Acute Drug Administration Research Articles

Early life phenobarbital exposure dysregulates the hippocampal transcriptome.

Introduction: Phenobarbital (PB) and levetiracetam (LEV) are the first-line therapies for neonates with diagnosed seizures, however, a growing body of evidence shows that these drugs given during critical developmental windows trigger lasting molecular changes in the brain. While the targets and mechanism of action of these drugs are well understood-what is not known is how these drugs alter the transcriptomic landscape, and therefore molecular profile/gene expression during these critical windows of neurodevelopment. PB is associated with a range of neurotoxic effects in developing animals, from cell death to altered synaptic development to lasting behavioral impairment. LEV does not produce these effects. Methods: Here we evaluated the effects of PB and Lev on the hippocampal transcriptome by RNA sequencing. Neonatal rat pups were given a single dose of PB, Lev or vehicle and sacrificed 72h later-at time at which drug is expected to be cleared. Results: We found PB induces broad changes in the transcriptomic profile (124 differentially expressed transcripts), as compared to relatively small changes in LEV-treated animals (15 transcripts). PB exposure decreased GABAergic and oligodendrocyte markers pvalb and opalin, and increased the marker of activated microglia, cd68 and the astrocyte- associated gene vegfa. These data are consistent with the existing literature showing developmental neurotoxicity associated with PB, but not LEV. Discussion: The widespread change in gene expression after PB, which affected transcripts reflective of multiple cell types, may provide a link between acute drug administration and lasting drug toxicity.

Multi-targeted anti-inflammatory drugs for the treatment of neurological disorders.

Multi-targeted anti-inflammatory drugs for the treatment of neurological disorders.

Human behavioral pharmacology of psychedelics.

The past decade has witnessed a rapid growth of research on the basic science and clinical understanding of psychedelics. This chapter provides an overview of the human behavioral pharmacology of psychedelics focusing on three prototypic classic psychedelics-psilocybin, lysergic acid diethylamide (LSD), and dimethyltryptamine (DMT). A brief historical overview of the classic psychedelics and naming and drug classification is first specified. Next, special considerations in the conduct of human behavioral pharmacology work with psychedelics is described including the role of set and setting, mystical experience measurement, the use of effective blinding and placebos, and the abuse liability of psychedelics. Following, a description of the subjective, physiological, and clinical effects of psilocybin, LSD, and DMT is provided. This body of work clearly documents a unique and complex collection of subjective effects following psychedelic use, both during acute drug administration and as related to long-term behavior change following use. Clinical research demonstrates potential therapeutic utility with early phase clinical trials showing positive and enduring effects in many difficult-to-treat conditions including treatment-resistant depression, alcohol use disorder, and cigarette smoking. Future work in this newly reemerged field is needed to reveal mechanisms of behavior change in psychedelic drug action. Behavioral pharmacology is ultimately well served to provide this direction answering questions at the intersection of environment and pharmacology.

Effects of Acute Drug Administration on Emotion: a Review of Pharmacological MRI Studies

Many drug users claim to use drugs to cope with negative emotions, which may, in turn, result in persistent emotional blunting or anhedonia even when they are not using drugs. The purpose of this review is to describe the ways acute administration of psychoactive drugs impacts brain regions during emotion-related tasks, as a first step in understanding how drugs influence emotion processing in the brain. Drugs have varying effects on neural responses to emotional stimuli. In general, alcohol, analgesics, and psychedelics reduce neural reactivity to negative emotional stimuli in the amygdala and other brain regions. Other drugs produce mixed effects: Stimulants such as caffeine and modafinil increase brain activation while viewing emotional stimuli, whereas MDMA decreases activation during presentation of negative images. The effects of cannabinoids (cannabidiol and THC) are mixed. There are also inconsistent findings on the associations between neural responses to emotional stimuli and subjective drug effects. Consistent with the notion that individuals might use drugs non-medically to diminish the experience of negative emotions, several drugs of abuse decrease neural responses to negative stimuli in limbic brain regions. These neural actions may underlie the reported 'emotional blunting' of drugs, which may contribute to drug-seeking behavior. Future work is needed to examine these limbic responses in relation to self-reports of changes in affect, both during acute administration and after extended drug use.

