old glutamic acid derivative which was initially used as a sedative medication but withdrawn from the market due to the high incidence of teratogenicity. Recently, it has reemerged because of its potential for counteracting number of diseases, including neurodegenerative disorders.Other than the antiemetic and hypnotic aspects, thalidomide exerts some anticonvulsant properties in experimental settings. However, the underlying mechanisms of thalidomide actions are not fully realized yet. Some investigations revealed that thalidomide could elicit immunomodulatory or neuromodulatory properties by affecting different targets, including cytokines (such as TNF α), neurotransmitters, and nitric oxide (NO). In this regard, we used a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether the anticonvulsant effect of thalidomide is affected through modulation of the l-arginine–nitric oxide pathway or not.Injection of a single effective dose of thalidomide (10 mg/kg, i.p. or higher) significantly increased the seizure threshold (P < 0.05). On the one hand, pretreatment with low and per se noneffective dose of l-arginine [NO precursor] (10, 30 and 60 mg/kg) prevented the anticonvulsant effect of thalidomide. On the other hand, NOS inhibitors [l-NAME and 7-NI] augmented the anticonvulsant effect of a subeffective dose of thalidomide (1 and 5 mg/kg, i.p.) at relatively low doses. Meanwhile, several doses of aminoguanidine [an inducible NOS inhibitor] (20, 50 and 100 mg/kg) failed to alter the anticonvulsant effect of thalidomide significantly. In summary, our findings demonstrated that the l-arginine–nitric oxide pathway can be involved in the anticonvulsant properties of thalidomide, and the role of constitutive nNOS is prominent in the reported neuroprotective feature.     

Role of nitric oxide in the anticonvulsive effect of progesterone

Described here is an investigation of the potential interaction of the nitric oxide signaling pathway with the anticonvulsant effects of progesterone. In ovariectomized Swiss mice, the threshold for seizures induced by intravenous infusion of pentylenetetrazole was determined after treatment with progesterone (25, 50, or 75 mg/kg, given subcutaneously 6 h before seizure testing) or vehicle. Progesterone induced significant anticonvulsive activity at moderate (50 mg/kg) and high (75 mg/kg) doses. This effect of progesterone was abolished by the NO precursor compound l-arginine (200 mg/kg). Moreover, when subeffective doses of progesterone (25 mg/kg) and the NO synthase inhibitor N^ω-nitro-l-arginine methyl ester (10 mg/kg) were injected, a strong anticonvulsant effect was observed. These findings suggest a potential role for NO signaling as an anticonvulsant target in females.     

Modulation of the anticonvulsant effect of swim stress by agmatine

Agmatine is an endogenous l-arginine metabolite with neuroprotective effects in the stress-response system. It exerts anticonvulsant effects against several seizure paradigms. Swim stress induces an anticonvulsant effect by activation of endogenous antiseizure mechanisms. In this study, we investigated the interaction of agmatine with the anticonvulsant effect of swim stress in mice on pentylenetetrazole (PTZ)-induced seizure threshold. Then we studied the involvement of nitric oxide (NO) pathway and endogenous opioid system in that interaction. Swim stress induced an anticonvulsant effect on PTZ seizures which was opioid-independent in shorter than 1-min swim durations and opioid-dependent with longer swims, as it was completely reversed by pretreatment with naltrexone (NTX) (10 mg/kg), an opioid receptor antagonist. Agmatine significantly enhanced the anticonvulsant effect of opioid-independent shorter swim stress, in which a combination of subthreshold swim stress duration (45 s) and subeffective dose of agmatine (1 mg/kg) revealed a significantly higher seizure threshold compared with either one. This effect was significantly reversed by NO synthase inhibitor N^G-nitro-l-arginine (L-NAME (Nω-Nitro-L-arginine methyl ester), 5 mg/kg), suggesting an NO-dependent mechanism, and was unaffected by NTX (10 mg/kg), proving little role for endogenous opioids in the interaction. Our data suggest that pretreatment of animals with agmatine acts additively with short swim stress to exert anticonvulsant responses, possibly by mediating NO pathway.     

