Effects Of Dextromethorphan Research Articles

Effects of Dextromethorphan on Nicotine-Induced Reward, Behavioral Sensitization, Withdrawal Signs, and Drug Seeking-Related Behavior in Rats.

Tobacco products are addictive, with nicotine serving as the major addictive ingredient. Chronic tobacco use or chronic administration of nicotine alone results in both physiological and psychological dependence. Our previous studies indicated that dextromethorphan (DM) could effectively attenuate the dependence of morphine and methamphetamine. Thus, we further investigated the possible effects of DM on nicotine dependence. Conditioned place preference (CPP) test was used to examine nicotine-induced rewarding effects as well as the drug-seeking-related behavior in rats. Nicotine dependence was induced by continuous subcutaneous infusion of nicotine via an osmotic minipump for 7 days and abstinence was initiated by removal of the pump. Withdrawal signs were observed and quantified. Locomotor activity was measured to determine the behavioral sensitization induced by nicotine. To investigate the activity of mesolimbic dopaminergic neuronal activity in correlation with the effects of nicotine, the animals were sacrificed and the nucleus accumbens (NAc), dorsal striatum (DS), and medial prefrontal cortex (mPFC) were dissected and used to determine the contents of dopamine (DA) and its metabolites using high-performance liquid chromatography (HPLC). Our results showed that DM could suppress nicotine-induced rewarding effect and drug-seeking-related behavior. In addition, co-administration and post-treatment of DM could both attenuate nicotine withdrawal signs. Moreover, DM could suppress nicotine-induced behavioral sensitization. Neurochemical experiments show that co-administration and post-treatment of DM abolished nicotine-induced increase of the DA turnover rate in the mPFC, but not in the NAc and DS. The results suggest that DM has a great therapeutic potential in the treatment of nicotine dependence. Our results showed that DM could suppress nicotine-induced rewarding effect and drug-seeking-related behavior. In addition, co-administration and post-treatment of DM could both attenuate nicotine withdrawal signs. Moreover, DM could suppress nicotine-induced behavioral sensitization. Neurochemical experiments show that co-administration and post-treatment of DM abolished nicotine-induced increase of the DA turnover rate in the mPFC, but not in the NAc and DS. These results suggest that DM has a great therapeutic potential in the treatment of nicotine dependence.

Preliminary Results on the Long-Term Effects of Dextromethorphan on MDMA-Mediated Serotonergic Deficiency and Volumetric Changes in Primates Based on 4-[18F]-ADAM PET/MRI.

Alterations to the serotonergic system due to 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy) consumption have been extensively documented. However, knowledge of the reversibility of these neurotoxic effects based on in vivo evaluations of serotonin transport (SERT) availability remains limited. This study aimed to evaluate the long-term neurotoxicity of MDMA after 66 months abstinence and explored whether Dextromethorphan, a non-competitive N-methyl-D-aspartate (NMDA) receptor, could attenuate MDMA-induced neurotoxicity using 4-[18F]-ADAM, an imaging ligand that selectively targets SERT, with positron emission tomography technology (PET). Nine monkeys (Macaca cyclopis) were used in this study: control, MDMA, and DM + MDMA. Static 4-[18F]-ADAM PET was performed at 60 and 66 months after drug treatment. Serotonin transport (SERT) availability was presented as the specific uptake ratios (SURs) of 4-[18F]-ADAM in brain regions. Voxel-based region-specific SERT availability was calculated to generate 3D PET/MR images. Structural Magnetic Resonance Imaging (MRI) volumetric analysis was also conducted at 60 months. Significantly decreased 4-[18F]-ADAM SURs were observed in the striatum and thalamus of the MDMA group at 60 and 66 months compared to controls; the midbrain and frontal cortex SURs were similar at 60 and 66 months in the MDMA and control groups. All eleven brain regions showed significantly lower (∼13%) self-recovery rates over time; the occipital cortex and cingulate recovered to baseline by 66 months. DM attenuated MDMA-induced SERT deficiency on average, by ∼8 and ∼1% at 60 and 66 months, respectively; whereas significant differences were observed between the thalamus and amygdala of the MDMA and DM + MDMA groups at 66 months. Compared to controls, the MDMA group exhibited significantly increased (∼6.6%) gray matter volumes in the frontal cortex, occipital cortex, caudate nucleus, hippocampus, midbrain, and amygdala. Moreover, the gray matter volumes of the occipital cortex, hippocampus and amygdala correlated negatively with the 4-[18F]-ADAM SURs of the same regions. DM (n = 2) did not appear to affect MDMA-induced volumetric changes. The 4-[18F]-ADAM SURs, lower self-recovery rate and increased volumetric values indicate the occipital cortex, hippocampus and amygdala still exhibit MDMA-induced neurotoxicity after 66 months’ abstinence. Moreover, DM may prevent MDMA-induced serotonergic deficiency, as indicated by increased 4-[18F]-ADAM SURs and SERT availability, but not volumetric changes.

