Six single nucleotide polymorphisms (SNPs) present in the PTGS2/PLA2G4A locus were detected among 118 British family trios of schizophrenia patients. The transmission disequilibrium test showed that SNP4 located in the 5′-flanking region of the PLA2G4A gene was associated with schizophrenia and that the haplotype analysis also showed a genetic association between the PTGS2 gene and schizophrenia. Because these two genes are arranged in a head-to-head configuration and separated by just about 149 kb of DNA, they may have a combined effect on susceptibility to schizophrenia in some cases.

European Journal of PainVolume 13, Issue S1 p. S71c-S72 221 EFFECT OF SEX HORMONES ON MECHANICAL AND COLD ALLODYNIA FOLLOWING SCIATIC NERVE LIGATION IN RATS A. Malyshkin, A. Malyshkin Pavlov State Medical University, Saint-Petersburg, RussiaSearch for more papers by this authorE. Shekunova, E. Shekunova Pavlov State Medical University, Saint-Petersburg, RussiaSearch for more papers by this authorV. Kashkin, V. Kashkin Pavlov State Medical University, Saint-Petersburg, RussiaSearch for more papers by this author A. Malyshkin, A. Malyshkin Pavlov State Medical University, Saint-Petersburg, RussiaSearch for more papers by this authorE. Shekunova, E. Shekunova Pavlov State Medical University, Saint-Petersburg, RussiaSearch for more papers by this authorV. Kashkin, V. Kashkin Pavlov State Medical University, Saint-Petersburg, RussiaSearch for more papers by this author First published: 12 January 2012 https://doi.org/10.1016/S1090-3801(09)60224-XRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume13, IssueS1September 2009Pages S71c-S72 RelatedInformation

Fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] was suggested to possess anxiolytic actions 30 years ago. Hoffmann-La Roche researchers recently reported that it is a selective and potent mGlu5 receptor antagonist, acting as a negative allosteric modulator. In the present study, we show that fenobam readily penetrates to the brain, reaching concentrations over 600 nM, clearly above the affinity for mGluR5 receptors. Fenobam (at 10, 30, and 100 mg/kg) did not affect horizontal locomotor activity in the open field test. Anxiolytic-like activity in the context freezing test was seen at 30 mg/kg, while fenobam was not active in the elevated plus maze test at the tested concentrations. Fenobam had antinociceptive actions in the formalin test at 10 and 30 mg/kg, but failed to attenuate mechanical allodynia in the chronic constriction injury model. Impairment of learning was revealed in the passive avoidance test at 30 mg/kg. Fenobam also impaired performance in both the Morris water maze and in the contextual fear conditioning test at the doses of 30 and 10 mg/kg, respectively. Prepulse inhibition, used as a model of psychomimetic activity, was not affected by fenobam at doses of up to 60 mg/kg. Our results indicate that the beneficial effects of fenobam occur in a similar dose range as the potential side-effects.

In the current study we compared the potency of the selective metabotropic glutamate receptor (mGluR1) antagonist A-841720 (7-Azepan-1-yl-4-dimethylamino-7H-9-thia-1,5,7-triaza-fluoren-8-one) in rodent models of pain with its effects in models of learning and memory, to obtain information regarding the therapeutic window of this compound. A-841720 significantly reduced formalin-induced behaviours and complete Freund's adjuvant (CFA)-induced tactile allodynia, starting at doses of 1 and 10 mg/kg, respectively. At the dose of 3 mg/kg, however, A-841720 significantly reduced the percentage of spontaneous alternations in a radial-maze task. In contextual-fear conditioning, A-841720, given at the dose of 10 mg/kg before acquisition, significantly reduced freezing behaviour tested 24 h later. In the same task, repeated treatment for 5 days did not reduce the impairing effect of the challenge dose, indicating a lack of tolerance development. In a passive-avoidance task, A-841720 at 10 mg/kg administered before acquisition, significantly reduced the latency to enter the dark box on the retention test. Given that complete Freund's adjuvant is a better measure of analgesia, these results indicate that the selective mGluR1 antagonist A-841720 has analgesic potential in a dose range at which it also produces memory impairments. This diminishes its therapeutic potential for the treatment of chronic pain.