Identification of the antidepressive properties of C1, a specific inhibitor of Skp2, in mice.

We have reported that SMIP004, an inhibitor of S-phase kinase-associated protein 2 (Skp2), displays antidepressant-like activities in stress-naïve and chronically stressed mice. Here, we investigated the antidepressant-like effect of C1, another inhibitor of Skp2, in mouse models following acute or chronic drug administration at different doses and treatment times by using the tail suspension test (TST), forced swimming test (FST), and social interaction test (SIT). The time- and dose-dependent results showed that the antidepressant-like effect of C1 occurred 8 days after the drug treatment, and C1 produced antidepressant-like activities at the dose of 5 and 10 but not 1 mg/kg in male or female mice. C1 administration (5 mg/kg) also induced antidepressant-like effects in stress-naïve mice in a three-times administration mode within 24 h (24, 5, and 1 h before the test) but not in an acute administration mode (1 h before the test). The C1 and fluoxetine co-administration produced additive effect on depression-like behaviors in stress-naïve mice. The antidepressant-like effect of C1 was not associated with the change in locomotor activity, as no increased locomotor activity was observed in different treatment modes. Furthermore, the long-term C1 treatment (5 mg/kg) was found to ameliorate the depression-like behaviors in chronic social defeat stress-exposed mice, suggesting that C1 can produce antidepressant-like actions in stress conditions. Since C1 is a specific inhibitor of Skp2, our results demonstrate that inhibition of Skp2 might be a potential strategy for the treatment of depression, and Skp2 may be potential target for the development of novel antidepressants.

Time-course of changes in key catecholaminergic receptors and trophic systems in rat brain after antidepressant administration

Several biochemical parameters within the brain are altered by antidepressants. However, it is still uncertain which parameters are important for the evaluation of the effectiveness of these drugs. What seems certain is that the response of the nervous system is dynamic. The dynamic nature of the nervous system is still poorly understood, although it has implications in clinical management. Criteria for evaluating treatment resistant depression are based on this temporal variability. The present study was designed to evaluate dynamic alterations in catecholaminergic receptors and calcyon (associated with monoaminergic theory of depression) in the rat brain as well as brain-derived neurotrophic factor (BDNF) and tyrosine kinase beta (TRKB; related to neurotrophin theory) induced by three antidepressant drugs (ADs) with various pharmacological profiles (imipramine, desipramine, and citalopram) administered for 21 days or acutely, followed by various drug-free periods. Receptor autoradiography and in situ hybridization studies allowed us to identify changes in various brain regions simultaneously in each rat. Repeated treatment with ADs induced biochemical alterations, which were in agreement with the results of previous studies. These alterations include the downregulation of β1, β2, and α1 adrenergic receptors, upregulation of α2-adrenergic receptors and dopamine D2 receptors, and increased expression of BDNF in the hippocampus. Additionally, we observed dynamic alterations in the measured parameters after acute drug administration, particularly at the level of dopamine receptors, which were extremely sensitive to a single dose of ADs followed by various drug-free periods. All three ADs induced the upregulation of dopamine D2 receptor mRNA levels in the nucleus accumbens. The same effect was induced by single doses of ADs followed by various drug-free periods. The obtained results indicate that alterations in the availability of neurotransmitters at synapses induced by ADs are strong enough to induce immediate and long-lasting adaptive changes in the neuronal network.

Characterization of Delta Opioid Receptor Activity of MMP2200, a Mixed Efficacy Mu and Delta Opioid Receptor Agonist