The effects of coenzyme Q10 on seizures in mice: The involvement of nitric oxide

Coenzyme Q10 is a potent antioxidant in both mitochondria and lipid membranes. It has also been recognized to have an effect on gene expression. This study was designed to investigate whether acute or subchronic treatment with coenzyme Q10 altered the seizures induced by pentylenetetrazole or electroshock in mice. We also evaluated the involvement of nitric oxide in the effects of coenzyme Q10 in pentylenetetrazole-induced seizure models. Acute oral treatment with different doses of coenzyme Q10 did not affect the seizure in intraperitoneal pentylenetetrazole, intravenous pentylenetetrazole, and electroshock models in mice. Subchronic oral administration of coenzyme Q10 (100 mg/kg or more) increased time latencies to the onset of myoclonic jerks and clonic seizures induced by intraperitoneal pentylenetetrazole and at the doses of 25 mg/kg or more increased the seizure threshold induced by intravenous infusion of pentylenetetrazole. Subchronic doses of coenzyme Q10 (50 mg/kg or more) also decreased the incidence of tonic seizures in the electroshock-induced seizure model. Moreover, acute treatment with the precursor of nitric oxide synthesis, l-arginine (60 mg/kg), led to a significant potentiation of the antiseizure effects of subchronic administration of coenzyme Q10 (400 mg/kg in intraperitoneal and 6.25 mg/kg in intravenous pentylenetetrazole tests). Acute treatment with l-NAME (5 mg/kg), a nonspecific nitric oxide synthase inhibitor, significantly attenuated the antiseizure effects of subchronic doses of coenzyme Q10 in both seizure models induced by pentylenetetrazole. On the other hand, acute administration of aminoguanidine (100 mg/kg), a specific inducible nitric oxide synthase inhibitor, did not affect the seizures in mice treated with subchronic doses of coenzyme Q10 in both intraperitoneal and intravenous pentylenetetrazole tests. In conclusion, only subchronic and not acute administration of coenzyme Q10 attenuated seizures induced by pentylenetetrazole or electroshock. We also demonstrated, for the first time, the interaction between nitric oxide and coenzyme Q10 in antiseizure activity probably through the induction of constitutive nitric oxide synthase.     

Anticonvulsant effect of dextrometrophan on pentylenetetrazole-induced seizures in mice: Involvement of nitric oxide and N-methyl-d-aspartate receptors

Dextrometrophan (DM), widely used as an antitussive, has recently generated interest as an anticonvulsant drug. Some effects of dextrometrophan are associated with alterations in several pathways, such as inhibition of nitric oxide synthase (NOS) enzyme and N-methyl d-aspartate (NMDA) receptors. In this study, we aimed to investigate the anticonvulsant effect of acute administration of dextrometrophan on pentylenetetrazole (PTZ)-induced seizures and the probable involvement of the nitric oxide (NO) pathway and NMDA receptors in this effect. For this purpose, seizures were induced by intravenous PTZ infusion. All drugs were administrated by intraperitoneal (i.p.) route before PTZ injection. Our results demonstrate that acute DM treatment (10–100 mg/kg) increased the seizure threshold. In addition, the nonselective NOS inhibitor L-NAME (10 mg/kg) and the neural NOS inhibitor, 7-nitroindazole (40 mg/kg), at doses that had no effect on seizure threshold, augmented the anticonvulsant effect of DM (3 mg/kg), while the inducible NOS inhibitor, aminoguanidine (100 mg/kg), did not affect the anticonvulsant effect of DM. Moreover, the NOS substrate l-arginine (60 mg/kg) blunted the anticonvulsant effect of DM (100 mg/kg). Also, NMDA antagonists, ketamine (0.5 mg/kg) and MK-801 (0.05 mg/kg), augmented the anticonvulsant effect of DM (3 mg/kg). In conclusion, we demonstrated that the anticonvulsant effect of DM is mediated by a decline in neural nitric oxide activity and inhibition of NMDA receptors.     

