Behavioural effects of a selective NMDA NR1A/2B receptor antagonist in rats with unilateral 6-OHDA + parafascicular lesions

Experimental lesions involving the parafascicular (Pf) nucleus and medial forebrain bundle (MFB) may model to some extent the pathological loss of glutamatergic neurons from the centromedian–parafascicular (CM–Pf) complex and nigral dopaminergic cell loss observed clinically at post-mortem in Parkinson's disease (PD) cases. Our study investigated whether there were alterations in symptomatology in such rats with unilateral 6-OHDA + Pf lesions after treatment with either a selective NR1A/NR2B NMDA antagonist and/or l-dopa. Rats were given dual surgery to the MFB with 6-hydroxydopamine (6-OHDA) and Pf with N-methyl-d-aspartate (NMDA). (i) An NR1A/NR2B selective NMDA antagonist (BZAD-01; 10 mg/kg), (ii) l-dopa (25 mg/kg), (iii) BZAD-01 + l-dopa (10 mg/kg; 25 mg/kg) or (iv) vehicle solution were administered for 6 weeks, during which behavioural testing was performed. BZAD-01 improved postural asymmetry in the first month as well as apomorphine-induced rotation. The latter was also improved by l-dopa in this model. These data support the use of selective NR1/NR2B NMDA antagonists in the therapeutics of PD.     

Mechanisms operated by endothelin ETA and ETB receptors in the trigeminal ganglion contribute to orofacial thermal hyperalgesia induced by infraorbital nerve constriction in rats

Endothelins, acting through specific endothelin ET_A and/or ET_B receptors, participate in nociceptive processing in models of cancer, inflammatory and neuropathic pain. The present study investigated which cell types express endothelin receptors in the trigeminal ganglion, and the contribution of mechanisms mediated by endothelin ET_A and ET_B receptors to orofacial heat hyperalgesia induced by unilateral constriction of the infraorbital nerve (CION). Both receptor types were identified by immunohistochemistry in the trigeminal ganglion, ET_A receptors on small-sized non-myelinated and myelinated A-fibers and ET_B receptors on both satellite glial cells and small-sized non-myelinated neuronal cells. CION promoted ipsilateral orofacial heat hyperalgesia which lasted from Day 2 until Day 10 after surgery. Ongoing CION-induced heat hyperalgesia (on Day 4) was reduced transiently, but significantly, by systemic or local treatment with antagonists of endothelin ET_A receptors (atrasentan, 10 mg/kg, i.v.; or BQ-123, 10 nmol/lip), endothelin ET_B receptors (A-192621, 20 mg/kg, i.v.; or BQ-788, 10 nmol/ lip), or of both ET_A/ET_B receptors (bosentan, 10 mg/kg, i.v.; or BQ-123 plus BQ-788, each at 10 nmol/lip). On the other hand, CION-induced heat hyperalgesia was transiently abolished over the first 90 min following i.p. injection of morphine hydrochloride (2.5 mg/kg), but fully resistant to reversal by indomethacin (4 mg/kg, i.p.) or celecoxib (10 mg/kg, i.p.). Thus, heat hyperalgesia induced by CION is maintained, in part, by peripheral signaling mechanisms operated by ET_A and ET_B receptors. Endothelin receptors might represent promising therapeutic targets for the control of trigeminal neuropathic pain.     

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.     

Istradefylline,an adenosine A2A receptor antagonist,for patients with Parkinson's Disease: A meta-analysis

ObjectivesTo assess the efficacy and safety of istradefylline as an adjunct to levodopa in patients with Parkinson's Disease (PD).MethodsIn this study, we searched the Cochrane Library, MEDLINE, Embase, China Academic Journal Full-text Database (CNKI), China Biomedical Literature Database (CBM), Chinese Scientific Journals Database (VIP), and Wanfang Database. The quality of included studies was strictly evaluated. Data analyses were performed by the Cochrane Collaboration's RevMan5.0 software.ResultsFive randomized controlled trials (RCTs) were included. The result showed a significant reduction of the awake time per day spent in the OFF state and improvement of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III in the ON state when receiving istradefylline compared with patients receiving placebo. There was no significant difference between the istradefylline 20 mg and the istradefylline 40 mg groups in the UPDRS Part III in the ON state (WMD = 1.27, 95% CI [? 0.40, 2.95]). The results showed significant differences in dyskinesia (RR = 1.63, 95% CI [1.16, 2.29]) compared to istradefylline 40 mg with placebo. There was no significant statistical difference with regard to other adverse events.ConclusionsThe present study showed that istradefylline is safe and effective as an adjunct to levodopa in patients with PD. Future large-scale, higher-quality, long-treatment, and placebo-controlled trials are needed.     