Pharmacological modulation of the delta opioid receptor (DOR) in conjunction with a mu‐opioid receptor (MOR) agonist produces antinociceptive effects with potentially a better side effect profile. MMP2200 (a.k.a.Lactomorphin) is a CNS permeable, glycosylated peptide and an agonist at both MORs and DORs. Previous reports characterized the MOR agonist effects of MMP2200; however, the DOR agonist effects of MMP2200in vivo have not been explored. DOR agonists, such as SNC80, have been shown to produce convulsions and discriminative stimulus effects in rodents. Therefore, based on the DOR agonist activity of MMP2200, we hypothesized that MMP2200 would produce DOR‐mediated convulsions in mice and SNC80‐like discriminative stimulus effects in rats. Convulsions were evaluated by continual observation for up to 60 min in an observation cage. For SNC80 discrimination experiments, rats were trained to discriminate an injection of 3.2 mg/kg SNC80 from saline under a fixed ratio 10 schedule of food reinforcement, and different doses of SNC80 or MMP2200 were substituted to evaluate percent generalization and response rates. MMP2200 produced brief, non‐lethal convulsions in C57BL/6N, but not ICR, mice that were blocked by the DOR antagonist naltrindole and by genetic deletion of DOR, indicating that MMP2200‐induced convulsions are DOR mediated. Following acute drug administration, mice were then given a second dose of the DOR agonist 24 h later. These mice were tolerant to convulsions induced by SNC80, but not to MMP2200‐induced convulsions. Tolerance to the convulsive effects of MMP2200 was apparent 8 h following the initial injection. SNC80 induced convulsions were enhanced in mice lacking arrestin 2 but were unaltered in mice lacking arrestin 3. However, MMP2200‐induced convulsions were attenuated in mice lacking either arrestin 2 or 3. In rats trained to discriminate SNC80, MMP2200 fully generalized to the discriminative stimulus effects of SNC80 and only slightly decreased rates of responding. Overall, these results demonstrate that the dual MOR/DOR agonist MMP2200 produces many behavioral effects that are similar to the prototypical DOR agonist SNC80. Interestingly, there are some distinct differences in these DOR agonist effects, which may be mediated by concurrent MOR agonist activity with MMP2200 or by activating differential intracellular signaling molecules downstream of DOR activation. Future studies will evaluate the effects of DOR agonists and signaling pathways mediating these effects.

Understanding Addiction Using Animal Models.

Drug addiction is a neuropsychiatric disorder with grave personal consequences that has an extraordinary global economic impact. Despite decades of research, the options available to treat addiction are often ineffective because our rudimentary understanding of drug-induced pathology in brain circuits and synaptic physiology inhibits the rational design of successful therapies. This understanding will arise first from animal models of addiction where experimentation at the level of circuits and molecular biology is possible. We will review the most common preclinical models of addictive behavior and discuss the advantages and disadvantages of each. This includes non-contingent models in which animals are passively exposed to rewarding substances, as well as widely used contingent models such as drug self-administration and relapse. For the latter, we elaborate on the different ways of mimicking craving and relapse, which include using acute stress, drug administration or exposure to cues and contexts previously paired with drug self-administration. We further describe paradigms where drug-taking is challenged by alternative rewards, such as appetitive foods or social interaction. In an attempt to better model the individual vulnerability to drug abuse that characterizes human addiction, the field has also established preclinical paradigms in which drug-induced behaviors are ranked by various criteria of drug use in the presence of negative consequences. Separation of more vulnerable animals according to these criteria, along with other innate predispositions including goal- or sign-tracking, sensation-seeking behavior or impulsivity, has established individual genetic susceptibilities to developing drug addiction and relapse vulnerability. We further examine current models of behavioral addictions such as gambling, a disorder included in the DSM-5, and exercise, mentioned in the DSM-5 but not included yet due to insufficient peer-reviewed evidence. Finally, after reviewing the face validity of the aforementioned models, we consider the most common standardized tests used by pharmaceutical companies to assess the addictive potential of a drug during clinical trials.

Intravital Imaging of Bright Cyan-Fluorescent AML Model Reveals Impact of CXCR4 Inhibitor on AML and Immune Cell Dynamics