5-HT(3) receptor mediates the dose-dependent effects of citalopram on pentylenetetrazole-induced clonic seizure in mice: Involvement of nitric oxide

Citalopram is a selective serotonin reuptake inhibitor (SSRI), widely used in the treatment of depressive disorders. It has been shown that citalopram affects seizure susceptibility. Although the exact mechanism of these effects are not yet fully understood, recent data suggest that 5HT(3) receptors and nitric oxide (NO) might participate in the central effects of SSRIs. In this study in a mouse model of clonic seizure induced by pentylenetetrazole we investigated whether 5-HT(3) receptors are involved in the effects of citalopram on seizure threshold. In our experiments, citalopram at lower doses (0.5 and 1mg/kg, i.p) significantly increased the seizure threshold and at higher doses (≥25mg/kg) showed proconvulsive effects. Moreover, mCPBG (a 5-HT(3) receptor agonist) at low and non-effective doses augmented while non-effective doses of tropisetron prevented the anticonvulsive properties of citalopram. On the other hand, Low doses of nitric oxide synthase inhibitors l-NAME and 7-NI alone or in combination with lower doses of 5-HT(3) receptor agonist enhanced the anticonvulsive property of citalopram, while l-arginine (NO precursor) alone or in combination with tropisetron blocked the protective effect of citalopram. In summary, our findings demonstrate that 5-HT(3) receptor mediates the anticonvulsant properties of low doses of citalopram, whereas it seems that the proconvulsive effect is mostly mediated through the NO pathway and can be totally blocked by NOS inhibitors. This could propose a new approach toward finding the mechanism of citalopram activity, curtailing the adverse effects of citalopram and perhaps managing the convulsions as a vicious consequence of citalopram overdose.     

ATP-sensitive potassium channels contribute to the time-dependent alteration in the pentylenetetrazole-induced seizure threshold in diabetic mice

Although there is evidence that diabetes affects seizure susceptibility, the underlying mechanism has not been completely understood. Several studies also suggest a pivotal role for K_ATP channels in the seizure modulation. The aim of the present study was to evaluate the seizure threshold induced by pentylenetetrazole in diabetic mice at different times (3 days, 1–8 weeks) after induction of diabetes with streptozocin and to examine the possible role of ATP-sensitive potassium (K_ATP) channels in this manner.Our data showed a time-dependent alteration in the threshold in diabetic mice, reaching a peak on week 2 after streptozocin injection and declining significantly afterwards. The seizure threshold in 8-week diabetic mice was even lower than control levels, though the difference was not significant. The K_ATP channel opener cromakalim (0.1–30 μg/kg, i.p.) significantly increased the seizure threshold in control mice. Although the K_ATP channel blocker glibenclamide (0.5, 1 mg/kg) had no effect, it prevented the effects of the potent dose of cromakalim (30 μg/kg) on seizure threshold in control mice. Glibenclamide (1 mg/kg, i.p.) also decreased the seizure threshold in 2-week diabetic mice to the control levels which was blocked by pre-treatment with cromakalim (10 μg/kg, i.p.). Cromakalim (10 μg/kg, i.p.) significantly increased the seizure threshold in 8-week diabetic mice which was inhibited by pre-treatment with glibenclamide (1 mg/kg, i.p.).We demonstrated a time-dependent alteration in the pentylenetetrazole-induced seizure threshold in diabetic mice. This phenomenon might be due to the probable alteration in the K_ATP channel functioning during the diabetic condition.     

Antinociceptive effects of intrathecally administered 2-methylserotonin in developing rats

The present study examined developmental patterns of antinociception mediated by the spinal 5-HT₃ receptor system in the neonatal rat. Intrathecally administered 2-methylserotonin (25–100 μg) first produced antinociception against formalin-induced acute inflammatory pain at 10 days postnatally, with effect only at the peak dose (100 μg). Intrathecal 2-methylserotonin produced dose-dependent antinociception at 14 and 28 days of age that was attenuated by i.t. pretreatment with the 5-HT₃ receptor antagonist MDL-72222 (10 μg).     