Functional and morphological examinations of P1A1 purinoceptors in the normal and inflamed urinary bladder of the rat

The aim of the present study was to investigate the relaxatory function of adenosine receptor subtypes in rat urinary bladder, and if it is altered in the state of inflammation. The in vitro responses to the P1 receptor agonist adenosine were investigated in the presence of the general P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS; 1 ? 10^? 4 M). Experiments were performed on preparations from normal (healthy) rats and rats with cyclophosphamide (CYP; 100 mg kg^? 1 i. p.)-induced cystitis. The specific P1A₁ antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 1 ? 10^? 5 M) decreased the adenosine relaxatory response in normal bladders (? 60%), but not in preparations from CYP pre-treated rats. Immunohistochemical findings support the hypothesis that the expression of P1A₁ receptors in the rat urinary bladder is decreased during cystitis. The adenosine-evoked relaxation was not affected by the specific P1A_2A antagonist SCH 58261 (3 ? 10^? 7 M), neither in normal nor in CYP pre-treated rats. The relaxation to adenosine was, however, significantly increased by the specific P1A₃ antagonist MRS 1523 (1 ? 10^? 5 M) in preparations from both normal and CYP pre-treated rats, suggesting P1A₃ to be mediating bladder contraction. Thus, in the rat urinary bladder the relaxation to adenosine is mainly due to the P1A₁ receptor, while the P1A₃ receptor seems to be responsible for contractile responses. The DPCPX-resistant part of the relaxation is possibly due to the P1A_2B receptor, the fourth subtype of the adenosine receptor family.     

The synthetic neuroactive steroid SGE-516 reduces status epilepticus and neuronal cell death in a rat model of soman intoxication

Organophosphorus nerve agents (OPNAs) are irreversible inhibitors of acetylcholinesterase that pose a serious threat to public health because of their use as chemical weapons. Exposure to high doses of OPNAs can dramatically potentiate cholinergic synaptic activity and cause status epilepticus (SE). Current standard of care for OPNA exposure involves treatment with cholinergic antagonists, oxime cholinesterase reactivators, and benzodiazepines. However, data from pre-clinical models suggest that OPNA-induced SE rapidly becomes refractory to benzodiazepines. Neuroactive steroids (NAS), such as allopregnanolone, retain anticonvulsant activity in rodent models of benzodiazepine-resistant SE, perhaps because they modulate a broader variety of GABA_A receptor subtypes. SGE-516 is a novel, next generation NAS and a potent and selective GABA_A receptor positive allosteric modulator (PAM). The present study first established that SGE-516 reduced electrographic seizures in the rat lithium-pilocarpine model of pharmacoresistant SE. Then the anticonvulsant activity of SGE-516 was investigated in the soman-intoxication model of OPNA-induced SE. SGE-516 (5.6, 7.5, and 10 mg/kg, IP) significantly reduced electrographic seizure activity compared to control when administered 20 min after SE onset. When 10 mg/kg SGE-516 was administered 40 min after SE onset, seizure activity was still significantly reduced compared to control. In addition, all cohorts of rats treated with SGE-516 exhibited significantly reduced neuronal cell death as measured by FluoroJade B immunohistochemistry. These data suggest synthetic NASs that positively modulate both synaptic and extrasynaptic GABA_A receptors may be candidates for further study in the treatment of OPNA-induced SE.     

GABAB receptor activation exacerbates spontaneous spike-and-wave discharges in DBA/2J mice

