Orvinol-based opioid receptor antagonist fluorinated at C(20)-pharmacophore.

Thevinols and their 3-O-demethylated relatives, orvinols, are derivatives of the Diels-Alder adduct of natural alkaloid thebaine with methyl vinyl ketone. Taken together, thevinols and orvinols constitute an important family of opioid receptor (OR) ligands playing an important role in both the OR mediated antinociception and OR antagonism. Herein, we disclose for the first time the antagonist activity of the N-allyl substituted orvinol derivative fluorinated within the pharmacophore associated with C(20) and its surrounding.

Advancing 3Rs: The Mouse Estrus Detector (MED) as a Low-Stress, Painless, and Efficient Tool for Estrus Determination in Mice.

Determining the estrous cycle stages in mice is essential for optimizing breeding strategies, synchronizing experimental timelines, and facilitating studies in behavior, drug testing, and genetics. It is critical for reducing the production of genetically unmodified offspring in the generation and investigation of genetically modified animal models. An accurate detection of the estrus cycle is particularly relevant in the context of the 3Rs-Replacement, Reduction, and Refinement.

Hyperdopaminergia in rats is associated with reverse effort-cost dependent performance.

Background: Dopamine is implicated in the effort-based control of motivational processes; however, whether tonic dopamine regulates the effort-cost impact on motivation, is still debated.

Aims: The rats lacking the dopamine transporter (DAT), which have dramatically increased levels of the synaptic dopamine, were used in the present study to elucidate the role of the synaptic dopamine in motivational processes.

Methods: To study the reward-related processes, the progressive ratio 3 (PR3) operant schedule of food reinforcement (the ratio increases by 3 after each earned reinforcer) was performed in adult male rats (DAT knockouts (DAT-KO), heterozygotes (DAT-HT) and wild-types (DAT-WT)).

C(21)-fluorinated thevinol scaffold for opioid ligands. 21,21,21-Trifluoro-6-O-nororvinols: Design, synthesis and analgesic activity.

Thevinols and their 3-O-demethylated relatives, orvinols, are derivatives of the Diels-Alder adduct of natural alkaloid thebaine with methyl vinyl ketone. Taken together, thevinols and orvinols constitute an important family of opioid receptor (OR) ligands playing an important role in both the OR mediated antinociception and OR antagonism. Herein, we disclose for the first time the OR activity of orvinols fluorinated within the pharmocophore associated with C(20) and its surrounding along with a dependence of the activity profile on the substituent at N(17).

Inhibition of PDE10A in a New Rat Model of Severe Dopamine Depletion Suggests New Approach to Non-Dopamine Parkinson's Disease Therapy.

Parkinson's disease is the second most common neurodegenerative pathology. Due to the limitations of existing therapeutic approaches, novel anti-parkinsonian medicines with non-dopamine mechanisms of action are clearly needed. One of the promising pharmacological targets for anti-Parkinson drug development is phosphodiesterase (PDE) 10A.

Chronic Lithium Treatment Affects Anxious Behaviors and theExpression of Serotonergic Genes in Midbrain Raphe Nuclei of Defeated Male Mice.

There is experimental evidence that chronic social defeat stress is accompanied by the development of an anxiety, development of a depression-like state, and downregulation of serotonergic genes in midbrain raphe nuclei of male mice. Our study was aimed at investigating the effects of chronic lithium chloride (LiCl) administration on anxiety behavior and the expression of serotonergic genes in midbrain raphe nuclei of the affected mice. A pronounced anxiety-like state in male mice was induced by chronic social defeat stress in daily agonistic interactions.

The Action of TAAR1 Agonist RO5263397 on Executive Functions in Rats.

Trace amine-associated receptor 1 (TAAR1) is a widely recognized new perspective target for the neuropsychiatric pharmacological treatment. Despite a growing number of studies investigating TAAR1 role in the animal models of different pathologies, information of TAAR1 agonists impact on executive cognitive functions is limited. The goal of the present study was to evaluate the activity of highly selective partial TAAR1 agonist RO5263397 on various executive cognitive functions.