Toluene exposure enhances acute and chronic formalin-induced nociception in rats: Participation of 5-HT3 receptors

The purpose of this study was to evaluate the effect of acute toluene exposure on formalin (0.5% and 1%)-induced acute and long-lasting nociceptive hypersensitivity in rats. In addition, we sought to investigate the role of peripheral 5-HT₃ receptors in the pronociceptive effect of toluene. Toluene exposure (6000 ppm) for 30 min enhanced 0.5% or 1% formalin-induced acute nociception and long-lasting secondary allodynia and hyperalgesia. In contrast, exposition to toluene for 30 min in rats previously injected (six days before) with 1% formalin did not affect long-lasting hypersensitivy. Local peripheral pre-treatment with alosetron (5-HT₃ receptor antagonist, 10–100 nmol) reduced the pronociceptive effect of toluene in acute nociception and long-lasting secondary allodynia and hyperalgesia. Alosetron (100 nmol) was also able to reduce the nociceptive effects of 1% formalin in absence of toluene. Moreover, local peripheral injection of m-CPBG (5-HT₃ receptor agonist, 300 nmol) enhanced 0.5% formalin-induced acute and long-lasting nociception in air- and toluene-exposed rats. Alosetron (10 nmol) blocked the pronociceptive effects of m-CPBG (300 nmol) on 0.5% formalin-induced acute and long-lasting hypersensitivity in rats exposed to toluene. Alosetron (at 10 nmol) did not modify formalin-induced nociceptive behaviors. Finally, local peripheral pre-treatment with methiothepin (non-selective 5-HT receptor antagonist, 1.5 nmol), did not affect the pronociceptive effect of toluene on 1% formalin-induced acute and long-lasting hypersensitivity. Our data demonstrate that acute exposure to toluene has pronociceptive effects in formalin-induced acute nociception and long-lasting hypersensitivity. Our data suggest that this pronociceptive effect depend on activation of peripheral 5-HT₃, but not methiothepin-sensitive 5-HT, receptors.     

Inhibition of NMDA-receptor mediated response in the rat medial prefrontal cortical pyramidal cells by the 5-HT3 receptor agonist SR 57227A and 5-HT: Intracellular studies

The techniques of intracellular recording and single-electrode voltage-clamp were used to study the effect of serotonin (5-HT) and the selective 5-HT₃ receptor agonist SR 57227A on N-methyl-D-aspartic acid (NMDA)-evoked responses in pyramidal cells of the rat medial prefrontal cortex (mPFC) in in vitro brain slice preparations. Bath application of 5-HT or SR 57227A produced a concentration-dependent inhibition of NMDA-induced membrane depolarization, action potentials, and inward current. The depressant action of 5-HT and SR 57227A had a slow onset and showed no signs of receptor desensitization. This action was markedly attenuated or completely blocked by the selective 5-HT₃ receptor antagonists granisetron and BRL 46470A, but not other receptor antagonists. In addition to inhibiting NMDA-evoked responses, SR 57227A also depressed significantly pharmacologically isolated, NMDA receptor-mediated, monosynaptic excitatory postsynaptic currents (EPSCs) elicited by electrical stimulation of the forceps minor; this inhibitory action was blocked by BRL 46470A but not other 5-HT receptor antagonists. Perfusion of Ca²⁺-free or low Ca²⁺ plus Cd²⁺ artificial cerebrospinal fluid prevented electrical stimulation-induced EPSCs, but did not affect the inhibitory action of 5-HT and SR 57227A. In conclusion, we demonstrate for the first time that 5-HT and SR 57227A interact with 5-HT₃-like receptors to produce a direct inhibitory action on NMDA receptor-mediated response in pyramidal cells of the mPFC. Synapse 29:257–268, 1998. © 1998 Wiley-Liss, Inc.     

The effect of minocycline on seizures induced by amygdala kindling in rats

PurposeMinocycline is known as a chemical with neuroprotective, anti-inflammatory, and antimicrobial properties. In this study, the effects of minocycline on seizures induced by amygdala kindling in rats were studied.MethodsKindled Wistar rats were injected intraperitoneally with saline and, on the following day, with minocycline (50, 25, and 12.5 mg/kg for the three groups (1–3), respectively). The animals in groups 1–3 had similar protocols. Groups 4 and 5 were given for the rotarod test and received 25 or 50 mg/kg minocycline, respectively, without any kindling stimulation. The animals in groups 6 and 7 (seven each) received 25 mg/kg minocycline or saline, respectively. All the injections were carried out 1 h before kindling stimulation. Seizure parameters, including after discharge duration (ADD), stage 4 latency (S₄L), stage 5 duration (S₅D), and seizure duration (SD), were recorded and compared with those of the saline groups.ResultsMinocycline (50 mg/kg) significantly reduced ADD, 1/S₄L, S₅D, and SD (P < 0.001, P < 0.05, P < 0.001, and P < 0.001, respectively) in group 1. While the administration of 25 mg/kg of minocycline decreased the ADD and S₅D (P < 0.05), in group 2. The injection of 12.5 mg/kg resulted in decreased S₅D (P < 0.001) in group 3. The daily injection of minocycline (25 mg/kg) significantly decreased ADD, S₅D, and SD (P < 0.001) in group 6.ConclusionThe obtained results revealed that minocycline has anticonvulsant effect on seizures induced by amygdala kindling. Thus, it may be useful for epilepsy treatment.     