Rich evidence has highlighted that stimulation of γ-amino-butyric acid (GABA)_B receptors increases the occurrence of spike-and-wave discharges (SWDs), the electroencephalographic (EEG) landmark of absence epilepsy (AE). Recent findings suggest that the outcomes of GABA_B activation in vivo are contingent on the chemical characteristics of the agonist. In particular, the endogenous ligand γ-hydroxybutyrate (GHB) and its precursor γ-butyro-lactone (GBL) have been shown to elicit different effects than the prototypical GABA_B agonist baclofen. In view of these premises, the present study was aimed at the characterization of the effects of baclofen (0.5–10 mg/kg, i.p.) and GBL (5–100 mg/kg, i.p.) on the spontaneous SWDs and locomotor activity of DBA/2J mice.While both baclofen and GBL dose-dependently increased SWDs episodes, high doses of the latter (100 mg/kg, i.p.) reduced the occurrence of these phenomena and increased the number of isolated spikes. Interestingly, both compounds elicited a dose-dependent reduction of locomotor activity, in comparison with their vehicle-treated controls. The GABA_B selective antagonist, SCH50911 (50 mg/kg, i.p.), reversed the changes in SWD occurrence and locomotion induced by baclofen and GBL, but failed to elicit intrinsic effects on either paradigm. These results indicate that GABA_B receptor signaling might exert differential effects on SWDs in DBA/2J mice.     

βCCT,an antagonist selective for α1GABAA receptors,reverses diazepam withdrawal-induced anxiety in rats

The abrupt discontinuation of prolonged benzodiazepine treatment elicits a withdrawal syndrome with increased anxiety as a major symptom. The neural mechanisms underlying benzodiazepine physical dependence are still insufficiently understood. Flumazenil, the non-selective antagonist of the benzodiazepine binding site of GABA_A receptors was capable of preventing and reversing the increased anxiety during benzodiazepine withdrawal in animals and humans in some, but not all studies. On the other hand, a number of data suggest that GABA_A receptors containing α₁ subunits are critically involved in processes developing during prolonged use of benzodiazepines, such are tolerance to sedative effects, liability to physical dependence and addiction. Hence, we investigated in the elevated plus maze the level of anxiety 24 h following 21 days of diazepam treatment and the influence of flumazenil or a preferential α₁-subunit selective antagonist βCCt on diazepam withdrawal syndrome in rats. Abrupt cessation of protracted once-daily intraperitoneal administration of 2 mg/kg diazepam induced a withdrawal syndrome, measured by increased anxiety-like behavior in the elevated plus maze 24 h after treatment cessation. Acute challenge with either flumazenil (10 mg/kg) or βCCt (1.25, 5 and 20 mg/kg) alleviated the diazepam withdrawal-induced anxiety. Moreover, both antagonists induced an anxiolytic-like response close, though not identical, to that seen with acute administration of diazepam. These findings imply that the mechanism by which antagonism at GABA_A receptors may reverse the withdrawal-induced anxiety involves the α₁ subunit and prompt further studies aimed at linking the changes in behavior with possible adaptive changes in subunit expression and function of GABA_A receptors.     

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.     

Propofol facilitated excitatory postsynaptic currents frequency on nucleus tractus solitarii (NTS) neurons

Propofol, an intravenous anesthetic, is broadly used for general anesthesia and diagnostic sedations due to its fast onset and recovery. Propofol depresses respiratory and cardiovascular reflex responses, however, their underlying mechanisms are not well known. Cardiorespiratory information from visceral afferent vagus nerves is integrated in the nucleus tractus solitarii (NTS). Cardiac and respiratory signals transducing vagal afferent neurons release the excitatory neurotransmitter glutamate onto NTS neurons in an activity dependent manner and trigger negative feedback reflex responses. In this experiment, the effects of propofol on glutamatergic synaptic responses at NTS neurons was tested using patch clamp methods. Glutamatergic excitatory postsynaptic currents (EPSC) were recorded at chloride reversal potential (? 49 mV) without γ-aminobutyric acid type A (GABA_A) receptor antagonists. Propofol (≥ 3 μM) facilitated frequency of the spontaneous EPSCs in a concentration dependent manner without altering amplitude and decay time. The GABA_A receptor selective antagonist, gabazine (6 μM), attenuated propofol effects on glutamate release. Propofol (10 μM) evoked glutamate release was also blocked in the presence of the voltage dependent Na⁺ and Ca²⁺ channel blockers TTX (0.3 μM) and Cd²⁺ (0.2 mM), respectively. In addition, the Na⁺–K⁺–Cl^? cotransporter type 1 antagonist bumetanide (10 μM) also inhibited propofol evoked increase in sEPSC frequency. These results suggest that propofol evoked glutamate release onto NTS neurons by GABA_A receptor-mediated depolarization of the presynaptic excitatory terminals.     

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.     