The Association Between Dextromethorphan Use and the Risk of Dementia.

Dementia is one of neurodegenerative disease without preventive medicine currently. Dextromethorphan (DXM) has been reported to reduce neuronal damage and neurodegeneration in animal and human models. The effect of DXM on the dementia has not been fully examined. We examined the medical records over 40 years old in Taiwan's National Health Insurance Research Database between 2000 and 2015 to establish matched cohorts. We used a Cox regression hazard model to identify risk factors of dementia during 16 years of follow-up, and the results indicate that a significantly lower percentage of subjects with DXM use (P < .001) developed dementia compared with those without DXM use (11.38%, 4541/39895 vs 18.66%, 29785/159580). After adjustment for age and other variables [adjusted hazard ratio: .567 (95% confidence interval: .413-.678, P < .001)], this study also demonstrated that DXM use appeared to reduce the risk of developing dementia. DXM use may potentially provide a protective effect against dementia.

Effect of dextromethorphan in the mouse forced swim and tail suspension tests: Evidence for involvement of the alpha receptors

Depression is a state of low mood that can seriously affect the quality of life of society. Therefore, finding new antidepressant agents with high efficacy is needed. Dextromethorphan (DXM) is an antitussive drug that has a potential effect on treating mood disorders, especially depression. However, because of limited data that relies on a few experimental animal studies mechanisms of action are yet not clear. The present study investigated the DXM effect in the forced swimming (FST) and tail suspension (TST) tests in mice and also the potential influence of the noradrenergic system in this effect. DXM (30 mg/kg, intraperitoneal (i.p.)) significantly decreased the immobility times in FST (P < 0.001) and TST (P < 0.01) comparable with positive controls, imipramine (IMI) 10 mg/kg and fluoxetine (20 mg/kg). Nevertheless, the number of crossings in the open-field test was not affected. The pretreatment with prazosin (1 mg/kg, i.p.; α1-adrenoceptor antagonist) or yohimbine (1 mg/kg, i.p.; α2-adrenoceptor antagonist) prevented the antidepressant effect of DXM (30 mg/kg, i.p). Moreover, the administration of a sub-effective dose of phenylephrine (5 mg/kg, i.p.; α1-adrenoceptor agonist) or clonidine (0.06 mg/kg, i.p.; α2-adrenoceptor agonist) potentiated the sub-effective dose of DXM (3 mg/kg, i.p.) in the FST and TST. The pretreatment with propranolol (5 mg/kg, i.p.; β-adrenoceptor antagonist) did not reverse the antidepressant-like effect of DXM. Thus, the present study suggests that the antidepressant-like effect of DXM may be partially related to α1/α2 adrenoceptors.

Dextromethorphan Attenuates Sensorineural Hearing Loss in an Animal Model and Population-Based Cohort Study.

The effect of dextromethorphan (DXM) use in sensorineural hearing loss (SNHL) has not been fully examined. We conducted an animal model and nationwide retrospective matched-cohort study to explore the association between DXM use and SNHL. Eight-week-old CBA/CaJ hearing loss was induced by a white noise 118 dB sound pressure level for 3 h. DXM (30 mg/kg) was administered intraperitoneally for 5 days and boost once round window DXM socking. In population-based study, we examined the medical records over 40 years old in Taiwan’s National Health Insurance Research Database between 2000 and 2015 to establish retrospective matched-cohort to explore the correlation between DXM use and SNHL. Using click auditory brainstem response (ABR), hearing threshold was measured as 48.6 ± 2.9 dB in control mice compared with 42.6 ± 7.0 dB in DXM mice, which differed significantly (p = 0.002) on day 60 after noise exposure with a larger ABR wave I amplitude in DXM mice. In human study, we used a Cox regression hazard model to indicate that a significantly lower percentage individuals developed SNHL compared with and without DXM use (0.44%, 175/39,895 vs. 1.05%, 1675/159,580, p < 0.001). After adjustment for age and other variables [adjusted hazard ratio: 0.725 (95% confidence interval: 0.624–0.803, p < 0.001)], this study also demonstrated that DXM use appeared to reduce the risk of developing SNHL. This animal study demonstrated that DXM significantly attenuated noise-induced hearing loss. In human study, DXM use may have a protective effect against SNHL.