INTRODUCTION: CXCR4 chemokine receptor inhibitors such as BL-8040 (BioLineRx) have been investigated by us and others as possible anti-leukemic drugs due to their ability to "mobilize" leukemia cells out of the BM and into the circulation, where they are more sensitive to chemotherapy. However, the exact mode of cell relocation remains unclear. CXCR4/CXCL12 signaling pathway also participates in BM homing of immune cells, including both central memory T cells and immunosuppressive CD4+FoxP3+ T-regulatory cells (T-reg). Therefore, CXCR4 inhibition has the potential to either counteract or enhance the process of AML immune surveillance. Therefore, we sought to develop a syngeneic AML model for intravital 2-photon microscopy (TPM) compatible with existing immune reporter mouse strains, which typically occupy the green, yellow and red fluorescence channels. HYPOTHESIS: CXCR4 inhibition decreases AML and T cell BM cellularity by increasing the rate of intravascular cell entry and/or decreasing the rate of circulating cell homing back to BM. MODEL: The cyan-colored fluorescent protein mTurquoise2 was lentivirally introduced into C57BL6-origin AML cells containing the MLL, ENL-FLT3, ITD, and p53-/- mutations, termed AML1-mTurq2. Syngeneic FoxP3-GFP/CD11c-YFP/hCD2-DsRed reporter mice were generated by inter-breeding of the corresponding strains, respectively highlighting T-reg, myeloid antigen presenting cells, and all T cells. After intravenous infusion of 1E5 AML1-mTurq2 cells, 1-2% blasts appeared in peripheral blood on day 9, increasing to 70% on day 15-20 when animals had to be euthanized. TREATMENT: Mice with >1% blasts were given BL-8040 I.P. in two daily 400 µg doses followed by imaging 24 h later, or intravenously during imaging 10 µg and 50 µg one hour later. ANALYSIS: Disease progression was characterized by blood flow cytometry, symptom scoring and thick-mount organ tissue fluorescence microscopy. Intravital TPM of the calvarial bone marrow (BM) was performed through intact bone under general anesthesia. By interline multiplexing dual femtosecond lasers with four-sensor detection for 8 distinct channels, mTurquoise2 and SHG were recorded by the same sensor at, respectively, 860 and 990 nm excitation, along with GFP, YFP, DsRed and dextran-TRITC (blood tracer). AML and T cell subsets were 3-D tracked using Imaris software. RESULTS: AML1-mTurq2 cells stably and uniformly expressed bright cyan fluorescence, suitable for intravital TPM with low incident laser powers and fast imaging rates in deep tissue locations. In C57BL6 mice, sparse AML cell clusters were found in BM perivascular spaces on day 1 after cell infusion. AML cells were slowly motile (~4 um/min) and highly proliferative, gradually filling BM spaces and emerging in other organs. T cells and CD11c dendritic cells were present in leukemic BM, and the vasculature appeared largely intact and well perfused. T cells interacted with AML cells and the stroma, migrating with high average velocities (~10 µm/min) and slowing down to ~3 µm/min in late-stage disease. After 2 days of BL-8040 treatment, disease symptom scores improved from 3 to 1 while the untreated controls progressed from 3 to 4 (range 0-6). TPM revealed a 4-fold reduction of AML cellularity in BM. Cellular velocities of both AML and T cells were unchanged by BL-8040 treatment. After acute drug administration, a fraction of stromal AML cells begun entering capillary vessel lumens by amoeboid movement. The intravasated AML cells adhered to vessel wall for 1-2 minutes before rapid detachment. Some cells remained tethered while already loose in the blood stream. CONCLUSIONS: A novel, brightly cyan-fluorescent syngeneic AML1-mTurq2 AML model is advantageous for 6-color intravital microscopy of cell trafficking and immune surveillance in optimal compatibility with green, yellow and red reporters of cell lineages and tissue architecture. Using this model, we show that CXCR4 inhibitor BL-8040 decreases AML BM cellularity by increasing the frequency of intravasation without increasing AML migratory velocity. Disclosures Zal: Daiichi-Sankyo: Research Funding; NIH-CTEP: Research Funding; BioLineRx: Research Funding; VueBio.com: Equity Ownership; NIH/NCI: Research Funding; CPRIT: Research Funding; Moleculin Biotech, Inc.: Research Funding. Andreeff:BiolineRx: Membership on an entity's Board of Directors or advisory committees; Aptose: Equity Ownership; Eutropics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding; CPRIT: Research Funding; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; NIH/NCI: Research Funding; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; AstaZeneca: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy.