Seizure susceptibility alteration through 5-HT3 receptor: Modulation by nitric oxide

There is some evidence that epileptic seizures could be induced or increased by 5-hydroxytryptamine (5-HT) attenuation, while augmentation of serotonin functions within the brain (e.g. by SSRIs) has been reported to be anticonvulsant. This study was performed to determine the effect of selective 5-HT₃ channel/receptor antagonist granisetron and agonist SR57227 hydrochloride on the pentylenetetrazole (PTZ)-induced seizure threshold in mice. The possible interaction of this effect with nitrergic system was also examined using the nitric oxide (NO) synthase inhibitor N^G-nitro-l-arginine methyl ester (l-NAME) and the NO precursor l-arginine. SR57227 (10 mg/kg, i.p.) significantly increased the seizure threshold compared to control group, while high dose granisetron (10 mg/kg, i.p.) proved proconvulsant. Co-administration of sub-effective doses of the 5-HT₃ agonist with l-NAME (5 and 60 mg/kg, i.p., respectively) exerted a significant anticonvulsive effect, while sub-effective doses of granisetron (3 mg/kg) was observed to have a proconvulsive action with the addition of l-arginine (75 mg/kg, i.p.). Our data demonstrate that enhancement of 5-HT₃ receptor function results in as anticonvulsant effect in the PTZ-induced seizure model, and that selective antagonism at the 5-HT₃ receptor yields proconvulsive effects. Furthermore, the NO system may play a role in 5-HT₃ receptor function.     

Naringin ameliorates pentylenetetrazol-induced seizures and associated oxidative stress,inflammation, and cognitive impairment in rats: Possible mechanisms of neuroprotection

Oxidative stress and cognitive impairment are associated with PTZ-induced convulsions. Naringin is a bioflavonoid present in the grapefruit. It is a potent antioxidant, and we evaluated its effect on PTZ-induced convulsions. Rats were pretreated with normal saline, naringin (20, 40, and 80 mg/kg, i.p.), or diazepam (5 mg/kg, i.p.) 30 min prior to the administration of PTZ. The administration of PTZ induced myoclonic jerks and generalized tonic–clonic seizures (GTSs). We observed that naringin significantly prolonged the induction of myoclonic jerks dose-dependently. Naringin (80 mg/kg, i.p.) pretreatment protected all rats, and this protective effect was annulled by the GABA_A receptor antagonist, flumazenil. In addition, naringin reduced brain MDA and TNF-α levels and conserved GSH. The pretreatment also enhanced the performance of rats in the passive avoidance task. Our observations highlight the antioxidant, antiinflammatory, and anticonvulsant potential of naringin. Also, naringin modulates the GABA_A receptor to produce anticonvulsant effects and to ameliorate cognitive impairment.     

Changes in the cannabinoids receptors in rats following treatment with antidepressants

The endocannabinoid (eCB) system plays a significant role in the pathophysiology of depression. The potential participation of this system in the mechanism of action of antidepressants has been highlighted in recent years. The aim of this study was to investigate the expression of cannabinoid (CB) receptors using Western blot and CB₁ receptor density using autoradiography after acute or chronic administration of antidepressant drugs [imipramine (IMI, 15 mg/kg), escitalopram (ESC, 10 mg/kg) and tianeptine (TIA, 10 mg/kg)]. Antidepressants given chronically elevated CB₁ receptor density in the cortical structures and hippocampal areas, while a decrease of CB₁ receptor density was observed in the striatum after IMI and ESC treatment. The CB₁ receptor expression decreases in the dorsal striatum after chronic administration of IMI and ESC or the receptor rise in the hippocampus after chronic ESC and TIA treatment were confirmed using Western blot analyses. An increase in the CB₂ receptor expression was observed in the cortical structures and hippocampus after chronic administration of ESC and TIA, while a decrease in this expression was noted in the striatum and cerebellum after chronic IMI treatment. Our results provide clear evidence that the antidepressant exposures provoke some modulations within the eCB system through CB receptors.     