N-acetylated-alpha-linked-acidic peptidase (NAAG peptidase) converts N-acetyl-aspartyl-glutamate (NAAG, mGluR3 agonist) into N-acetyl-aspartate and glutamate. The NAAG peptidase inhibitor 2-PMPA (2-(phosphonomethyl)pentanedioic acid) had neuroprotective activity in an animal model of stroke and anti-allodynic activity in CCI model despite its uncertain ability to penetrate the blood-brain barrier. The NAAG concentration in brain ECF under basal conditions and its alteration in relation to the brain ECF concentration of 2-PMPA is unclear. We therefore assessed those brain concentrations after i.p. administration of 2-PMPA, using in vivo microdialysis combined with LC/MS/MS analysis. Administration of 2-PMPA (50mg/kg) produced a mean peak concentration of 2-PMPA of 29.66+/-8.1microM. This concentration is about 100,000 fold more than is needed for inhibition of NAAG peptidase, and indicates very good penetration to the brain. Application of 2-PMPA was followed by a linear increase of NAAG-concentration reaching a maximum of 2.89+/-0.42microM at the end of microdialysis. However, during the time the anti-allodynic effects of 2-PMPA were observed, the NAAG concentration in the ECF did not reach levels which are likely to have an impact on any known target. It appears therefore that the observed behavioural effects of 2-PMPA may not be mediated by NAAG nor, in turn, by mGluR3 receptors.

Previous studies suggested that combining N-methyl-d-aspartate (NMDA) receptor antagonists with either mu-opioid agonist morphine or alpha2-adrenoreceptor agonist clonidine results in the significant synergistic enhancement of analgesic activity in the animal models of acute and neuropathic pain. When given alone, NMDA receptor antagonists, morphine and clonidine are capable of attenuating tactile allodynia associated with chronic nerve injury. The present study aimed to assess anti-allodynic effects of these compounds and to test additivity of these interactions using isobolographic analysis. Adult male Wistar rats with unilateral loose ligation of sciatic nerve developed significant tactile allodynia (between-paw difference of about 18-20 g). In separate groups of animals, dose-dependent anti-allodynic activity was confirmed for memantine (1.8-17.8 mg/kg), neramexane (1.8-17.8 mg/kg), morphine (1-10 mg/kg) and clonidine (0.01-0.1 mg/kg). In a subsequent series of experiments, memantine (or neramexane) and morphine (or clonidine) were co-administered at the fixed equi-effective dose ratios (six dose levels per drug combination). None of the tested combinations produced supra-additive, synergistic effects. In fact, memantine+clonidine, neramexane+clonidine and morphine+neramexane were producing simple additive effects, while morphine+memantine was characterized as the infra-additive combination. Thus, despite expectations based on previous studies, NMDA receptor channel blockers, memantine and neramexane, produce no synergistic interactions with either morphine or clonidine when administered acutely to rats with nerve injury-induced tactile allodynia.

Racial differences in erythrocyte potassium effluxes mediated by two loop-diuretic sensitive modes of cotransport were compared. In red cells loaded to contain approximately equimolar amounts of sodium and potassium, black subjects had lower bumetanide-sensitive sodium-dependent net potassium effluxes as compared to whites. In fresh, washed erythrocytes pretreated with N-ethylmaleimide (NEM), maximal net potassium efflux was greater in blacks than in whites. NEM-stimulated potassium efflux was partially inhibited by bumetanide but only at very high concentrations. The quantitative differences in these two modes of potassium efflux suggest that NEM-stimulated potassium efflux is not an altered mode of sodium-dependent potassium efflux.