Gevo & Praj Industries enter agreement to commercialize renewable isobutanol

There is a strong support for the role of serotonin (5-HT) neurotransmission in depression and in the mechanism of action of antidepressants. Among 5-HT receptors, 5-HT2A receptor subtype seems to be an important target implicated in the above disorder.The aim of the study was to investigate the effects of antidepressants, such as imipramine (15 mg/kg), escitalopram (10 mg/kg) and tianeptine (10 mg/kg) as well as drugs with antidepressant activity, including N-acetylcysteine (100 mg/kg) and URB597 (a fatty acid amide hydrolase inhibitor, 0.3 mg/kg) on the 5-HT2A receptor labeling pattern in selected rat brain regions. Following acute or chronic (14 days) drug administration, rat brains were analyzed by using autoradiography with the 5-HT2A receptor antagonist [3H]ketanserin.Single dose or chronic administration of imipramine decreased the radioligand binding in the claustrum and cortical subregions. The [3H]ketanserin binding either increased or decreased in cortical areas after acute N-acetylcysteine and URB597 administration, respectively. A similar shift towards reduction of the [3H]ketanserin binding was detected in the nucleus accumbens shell following either acute treatment with imipramine, escitalopram, N-acetylcysteine and URB597 or repeated administration of imipramine, tianeptine and URB597.In conclusion, the present result indicate different sensitivity of brain 5-HT2A receptors to antidepressant drugs depending on schedule of drug administration and rat brain regions. The decrease of accumbal shell 5-HT2A receptor labeling by antidepressant drugs exhibiting different primary mechanism of action seems to be a common targeting mechanism associated with the outcome of depression treatment.

Bimetallic catalytic complexes for the polymerisation of carbon dioxide and an epoxide

There is a strong support for the role of serotonin (5-HT) neurotransmission in depression and in the mechanism of action of antidepressants. Among 5-HT receptors, 5-HT2A receptor subtype seems to be an important target implicated in the above disorder.The aim of the study was to investigate the effects of antidepressants, such as imipramine (15 mg/kg), escitalopram (10 mg/kg) and tianeptine (10 mg/kg) as well as drugs with antidepressant activity, including N-acetylcysteine (100 mg/kg) and URB597 (a fatty acid amide hydrolase inhibitor, 0.3 mg/kg) on the 5-HT2A receptor labeling pattern in selected rat brain regions. Following acute or chronic (14 days) drug administration, rat brains were analyzed by using autoradiography with the 5-HT2A receptor antagonist [3H]ketanserin.Single dose or chronic administration of imipramine decreased the radioligand binding in the claustrum and cortical subregions. The [3H]ketanserin binding either increased or decreased in cortical areas after acute N-acetylcysteine and URB597 administration, respectively. A similar shift towards reduction of the [3H]ketanserin binding was detected in the nucleus accumbens shell following either acute treatment with imipramine, escitalopram, N-acetylcysteine and URB597 or repeated administration of imipramine, tianeptine and URB597.In conclusion, the present result indicate different sensitivity of brain 5-HT2A receptors to antidepressant drugs depending on schedule of drug administration and rat brain regions. The decrease of accumbal shell 5-HT2A receptor labeling by antidepressant drugs exhibiting different primary mechanism of action seems to be a common targeting mechanism associated with the outcome of depression treatment.

Adaptive mechanisms following antidepressant drugs: Focus on serotonin 5-HT2A receptors.