Central Sensitization, N-methyl-D-aspartate Receptors, and Human Experimental Pain Models: Bridging the Gap between Target Discovery and Drug Development.

Central Sensitization, N-methyl-D-aspartate Receptors, and Human Experimental Pain Models: Bridging the Gap between Target Discovery and Drug Development.

NMDA receptor antagonists and pain relief: A meta-analysis of experimental trials.

We conducted a meta-analysis of controlled trials that used experimental models of acute pain and hyperalgesia to examine the analgesic effects of NMDA receptor (NMDAR) antagonists. Six major databases were systematically searched (to March 2018) for studies using human evoked pain models to compare NMDAR antagonists with no-intervention controls. Pain outcome data were analyzed with random-effects meta-analysis. Searches identified 70 eligible trials (n = 1,069). Meta-analysis found that low-dose ketamine (<1 mg/kg) produced a decrease in hyperalgesic area (standardized mean difference 0.54, 95% confidence interval [CI] 0.34, 0.74, p < 0.001) and a 1.2-point decrease (95% CI 0.88, 1.44, p < 0.001) in pain ratings from 4.6 to 3.4 on a 0-10 scale (a 26% reduction). Similar analgesia was observed for acute and hyperalgesic models and was constant across the dosing range (0.03-1.00 mg/kg). Moderate to high variability in effect size was observed and mild side effects (e.g., sedation, sensory disturbance) were common. No effects of dextromethorphan were found. Findings provide robust evidence for analgesic and antihyperalgesic effects of ketamine, supporting its utility for acute and chronic pain management. However, pain relief was modest, suggesting ketamine may potentially be most useful when opioids are contraindicated, rapid analgesia is required, or for pain resistant to conventional medication.

Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: effects on cognition.

Classic psychedelics (serotonin 2A receptor agonists) and dissociative hallucinogens (NMDA receptor antagonists), though differing in pharmacology, may share neuropsychological effects. These drugs, however, have undergone limited direct comparison. This report presents data from a double-blind, placebo-controlled within-subjects study comparing the neuropsychological effects of multiple doses of the classic psychedelic psilocybin with the effects of a single high dose of the dissociative hallucinogen dextromethorphan (DXM). Twenty hallucinogen users (11 females) completed neurocognitive assessments during five blinded drug administration sessions (10, 20, and 30 mg/70 kg psilocybin; 400 mg/70 kg DXM; and placebo) in which participants and study staff were informed that a large range of possible drug conditions may have been administered. Global cognitive impairment, assessed using the Mini-Mental State Examination during peak drug effects, was not observed with psilocybin or DXM. Orderly and dose-dependent effects of psilocybin were observed on psychomotor performance, working memory, episodic memory, associative learning, and visual perception. Effects of DXM on psychomotor performance, visual perception, and associative learning were in the range of effects of a moderate to high dose (20 to 30 mg/70 kg) of psilocybin. This was the first study of the dose effects of psilocybin on a large battery of neurocognitive assessments. Evidence of delirium or global cognitive impairment was not observed with either psilocybin or DXM. Psilocybin had greater effects than DXM on working memory. DXM had greater effects than all psilocybin doses on balance, episodic memory, response inhibition, and executive control.

Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT.