A water extract of Mucuna pruriens provides long-term amelioration of parkinsonism with reduced risk for dyskinesias

Dopaminergic anti-parkinsonian medications, such as levodopa (LD) cause drug-induced dyskinesias (DID) in majority of patients with Parkinson’s disease (PD). Mucuna pruriens, a legume extensively used in Ayurveda to treat PD, is reputed to provide anti-parkinsonian benefits without inducing DID. We compared the behavioral effects of chronic parenteral administration of a water extract of M. pruriens seed powder (MPE) alone without any additives, MPE combined with the peripheral dopa-decarboxylase inhibitor (DDCI) benserazide (MPE + BZ), LD + BZ and LD alone without BZ in the hemiparkinsonian rat model of PD. A battery of behavioral tests assessed by blinded investigators served as outcome measures in these randomized trials. In experiment 1, animals that received LD + BZ or MPE + BZ at high (6 mg/kg) and medium (4 mg/kg) equivalent doses demonstrated significant alleviation of parkinsonism, but, developed severe dose-dependent DID. LD + BZ at low doses (2 mg/kg) did not provide significant alleviation of parkinsonism. In contrast, MPE + BZ at an equivalent low dose significantly ameliorated parkinsonism. In experiment 2, MPE without any additives (12 mg/kg and 20 mg/kg LD equivalent dose) alleviated parkinsonism with significantly less DID compared to LD + BZ or MPE + BZ. In experiment 3, MPE without additives administered chronically provided long-term anti-parkinsonian benefits without causing DID. In experiment 4, MPE alone provided significantly more behavioral benefit when compared to the equivalent dose of synthetic LD alone without BZ. In experiment 5, MPE alone reduced the severity of DID in animals initially primed with LD + BZ. These findings suggest that M. pruriens contains water-soluble ingredients that either have an intrinsic DDCI-like activity or mitigate the need for an add-on DDCI to ameliorate parkinsonism. These unique long-term anti-parkinsonian effects of a parenterally administered water extract of M. pruriens seed powder may provide a platform for future drug discoveries and novel treatment strategies in PD.     

Administration of lithium and magnesium chloride inhibited tolerance to the anticonvulsant effect of morphine on pentylenetetrazole-induced seizures in mice

Although morphine has an anticonvulsant effect in several animal models of seizures, its potential clinical application in epilepsy may be hindered by its adverse effects like opioid tolerance. The present study evaluated the development of tolerance to the anticonvulsant effect of morphine in a model of clonic seizures induced with pentylenetetrazole (PTZ) in male Swiss mice. We also examined whether administration of either lithium chloride (LiCl) or magnesium chloride (MgCl₂) was able to prevent the probable tolerance. Our data demonstrated that the anticonvulsant effect of a potent dose of morphine (1 mg/kg) was abolished in chronic morphine-treated mice (mice administered the same dose of morphine intraperitoneally twice daily for 4 days). Four days of pretreatment with low and noneffective doses of MgCl₂ (2 and 5 mg/kg) and LiCl (5 mg/kg) inhibited the development of tolerance to the anticonvulsant effect of morphine (1 mg/kg, ip). Moreover, a single acute injection of the aforementioned agents at the same doses reversed the expression of tolerance to the anticonvulsant effects of morphine (1 mg/kg, ip). Chronic 17-day treatment with LiCl (600 mg/L in drinking water) also inhibited the development of tolerance to the anticonvulsant effects of 1 mg/kg morphine. These results demonstrate that the anticonvulsant effect of morphine is subject to tolerance after repeated administration. Both development and expression of tolerance are inhibited by either LiCl or MgCl₂. As both LiCl and MgCl₂ can modulate the function of N-methyl-d-aspartate (NMDA) receptors, we discuss how NMDA receptor functioning might be involved in the effects of LiCl and MgCl₂ on the development of tolerance to the anticonvulsant effect of morphine.     

Changes in hippocampal GABAA/cBZR density during limbic epileptogenesis: Relationship to cell loss and mossy fibre sprouting

Reduced GABA_A/central benzodiazepine receptor (GABA_A/cBZR) density, mossy fibre sprouting (MFS) and hippocampal cell loss are well described pathological features of human temporal lobe epilepsy (TLE), and animal models thereof. However, the temporal relationship of their development, and their roles in the emergence of the epilepsy, are uncertain. This was investigated in the kainic acid (KA)-induced post-status epilepticus (SE) model of TLE. Male Wistar rats (7 weeks, n = 53) were randomised into control and KA groups. At 24 h, 2, 4 or 6 weeks sham and KA post-SE animals were euthanised, brains extracted and GABA_A/cBZR density, neuronal loss and MFS measured in hippocampal sub-regions. GABA_A/cBZR density (B_max) was measured by saturation-binding analysis using [³H]-flumazenil. At 24 h post-SE GABA_A/cBZR density was increased in almost all hippocampal subregions, but was decreased at the later time points with the exception of the dentate gyrus. There was significant neuronal loss in the CA3 SPc region (?24±9.3%, p<0.05) at 24h, which remained stable at the later time points associated with an elevated GABA_A/cBZR density per surviving neuron at 24h post-SE (+56.4%; p<0.05) which returned to control levels by 6 weeks post-SE. MFS in the dentate gyrus progressively increased over the 6 weeks following SE (+ 70.6% at 6 weeks), at which time there was a significant inverse relationship with GABA_A/cBZR binding (r² = 0.87; p = 0.02). The temporal evolution of GABA_A/cBZR density changes post-KA-induced SE, and the relationship with decreases in hippocampal pyramidal cell numbers and MFS, may point to a key role for these changes in the pathogenesis of acquired limbic epileptogenesis.     