Antidepressant-like effects of SR 57227A,a 5-HT3 receptor agonist,in rodents

Summary We have investigated the effect of SR 57227A, a selective 5-HT₃ receptor agonist which crosses the blood brain barrier, on three rodent models in which antidepressants are active. In the forced swimming test, SR 57227A dose-dependently reduced the duration of immobility in mice and rats after i.p. administration. (ED₅₀=14.2mg/kg i.p. in mice, and 7.6 mg/kg i.p. in rats.) The compound was also active in both species after oral administration. In a time-course study in mice, SR 57227A (20 mg/kg p.o.) produced a significant effect lasting 6 h. SR 57227A (1 and 3 mg/kg i.p.) reduced the elevation of the escape failures in the learned helplessness model in rats by 50–60% on the last two days of the avoidance task, and reduced isolation-induced aggressivity in mice by 50 to 85%, an effect which was antagonised by zacopride (1 mg/kg i.p.). These results suggest that the stimulation of 5-HT₃ receptors can produce antidepressant-like effects in behavioural tests in rodents.     

A2A receptor antagonists do not induce dyskinesias in drug-naive or l-dopa sensitized rats

l-Dopa, the precursor to dopamine, is currently the gold standard treatment for Parkinson's disease (PD). However, chronic exposure is associated with l-dopa-induced dyskinesias (LIDs), a serious side effect characterized by involuntary movements. Adenosine A_2A receptor antagonists have been studied as a novel non-dopaminergic PD treatment. Because A_2A receptor antagonists do not act on dopamine receptors, it has been hypothesized that they will not induce dyskinesias characteristic of l-dopa. To test this hypothesis in a rodent model, the A_2A receptor antagonists SCH 412348 (3 mg/kg), vipadenant (10 mg/kg), caffeine (30 mg/kg), or istradefylline (3 mg/kg) were chronically (19–22 days) administered to Sprague Dawley rats, and dyskinetic behaviors were scored across this chronic dosing paradigm. Unlike l-dopa, there was no evidence of dyskinetic activity resulting from any of the four A_2A receptor antagonists tested. When delivered to animals previously sensitized with l-dopa (6 mg/kg), SCH 412348, vipadenant, caffeine or istradefylline treatment produced no dyskinesias. When administered in combination with l-dopa (6 mg/kg), SCH 412348 (3 mg/kg) neither exacerbated nor prevented the induction of LIDs over the course of 19 days of treatment. Collectively, our data indicate that A_2A receptor antagonists are likely to have a reduced dyskinetic liability relative to l-dopa but do not block dyskinesias when coadministered with l-dopa. Clinical studies are required to fully understand the dyskinesia profiles of A_2A receptor antagonists.     

Assessing the role of serotonergic receptors in cannabidiol's anticonvulsant efficacy

Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several animal models of seizure. The current experiment validated CBD's anticonvulsant effect using the acute pentylenetetrazol (PTZ) model. Furthermore, it tested whether CBD reduces seizure activity by interacting with either the serotonergic 5HT1A or 5HT2A receptor. 120 male adolescent Wistar-Kyoto rats were randomly assigned to 8 treatment groups in two consecutive experiments. In both experiments, subjects received either CBD (100 mg/kg) or vehicle 60 min prior to seizure testing. In Experiment 1, subjects received either WAY-100635 (1 mg/kg), a 5HT1A antagonist, or saline vehicle injection 80 min prior to seizure testing. In Experiment 2, subjects received either MDL-100907 (0.3 mg/kg), a specific 5HT2A antagonist, or 40% DMSO vehicle 80 min prior to seizure testing. 85 mg/kg of PTZ was administered to induce seizure, and behavior was recorded for 30 min. Seizure behaviors were subsequently coded using a 5-point scale of severity. Across both experiments, subjects in the vehicle control groups exhibited high levels of seizure activity and mortality. In both experiments, CBD treatment significantly attenuated seizure activity. Pre-treatment with either WAY-100635 or MDL-100907 did not block CBD's anticonvulsant effect. WAY-100635 administration, by itself, also led to a significant attenuation of seizure activity. These results do not support the hypothesis that CBD attenuates seizure activity through activation of the 5HT1A or 5HT2A receptor. While this work further confirms the anticonvulsant efficacy of CBD and supports its application in the treatment of human seizure disorders, additional research on CBD's mechanism of action must be conducted.     

Evidence for the involvement of the monoaminergic system in the antidepressant-like effect of magnesium

Literature data has shown that acute administration of magnesium reduces immobility time in the mouse forced swimming test (FST), which suggests potential antidepressant activity in humans. However, its mechanism of action is not completely understood. Thus, this study is aimed at investigating the antidepressant-like action of magnesium and the possible involvement of the monoaminergic system in its effect in the FST. The immobility time in the FST was significantly reduced by magnesium chloride administration (30–100 mg/kg, i.p.) without accompanying changes in ambulation when assessed in an open-field test. The pre-treatment of mice with NAN-190 (0.5 mg/kg, i.p. a 5-HT_1A receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT_1A receptor antagonist), ritanserin (4 mg/kg, i.p., a 5-HT_2A/2C receptor antagonist), ketanserin (5 mg/kg, a preferential 5-HT_2A receptor antagonist), prazosin (1 mg/kg, i.p., an α₁-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist), haloperidol (0.2 mg/kg, i.p., a non selective dopaminergic receptor 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) 30 min before the administration of magnesium chloride (30 mg/kg, i.p.) significantly prevented its anti-immobility effect in the FST. Moreover, the administration of sub-effective doses of fluoxetine (10 mg/kg, i.p., serotonin reuptake inhibitor), imipramine (5 mg/kg, i.p., a mixed serotonergic noradrenergic reuptake inhibitor), bupropion (1 mg/kg, i.p., dopamine reuptake inhibitor) was able to potentiate the action of sub-effective doses of magnesium chloride. In conclusion, the present study provides evidence indicating that the antidepressant-like effect of magnesium in the FST is dependent on its interaction with the serotonergic (5-HT_1A and 5-HT_2A/2C receptors), noradrenergic (α₁- and α₂- receptors) and dopaminergic (dopamine D₁ and D₂ receptors) systems.     

Levetiracetam in submaximal subcutaneous pentylentetrazol-induced seizures in rats

Despite anticonvulsant efficacy in animal models of generalized epilepsy, levetiracetam was not effective in the maximal subcutaneous PTZ model in mice and rats.Aim of this study was to assess the efficacy of levetiracetam (LEV) against submaximal, s.c. MET test (PTZ at the dose of 70 mg/kg) acute seizures in Wistar rats, in comparison to valproic acid (VPA).Thirty male Wistar rats (P42) were divided in three drug-treatment groups (10 rats in each group) as follows: valproic acid, levetiracetam, and controls. All animals were tested for seizure threshold at age P50. VPA (110 mg/kg) and LEV (108 mg/kg) were freshly dissolved in saline and injected i.p. in 2–3 ml/kg, 15 and 30 min, respectively, before pentylenetetrazol (PTZ) injection at the dose of 70 mg/kg.The average latency of the seizure type 3 (generalized clonic seizure with loss of righting reflexes) significantly differed between controls and the drug-treated animal groups (p ≤ 0.02). The average duration of the seizure type 2 (threshold seizure) was significantly longer in both groups compared to controls (<0.02).In conclusion, LEV plays a role against seizures triggered by subcutaneous PTZ injection given at submaximal doses in rats, as demonstrated by a significant increase in duration of the seizure type 2 (threshold seizure).