3,4-Methylenedioxymethamphetamine (MDMA), a common recreational drug, is known to cause serotonergic neurotoxicity in the brain. Dextromethorphan (DM) is a widely used antitussive reported to exert anti-inflammatory effect in vivo. In this study, we examined the long-term effect of MDMA on the primate serotonergic system and the protective property of DM against MDMA-induced serotonergic abnormality using single photon emission computed tomography (SPECT). Nine monkeys (Macaca cyclopis) were divided into three groups, namely control, MDMA and co-treatment (MDMA/DM). [123I]-ADAM was used as the radioligand for serotonin transporters (SERT) in SPECT scans. SERT levels of the brain were evaluated and presented as the uptake ratios (URs) of [123I]-ADAM in several regions of interest of the brain including midbrain, thalamus and striatum. We found that the URs of [123I]-ADAM were significantly lower in the brains of MDMA than control group, indicating lower brain SERT levels in the MDMA-treated monkeys. This MDMA-induced decrease in brain SERT levels could persist for over four years. However, the loss of brain SERT levels was not observed in co-treatment group. These results suggest that DM may exert a protective effect against MDMA-induced serotonergic toxicity in the brains of the non-human primate.

Effects of dextromethorphan as add-on to sitagliptin on blood glucose and serum insulin concentrations in individuals with type 2 diabetes mellitus: a randomized, placebo-controlled, double-blinded, multiple crossover, single-dose clinical trial.

In this clinical trial, we investigated the blood glucose (BG)‐lowering effects of 30, 60 and 90 mg dextromethorphan (DXM) as well as 100 mg sitagliptin alone versus combinations of DXM and sitagliptin during an oral glucose tolerance test (OGTT) in 20 men with T2DM. The combination of 60 mg DXM plus 100 mg sitagliptin was observed to have the strongest effect in the OGTT. It lowered maximum BG concentrations and increased the baseline‐adjusted area under the curve for serum insulin concentrations in the first 30 min of the OGTT (mean ± standard deviation 240 ± 47 mg/dl and 8.1 ± 6.1 mU/l/h, respectively) to a significantly larger extent than did 100 mg sitagliptin alone (254 ± 50 mg/dl and 5.8 ± 2.5 mU/l/h, respectively; p < 0.05) and placebo (272 ± 49 mg/dl and 3.9 ± 3.0 mU/l/h, respectively; p < 0.001). All study drugs were well tolerated, alone and in combination, without serious adverse events or hypoglycaemia. Long‐term clinical trials are now warranted to investigate the potential of the combination of 30 or 60 mg DXM and dipeptidyl peptidase‐4 inhibitors in the treatment of individuals with T2DM, in particular as preclinical studies have identified the β‐cell protective properties of DXM.

Effects of dextromethorphan and oxycodone on treatment of neuropathic pain in mice.

BackgroundNeuropathic pain is a very troublesome and difficult pain to treat. Although opioids are the best analgesics for cancer and surgical pain in clinic, only oxycodone among opioids shows better efficacy to alleviate neuropathic pain. However, many side effects associated with the use of oxycodone render the continued use of it in neuropathic pain treatment undesirable. Hence, we explored whether dextromethorphan (DM, a known N-methyl-D-aspartate receptor antagonist with neuroprotective properties) could potentiate the anti-allodynic effect of oxycodone and underlying mechanisms regarding to glial cells (astrocytes and microglia) activation and proinflammatory cytokines release in a spinal nerve injury (SNL) mice model.ResultsOxycodone produced a dose-dependent anti-allodynic effect. Co-administration of DM at a dose of 10 mg/kg (i.p.) (DM10) which had no anti-allodynic effect by itself enhanced the acute oxycodone (1 mg/kg, s.c.) effect. When the chronic anti-allodynic effects were examined, co-administration of DM10 also significantly enhanced the oxycodone effect at 3 mg/kg. Furthermore, oxycodone decreased SNL-induced activation of glial cells (astrocytes and microglia) and plasma levels of proinflammatory cytokines (IL-6, IL-1β and TNF-α). Co-administration of DM10 potentiated these effects of oxycodone.ConclusionThe combined use of DM with oxycodone may have therapeutic potential for decreasing the effective dose of oxycodone on the treatment of neuropathic pain. Attenuation of the glial activation and proinflammatory cytokines in the spinal cord may be important mechanisms for these effects of DM.

The Effects of Dextromethorphan on Driving Performance and the Standardized Field Sobriety Test.