In contrast to conventional opioid analgesics, antagonists acting at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors are capable of suppressing pain-related phenomena in chronic pain models while having little or no effect on acute nociception. One of the few clinically used NMDA receptor antagonists, memantine, differs from prototypic antagonists with psychotomimetic activity such as phencyclidine and (+)MK-801, in showing lower receptor affinity, faster unblocking kinetics and stronger voltage-dependency. Recently, a series of novel amino-alkyl-cyclohexanes was reported to interact with NMDA receptors in a manner similar to that of memantine. The present study aimed to evaluate the effects of these compounds as well as (+)MK-801 and memantine in two rat models of chronic pain and the rotarod test. Unlike (+)MK-801 and memantine, most of the tested compounds were inactive against tactile allodynia induced by sciatic nerve ligation. On the other hand, all tested drugs were found to inhibit formalin-induced grooming behavior—a model of chronic pain induction. In agreement with previous reports on the effects of NMDA receptor antagonists in similar assays, the late phase seemed to be inhibited to a greater extent than the early phase. For all tested compounds, inhibition of formalin-induced behaviors occurred at dose levels that were also producing significant motor deficits (rotarod test). These results confirm low efficacy of acute administration of NMDA receptor antagonists in the models of established pain states. Thus, studies on the prevention and management of chronic pain should focus on preemptive or long-term administration of NMDA receptor antagonists.

Several drugs, such as N-methyl-D-aspartate (NMDA) receptor channel blockers (memantine), naltrexone (but not naloxone) and acamprosate, have previously been reported to attenuate the expression of the alcohol deprivation effect, a phenomenon seen as an increase in post-deprivation alcohol consumption. The present study aimed to evaluate the effects of these drugs on the development and expression of the saccharin deprivation effect in adult male Wistar rats. Memantine (13 mg/kg per day) and naltrexone (5 mg/kg, twice daily), but not naloxone (24 mg/kg per day) or acamprosate (200 mg/kg, twice daily), prevented the increase in the consumption of saccharin after a 1-week deprivation from free-choice, unlimited access to saccharin (0.1%, w/v). Taken together with the results of previous studies, these results suggest that naltrexone and memantine attenuate the expression of both the alcohol and saccharin deprivation effects.

Animal models are needed to study the abuse-related behavioral and pharmacological effects of inhaled solvents. Previous studies have suggested that intracranial self-stimulation techniques may be successfully adapted for testing the effects of solvent exposure. The present study aimed to assess the effects of toluene, cyclohexane, acetone, and petroleum benzine (a widely used mixture of hexanes and heptanes) in rats trained to lever press or nose-poke for electrical stimulation delivered through electrodes implanted into the medial forebrain bundle. It was found that toluene, cyclohexane, and benzine but not acetone, increased rates of responding, particularly at the lower stimulation intensities. In another set of experiments utilizing an auto-titration procedure, all tested solvents significantly reduced self-stimulation thresholds. However, only for toluene and benzine were these effects observed at the exposure levels that did not impair rates of operant performance. There may not be such a clear separation of effects for acetone and cyclohexane. Thus, toluene and benzine appear to selectively affect brain reward systems in a manner similar to that for most other abused drugs. Data from intracranial self-stimulation studies of solvents may be useful in abuse potential assessment of individual compounds and for examining neural and behavioral processes involved in inhalant abuse.

In humans and laboratory animals, drug withdrawal often is associated with depression-like behaviors. In the present study, rats had unlimited free-choice access to water and a saccharin-containing solution before being subjected to repeated episodes of saccharin deprivation. Saccharin deprivation (1) reduced immobility time in the forced swim test, (2) increased reinforcement rate in rats trained to lever-press under the differential reinforcement of a low-rate (72-sec) schedule of food reinforcement, and (3) lowered intracranial self-stimulation thresholds in a discrete-trial current titration procedure. Taken together, these findings suggest that deprivation from a nondrug reinforcer, saccharin, is not associated with depression-like behaviors. In contrast, saccharin-deprived rats demonstrated improved performance in the behavioral paradigms used here.