There is a strong support for the role of serotonin (5-HT) neurotransmission in depression and in the mechanism of action of antidepressants. Among 5-HT receptors, 5-HT2A receptor subtype seems to be an important target implicated in the above disorder. The aim of the study was to investigate the effects of antidepressants, such as imipramine (15 mg/kg), escitalopram (10 mg/kg) and tianeptine (10 mg/kg) as well as drugs with antidepressant activity, including N-acetylcysteine (100 mg/kg) and URB597 (a fatty acid amide hydrolase inhibitor, 0.3 mg/kg) on the 5-HT2A receptor labeling pattern in selected rat brain regions. Following acute or chronic (14 days) drug administration, rat brains were analyzed by using autoradiography with the 5-HT2A receptor antagonist [3H]ketanserin. Single dose or chronic administration of imipramine decreased the radioligand binding in the claustrum and cortical subregions. The [3H]ketanserin binding either increased or decreased in cortical areas after acute N-acetylcysteine and URB597 administration, respectively. A similar shift towards reduction of the [3H]ketanserin binding was detected in the nucleus accumbens shell following either acute treatment with imipramine, escitalopram, N-acetylcysteine and URB597 or repeated administration of imipramine, tianeptine and URB597. In conclusion, the present result indicate different sensitivity of brain 5-HT2A receptors to antidepressant drugs depending on schedule of drug administration and rat brain regions. The decrease of accumbal shell 5-HT2A receptor labeling by antidepressant drugs exhibiting different primary mechanism of action seems to be a common targeting mechanism associated with the outcome of depression treatment.

Long-lasting antidepressant-like activity of the GPR39 zinc receptor agonist TC-G 1008

BackgroundThe discovery of the zinc-sensing receptor, has provided new possibilities for explaining the neurobiology of zinc. Recent studies indicate that the GPR39 zinc receptor may play an important role in the pathogenesis of depression as well as in the antidepressant mechanism of action. MethodsIn this study we evaluated the time-course of the antidepressant response of the GPR39 agonist (TC-G 1008), imipramine, ZnCl2 and MK-801 in the forced swim test in mice 30 min, 3 h, 6 h and 24 h after acute drug administration as well as after 14-day treatment. Zinc level was measured in serum of mice. BDNF protein level was evaluated in hippocampus following both acute and chronic TC-G 1008 treatment. ResultsA single administration of the GPR39 agonist caused an antidepressant-like effect lasting up to 24 h following the injection, which is longer than the effect of imipramine, ZnCl2 and MK-801. Chronic treatment with these compounds caused a decrease in immobility time in the FST. Serum zinc concentrations showed an increased level following chronic ZnCl2 administration, but not following administration of TC-G 1008, imipramine or MK-801. We also observed some tendencies for increased BDNF following acute TC-G 1008 treatment. LimitationsTC-G 1008 is new drug designed to study GPR39 therefore additional pharmacodynamic and pharmacokinetic properties in preclinical studies are required. ConclusionThis study shows for the first time the long-lasting antidepressant effect of the GPR39 agonist in comparison with imipramine, ZnCl2 and MK-801. Our findings suggest that GPR39 should be considered as a target in efforts to develop new antidepressant drugs.

Alternate versions of a fixed-choice, delay-discounting assessment for repeated-measures designs.

Delay discounting, reflected in the tendency to prefer immediate rewards over delayed rewards, is associated with most forms of problematic substance use. When assessed multiple times to examine within-individual changes, for example, following acute drug administration or an intervention, shifts in delay discounting simply because of repeated assessment is a concern, particularly when the assessment task is identical. This may be true for the Monetary Choice Questionnaire (MCQ), a widely used, fixed-item assessment of delay discounting. The present research examined possible within-individual difference/equivalence of MCQ indices at test/retest. This was contrasted with within-individual difference/equivalence when using an alternate version of the MCQ at retest, specifically developed to maintain the assessment structure and scoring of the original MCQ but with different choice items. Eighty-four participants completed delay discounting at test and retest with a 1-week interval; participants were randomized to complete the MCQ at both test and retest (MCQ/MCQ; n = 43) or complete the MCQ at test and an alternate version of the MCQ at retest (MCQ/MCQ-A; n = 41). Conventional hypothesis testing indicated no significant changes in delay discounting in the MCQ/MCQ condition or MCQ/MCQ-A condition. However, equivalence analysis, which is able to established whether scores are statistically equivalent, indicated that test/retest scores were not equivalent in some cases. Specifically, only 1 magnitude in the MCQ/MCQ condition was equivalent at test/retest, whereas 2 magnitudes in the MCQ/MCQ-A condition were equivalent at test/retest. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Effects of dimethyl fumarate in murine models of depression and anxiety