Positive modulation of α5 GABAA receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide

We previously demonstrated that lipopolysaccharide (LPS) administered intraperitoneally (i.p.) to pregnant Wistar rat dams, at embryonic days 15 and 16 (E15/16), induced a decrease of baseline locomotor activity and diminished reactivity to amphetamine in adult female offspring. In the present study we aimed to assess the duration of LPS-induced maternal immune activation (MIA) and investigate possible changes in levels of main neurotransmitters in fetal brain during MIA. We hypothesized that the observed behavioral changes may be linked with MIA-induced disturbance of prenatal GABAergic system development, especially with α5 GABA_A receptors (α5GABA_ARs), expression of which takes place between E14 and E17. Thereafter, we set to investigate if later potentiation of α5GABA_ARs in offspring’s preadolescence (from postnatal day 22–28) could prevent the deficit in locomotor reactivity to amphetamine observed in adulthood, at postnatal day P60. The elevation of IL-6 in amniotic fluid 6 h after LPS treatment (100 μg/kg, i.p.) at E15 was concurrent with a significant increase of GABA and decrease of glutamate concentration in fetal brain. Moreover, repeated administration of MP-III-022, a selective positive allosteric modulator of α5GABA_ARs, at a dose (2 mg/kg daily, i.p.) derived from a separate pharmacokinetic study, prevented the LPS-induced decrease in locomotor reactivity to amphetamine (0.5 mg/kg, i.p.) in adult females. These results were not mirrored in the parallel set of experiments with male offspring from LPS-treated rats. The results suggest that pharmacological potentiation of α5GABA_ARs activity in preadolescence may ameliorate at least some of adverse consequences of exposure to MIA in utero.     

Effects of asenapine,olanzapine, and risperidone on psychotomimetic-induced reversal-learning deficits in the rat

BackgroundAsenapine is a new pharmacological agent for the acute treatment of schizophrenia and bipolar disorder. It has relatively higher affinity for serotonergic and α₂-adrenergic than dopaminergic D₂ receptors. We evaluated the effects of asenapine, risperidone, and olanzapine on acute and subchronic psychotomimetic-induced disruption of cued reversal learning in rats.MethodsAfter operant training, rats were treated acutely with d-amphetamine (0.75 mg/kg intraperitoneally [i.p.]) or phencyclidine (PCP; 1.5 mg/kg i.p.) or subchronically with PCP (2 mg/kg i.p. for 7 days). We assessed the effects of acute coadministration of asenapine, risperidone, or olanzapine on acute d-amphetamine- and PCP-induced deficits and the effects of long-term coadministration of these agents (for 28 additional days) on the deficits induced by subchronic PCP.ResultsDeficits in reversal learning induced by acute d-amphetamine were attenuated by risperidone (0.2 mg/kg i.p.). Acute PCP-induced impairment of reversal learning was attenuated by acute asenapine (0.025 mg/kg subcutaneously [s.c.]), risperidone (0.2 mg/kg i.p.), and olanzapine (1.0 mg/kg i.p.). Subchronic PCP administration induced an enduring deficit that was attenuated by acute asenapine (0.075 mg/kg s.c.) and by olanzapine (1.5 mg/kg i.p.). Asenapine (0.075 mg/kg s.c.), risperidone (0.2 mg/kg i.p.), and olanzapine (1.0 mg/kg i.p.) all showed sustained efficacy with chronic (29 days) treatment to improve subchronic PCP-induced impairments.ConclusionThese data suggest that asenapine may have beneficial effects in the treatment of cognitive symptoms in schizophrenia. However, this remains to be validated by further clinical evaluation.