Dextromethorphan (DXM) is abused most commonly among adolescents as a recreational drug to generate a dissociative experience. The objective of the study was to assess driving with and without DXM ingestion. The effects of one-time maximum daily doses of DXM 120 mg versus a guaifenesin 400 mg dose were compared among 40 healthy subjects using a crossover design. Subjects' ability to drive was assessed by their performance in a driving simulator (STISIM® Drive driving simulator software) and by conducting a standardized field sobriety test (SFST) administered 1-h postdrug administration. The one-time dose of DXM 120 mg did not demonstrate driving impairment on the STISIM® Drive driving simulator or increase SFST failures compared to guaifenesin 400 mg. Doses greater than the currently recommended maximum daily dose of 120 mg are necessary to perturb driving behavior.

Effects of dextromethorphan on glial cell function: Proliferation, maturation, and protection from cytotoxic molecules

Dextromethorphan (DM), a sigma receptor agonist and NMDA receptor antagonist, protects neurons from glutamate excitotoxicity, hypoxia and ischemia, and inhibits microglial activation, but its effects on differentiation and protection of cells in the oligodendroglial lineage are unknown. It is important to protect oligodendroglia (OL) to prevent demyelination and preserve axons, and to protect oligodendroglial progenitors (OPC) to optimize myelination during development and remyelination following damage. Enriched glial cultures from newborn rat brain were used 1-2 days or 6-8 days after shakeoff for OPC or mature OL. DM had large effects on glial proliferation in less mature cultures in contrast to small variable effects in mature cultures; 1 μM DM stimulated proliferation of OPC by 4-fold, microglia (MG) by 2.5-fold and astroglia (AS) by 2-fold. In agreement with increased OPC proliferation, treatment of OPC with DM for 3 days increased the % of OPC relative to OL, with a smaller difference by 5 days, suggesting that maturation of OPC to OL was "catching up" by 5 days. DM at 2 and 20 μM protected both OL and OPC from killing by glutamate as well as NMDA, AMPA, quinolinic acid, staurosporine, and reactive oxygen species (ROS). DM did not protect against kynurenic acid, and only modestly against NO. These agents and DM were not toxic to AS or MG at the concentrations used. Thus, DM stimulates proliferation of OPC, and protects both OL and OPC against excitotoxic and inflammatory insults.

Signs &amp; Symptoms of Dextromethorphan Exposure from YouTube

Detailed data on the recreational use of drugs are difficult to obtain through traditional means, especially for substances like Dextromethorphan (DXM) which are available over-the-counter for medicinal purposes. In this study, we show that information provided by commenters on YouTube is useful for uncovering the toxicologic effects of DXM. Using methods of computational linguistics, we were able to recreate many of the clinically described signs and symptoms of DXM ingestion at various doses, using information extracted from YouTube comments. Our study shows how social networks can enhance our understanding of recreational drug effects.

Effects Of Dextromethorphan Mediated Bitter Taste Receptor Activation In Pulmonary Artery Smooth Muscle Cells

Activation of bitter taste receptors (T2Rs) in human airway smooth muscle cells lead to muscle relaxation and bronchodilation. However, the presence of T2Rs in human pulmonary artery smooth muscle cells (hPASMCs) has not been established. The previous finding in airway smooth muscle led to our hypothesis that T2Rs, if present in hPASMCs, might be involved in regulating the vascular tone. RT‐PCR analysis revealed the expression of multiple T2R transcripts in hPASMCs. Functional analysis showed that these cells responded to many bitter‐tasting compounds, by increasing intracellular calcium concentration, indicating that T2Rs in hPASMCs are functional. Since the response of T2R1 to dextromethorphan (DXM) has been characterized in our previous studies, T2R1 was selected for further analysis in this study. Knockdown with T2R1‐specific shRNA decreased mRNA levels and DXM‐induced calcium responses by up to 40%. ELISA data obtained from in vitro studies using hPASMC showed that DXM‐treatment led to increased levels of endothelin‐1, biomarker of systemic hypertension. To analyze if T2R1 is involved in regulating the pulmonary vascular tone, ex vivo studies using pulmonary arterial rings are being pursued. Furthermore, it remains to be analyzed if this effect of DXM in hPASMCs is T2R1 specific or due to the blockade of NMDA receptors.Supported by MHRC, NSERC and a New Investigator Award from HSFC.