Depression and anxiety are psychiatric disorders, which are leading causes of disability and often accompany chronic diseases. Increased oxidative stress occurs in both disorders. This study investigated the effects of dimethyl fumarate (DMF) in animal models of depression and anxiety. Different groups of mice were treated with either the vehicle, 50, 100 mg/kg DMF or imipramine and subjected to either the forced swim tes t (FST) or the tail suspension test (TST). Another set of mice were treated daily with either the vehicle, DMF 50 and 100 mg/kg and imipramine for two weeks and subjected to either the FST or TST. Thereafter, animals were sacrificed; whole brains isolated and brain catalase levels assayed. The same procedure was followed for evaluation of anxiolytic property of DMF using the staircase and hole-board tests as test indices and diazepam as the reference drug. In the test for depression, 50 and 100 mg/kg DMF significantly (p<0.05) reduced periods of immobility in both the FST and TST after acute and chronic drug administration; and significantly (p<0.05) increased brain catalase levels. In the test for anxiolysis, both doses of DMF did not produce significant changes in the staircase test indices following acute and chronic drug treatment. However, low dose DMF -50 mg/kg significantly increased (p<0.05) the number of head dips in the holeboard test post chronic drug treatment; both doses increased levels of cata lase in the brain. DMF exhibited antidepressant activity and anxiolytic properties and increased levels of catalase in the brains of mice .Keywords: Catalase; Forced swim test; Staircase test; Antioxidants; Depression

Borneol enhances the antidepressant effects of asiaticoside by promoting its distribution into the brain

Asiaticoside (AS) has antidepressant effects, with poor druggability characterized with inaccessibility into the brain. Here, we assessed AS distribution in the asiaticoside-borneol formula (FAB), with AS administrated orally. High performance liquid chromatography (HPLC) was applied for AS detection. The antidepressant effects of both FAB and AS were evaluated. Rats were subjected to behavioral despair paradigms and chronic unpredictable stress model (CUS) after acute and chronic drug administration, respectively. Hippocampal 5-HT, NE, BDNF, and TNF-α levels were detected, and pathological changes were observed by H&E staining. AS was detected in rat brain tissues after FAB administration, while AS was not detected when administered alone, indicating that borneol (BOR) promoted its distribution into the rat brain. Interestingly, FAB significantly reduced the immobility time in modified forced swimming test (FST) unlike AS used as a single therapy, also reversing sucrose intake more significantly compared with AS. Furthermore, FAB upregulated BDNF and 5-HT more significantly compared with AS, which revealed a possible multi-mechanism of action.

The Neurobiology of Depression: an Integrated Overview from Biological Theories to Clinical Evidence.

Depressive disorders are heterogeneous diseases, and the complexity of symptoms has led to the formulation of several aethiopathological hypotheses. This heterogeneity may account for the following open issues about antidepressant therapy: (i) antidepressants show a time lag between pharmacological effects, within hours from acute drug administration, and therapeutic effects, within two-fourweeks of subchronic treatment; (ii) this latency interval is critical for the patient because of the possible further mood worsening that may result in suicide attempts for the seemingly ineffective therapy and for the apparent adverse effects; (iii) and only 60-70% of treated patients successfully respond to therapy. In this review, the complexity of the biological theories that try to explain the molecular mechanisms of these diseases is considered, encompassing (i) the classic "monoaminergic hypothesis" alongside the updated hypothesis according to which long-term therapeutical action of antidepressants is mediated by intracellular signal transduction pathways and (ii) the hypothalamic-pituitary-adrenal axis involvement. Although these models have guided research efforts in the field for decades, they have not generated a compelling and conclusive model either for depression pathophysiology or for antidepressant drugs' action. So, other emerging theories are discussed: (iii) the alterations of neuroplasticity and neurotrophins in selective vulnerable cerebral areas; (iv) the involvement of inflammatory processes; (v) and the alterations in mitochondrial function and neuronal bioenergetics. The focus is put on the molecular and theoretical links between all these hypotheses, which are not mutually exclusive but otherwise tightly correlated, giving an integrated and comprehensive overview of the neurobiology of depressive disorders.

A Centrally Active, Peripherally Available Mixed Efficacy MOR/DOR Ligand that Displays Reduced Development of Negative Side Effects

Mu‐opioid receptor (MOR) agonists have long been used in the treatment of pain and are currently the gold standard for pain management in the clinic. While these compounds produce considerable analgesia, their use produces many adverse effects, such as the development of antinociceptive tolerance, physical dependence, euphoria, and constipation. It has been suggested that the co‐administration of a MOR agonist with a delta opioid receptor (DOR) antagonist may produce MOR‐mediated analgesia with reduced side effects. However, administering drug cocktails has considerable complications related to potential diverse pharmacokinetic properties of the two chemical entities. We therefore explored the development of multifunctional ligands that display both MOR agonism and DOR antagonism in a single molecule. We have previously reported a cyclic peptide with a C‐terminal β‐glucoserine, VRP26, which displays the desired MOR agonist/DOR antagonist profile in vitro and produces opioid mediated antinociception in the warm water tail withdrawal assay after peripheral administration in male C57BL/6N mice. The goals of the current study were to evaluate whether VRP26: 1) crosses the blood brain barrier and 2) produces tolerance, dependence, rewarding effects, and constipation. The effects of VRP26 on centrally‐mediated behaviors in nitroglycerin‐induced hyperalgesia assay and the tail suspension test were evaluated. Tolerance and dependence were evaluated following continuous VRP26 infusion for 7 days, rewarding effects were evaluated in a conditioned place preference assay, and constipation was evaluated by fecal bolus production following acute drug administration. VRP26 reversed nitroglycerin‐induced hyperalgesia and attenuated antidepressant‐like effects induced by the DOR agonist SNC80. Unlike fentanyl, 7 day continuous administration of VRP26 failed to produce a rightward shift in the antinociceptive dose response curve and produced fewer signs of naltrexone‐precipitated withdrawal than fentanyl. VRP26, unlike fentanyl, did not produce significant conditioned place preference. VRP26 also was less potent that morphine in producing constipating effects. In conclusion, VRP26 produces centrally mediated antinociception, with limited development of antinociceptive tolerance, physical dependence, and rewarding effects. Further, VRP26 has a greater therapeutic index between antinociceptive and constipating effects, demonstrating potential increased tolerability. VRP26 demonstrates proof of concept that mixed efficacy opioid ligands may be better alternatives to traditional opioid analgesics for chronic pain management, producing pain relief with limited negative effects.Support or Funding InformationThis work was funded by NIH Grant DA003910. J.P.A was supported by the National Institutes of Health under Ruth L. Kirschstein National Research Service Award T32 DA007267. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

The Inconvenient Truth About MRI in Psychiatric Research

The Inconvenient Truth About MRI in Psychiatric Research

Analysis of the potential pathways and target genes in spinal cord injury using bioinformatics methods

Spinal cord injury (SCI) remains to be the most devastating type of trauma for patients because of long lasting disability and limited response to the acute drug administration and efforts at rehabilitation. With the purpose to identify potential targets for SCI treatment and to gain more insights into the mechanisms of SCI, the microarray data of GSE2270, including 119 raphe magnus (RM) samples and 125 sensorimotor cortex (SMTC) samples, was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened in RM group and SMTC group compared with their corresponding controls, respectively. A protein–protein interaction (PPI) network was constructed based on the common DEGs identified in both RM group and SMTC group. Gene ontology (GO) and pathway enrichment analyses of the overlapping DEGs were performed. Furthermore, the common DEGs enriched in each pathway were analyzed to identify significant regulatory elements. Totally, 173 overlapping DEGs (130 up-regulated and 43 down-regulated) were identified in both RM and SMTC samples. These overlapping DEGs were enriched in different GO terms. Pathway enrichment analysis revealed that DEGs were mainly related to inflammation and immunity. CD68 molecule (CD68) was a hub protein in the PPI network. Moreover, the regulatory network showed that ras-related C3 botulinum toxin substrate 2 (RAC2), CD44 molecule (CD44), and actin related protein 2/3 complex (ARPC1B) were hub genes. RAC2, CD44, and ARPC1B may be significantly involved in the pathogenesis of SCI by participating significant pathways such as extracellular matrix-receptor signaling pathway and Toll-like receptor signaling pathway.