Suppressing Effect of Dextromethorphan or Clonidine on Fentanyl- Induced Coughing: A Double- Blind, Prospective, Randomized Placebo- Controlled Study

Background: Various medications have been examined to reduce fentanyl-induced cough. We studied the efficacy and safety of premedication with dextromethorphan or clonidine versus placebo prior to intravenous fentanyl injection on the cough reflex. Methods and Materials: In a randomized double-blind placebo controlled trial, 360 adult patients of American Society of Anesthesiologists physical status I-II, scheduled for elective surgery under general anesthesia were randomly allocated into three groups receiving clonidine (0.2 mg tablet orally),dextromethorphan (15 mg orally), or placebo 60 minutes before induction of anesthesia. The incidence of cough was recorded for 1 minute after fentanyl injection and graded as none (0), mild (1–2), moderate (3–5), and severe (>5 cough). Seventy three (20.3%) exhibited vigorous cough attacks during intravenous fentanyl administration. Results: The overall incidence of coughing in clonidine group (15.0%) and dextromethorphan (11.7%) group was lower than the placebo group (34.2%). Also, 3.3% of cases in the clonidine group and none of the patients in the dextromethorphan suffered from severe coughing, while 8.3% of the cases in the placebo group considered to have severe cough. Pretreatment with clonidine or dextromethorphan was positively associated with reduced incidence of fentanyl-induced cough after adjustment for potential confounders. Vital signs were all significantly lower following clonidine administration compared to both pretreatment regimens including dextromethorphan and placebo before and after intravenous fentanyl injection. Conclusion: Administering dextromethorphan or clonidine reduces the incidence of fentanyl-induced cough with better haemodynamic stability following the use of clonidine than dextromethorphan.

Immunobiology and Pharmacologic Manipulation of Dendritic and Regulatory Cells

Antigen presenting cells (APCs), especially dendritic cells (DCs), play a major role in the hierarchy of the induction of immune reactions. DCs are widely accepted as the most potent APCs capable of inducing protective adaptive immune responses in addition to tolerance to self-antigens. The role of DCs is currently being investigated in the context of many disease and therapeutic settings. In response to a variety of microbial and endogenous stimuli, resting DCs in peripheral tissues undergo a complex maturation process that might involve the regulation of genes that control distinct DC functions. The different functional properties of DCs are also linked to the existence of several subpopulations in humans and animals that differ in response to stimuli. In this special issue, several articles addressed some recent findings highlighting the interactions between key immune effectors both in vitro and in vivo and in different disease settings. V. R. Yanofsky et al. provided an in-depth analysis of DC biology, with a particular focus on skin DCs and their role in cutaneous carcinoma. C. Y. J. Chung et al. provided an overview of the role of DCs in the immunopathogenesis of autoimmunity, as well as recent concepts of DC-based therapeutic opportunities in autoimmune diseases. On the other hand, P. Ruiz et al. described the different treatments and some of the novel immunotherapeutic strategies undertaken to induce transplantation tolerance in general. More specifically, M. Michael et al. discussed the current knowledge of Treg biology and its potential for cell-based immunotherapy in allogeneic stem cell transplantation. The review by A. K. Gloudemans et al. summarized the latest literature on the role of mucosal IgA in protection against allergic airway disease, the mechanisms described to induce secretory IgA, and the role of (mucosal) DCs in this process. D.-Y. Chen et al. examined the effect of dextromethorphan (DXM), a common cough suppressant, on the activation and function of DCs. Interestingly, DXM decreased the LPS-induced surface expression of CD80, CD83, and HLA-DR and the secretion of IL-6 and IL-12 in human monocyte-derived DCs. These findings provide a new insight into the impact of DXM treatment on DCs and suggest that DXM has the potential to be used in treating DC-related acute and chronic diseases. Similarly, L. Adalid-Peralta et al. showed that cysticerci may modulate DCs to favor a suppressive environment, which may help parasite establishment, minimizing the excessive inflammation, which may lead to tissue damage. In the same line, R. N. Ramos et al. described that cytokines such as IL-10 and TGF-beta, as well as cell surface molecules like PD-L1 and ICOS, seem to be significantly involved in the redirection of DCs towards tolerance induction, and tumor cells may modulate distinct DC subpopulations through the involvement of these molecules. Another work from X. Gu et al. suggested that regulation of B7-H1 expression on hepatic stellate cells by IFN-γ represents an important mechanism that regulates immune responses in the liver favoring tolerogenicity rather than immunogenicity. Finally, A. Brosbol-Ravnborg et al. described how vitamin D3 and TLR agonists acted in synergy to alter secretion of cytokines from human DCs in a direction that may provide an anti-inflammatory environment. From a therapeutic perspective, C. Penna et al. elegantly showed that a combined treatment, including dexamethasone preconditioning followed by an inoculation of short-term LPS-stimulated type II collagen-loaded DCs, provides an improved strategy for attenuating arthritis severity. On the other hand, data from S. O. Akefeldt et al. suggested that targeting MCL1 and BCL2A1 in infiltrating DC may affect the clinical outcomes in rheumatoid arthritis (RA) and Langerhans cell histiocytosis (LCH). P. Cordiali-Fei et al. showed that in patients with limited systemic sclerosis, Treg cells were inversely correlated to disease duration, suggesting that their levels may represent a marker of disease progression. Interestingly, C. Donas et al. showed that Trichostatin A (TSA) could potentially be used to enhance the differentiation and suppressive function of CD4+Foxp3+ Treg cells. Finally, L. de la Cruz-Merino et al. reviewed some important aspects about the role of tumor-infiltrating lymphocytes (TIL) and their subtypes, tumor-associated macrophages (TAM), and myeloid-derived suppressive cells (MDSC) that will eventually be incorporated into diagnostic and therapeutic algorithms of breast cancer. The work from W. Maes et al. discussed based on an animal model the value of local elimination of Tregs within the tumor microenvironment which might represent an important tool from both fundamental and clinical perspectives. All in all, articles published in this special issue clearly show that DCs and Tregs are currently being considered as attractive targets towards manipulation of the immune system for therapeutic purposes in different human disease settings. Mohamad Mohty Arnon Nagler Nicolaus Kroger Beatrice Gaugler

Effect of Dextromethorphan on Reference Memory Assessed in Rats by a Three-panel Runway Task

The effects of dextromethorphan (DM, CAS 6700-34-1), a common over-the-counter cough suppressant, on the reference memory have been investigated by a three-panel runway setup in rats. This study was designed by using a repeated acquisition procedure such as a radialarm maze task or a water maze task. DM (20-40 mg/kg i.p.) produced a significant decrease in the number of errors (pushes made on the two incorrect panels of the three panel gates at four choice points) and latency. Systemically administered scopolamine (CAS 114-49-8) (1 mg/kg i.p.) impaired the performance on both parameters. DM (40 mg/kg i.p.) was effective in reversing the reference memory deficit induced by administration of scopolamine. DM acts as a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptors. Our results suggest that inhibition of NMDA receptors by DM supports its potential positive properties. This finding might present an oppurtunity for the evaluation of this old antitussive drug.

Differential alterations of GABAA receptor (α1, β2, γ2 subunit) expression and increased seizure susceptibility in rat offspring from morphine-addicted mothers: Beneficial effect of dextromethorphan

Differential alterations of GABAA receptor (α1, β2, γ2 subunit) expression and increased seizure susceptibility in rat offspring from morphine-addicted mothers: Beneficial effect of dextromethorphan

Dextromethorphan inhibits 5-hydroxytryptamine uptake by human blood platelets and decreases 5-hydroxyindoleacetic acid content in rat brain

The effect of dextromethorphan on the uptake and metabolism of 5-hydroxytryptamine (5-HT) was studied in human blood platelets and in rat brain. In the concentration of 120 nM dextromethorphan inhibited the uptake of 5-HT (1 mu-M) into platelets by 50%. The corresponding concentrations of imipramine and methadone under similar conditions were 22 and 590 nM, respectively. Dextromethorphan (20 to 40 mg kg-1) decreased the concentration of brain 5-hydroxyindoleacetic acid (5-HIAA) and the probenecid-induced accumulation of 5-HIAA time- and dose-dependently. However, dextromethorphan did not alter the pargyline-induced changes in brain 5-HT metabolism. Dextromethorphan-induced changes in brain 5-HT metabolism could arise from the inhibition of the re-uptake of 5-HT into neurons.