Efficacy and side effects of baclofen and the novel GABA receptor positive allosteric modulator CMPPE in animal models for alcohol and cocaine addiction.

Rationale: Preclinical studies suggest that the GABA receptor is a potential target for treatment of substance use disorders. However, recent clinical trials report adverse effects in patients treated with the GABA receptor agonist baclofen and even question efficacy. How can the discrepancy between preclinical and clinical findings be explained?

Objective: To test efficacy and adverse effects of baclofen and the novel GABA positive allosteric modulator (PAM) CMPPE in rat addiction models, which were developed in accordance with DSM.

[NFLUENCE OF SPONTANEOUS PARTIAL SENSORY DEPRIVATION ON MALE C57BL/6N MICE BEHAVIOR].

Vibrissae loss associated with the peculiarities of the intragroup social interaction may be an important factor affecting the animals’ performance in various behavioral tests. To evaluate the influence of spontaneous partial sensory deprivation as a consequence of the barbering activity of a cage mate, the battery of tests was conducted in male C57Bl/6N mice. The results indicate that the behavior of mice without vibrissae significantly differs from control animals in the tube, open field, social interaction and forced swim tests.

Morphine-induced Straub tail reaction in mice treated with serotonergic compounds.

Constitutively active 5-HT receptors have been suggested to contribute to motoneuronal excitability, muscle spasms and spasticity. Accordingly, 5-HT receptor inverse agonists have been demonstrated in pilot experiments to reduce spasticity in animal model of spasticity and patients with spinal cord injuries. Thus, 5-HT receptor inverse agonists may represent a novel class of anti-spasticity agents justifying a search for compounds with robust 5-HT receptor inverse agonist activity either among the existing medications or via a dedicated drug discovery program.

[The issues of medical/social expertise in Parkinson's disease].

Parkinson's disease (PD) is a chronic progressive neurodegenerative disease that restricts activities of daily living. The prevalence of PD and inevitable disability show the importance of medical/social expertise (MSE) in the system of care for PD patients. Currently, the MSE is based on the Hoehn and Yahr scale that indicates the prevalence of disease but does not evaluate the severity of symptoms.

Optical isomers of phenibut inhibit [H(3)]-Gabapentin binding in vitro and show activity in animal models of chronic pain.

Background: We report that R- and S-phenibut (β-phenyl-γ-aminobutyric acid) - derivatives of GABA - bind with an affinity of c.a. 90μM to the gabapentin binding site in a competitive assay, a value comparable to that for previously claimed targets for this enantioermic molecule.

[Morphine-induced Straub tail reaction as a model of spasticity in mice: effects of serotonergic compounds].

Aim: To adopt and validate the Straub tail reaction (SR) for comparative assessment of spastic effects of serotonergic compounds.

Material And Methods: To measure the muscle relaxant activity, the morphine-induced Straub-tail assay was used. SR was graded according to modified intensity-score basis in a scale decribed by Kameyama et al.

Nicotine exposure throughout early development promotes nicotine self-administration in adolescent mice and induces long-lasting behavioural changes.

Maternal cigarette smoking during pregnancy can result in behavioural problems of the offspring. Although the causative agent in tobacco smoke that leads to these aberrations is not known, some studies using animal models have supported the hypothesis that nicotine may cause impairments in fatal and neonatal development. However, in many of the animal studies nicotine has been administered by subcutaneous injections, which could lead to significant fetal hypoxia; some routes of drug administration included stressful procedures to pregnant dams that could create unfavorable fetal environment.

The anxiolytic and analgesic properties of fenobam, a potent mGlu5 receptor antagonist, in relation to the impairment of learning.

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.

Effect of inhibiting carnitine biosynthesis on male rat sexual performance.

l-carnitine has a documented role as a cofactor in cellular energy metabolism and fatty acid beta-oxidation pathways and it has also been considered to function in reproductive biology. We investigated whether decreasing concentrations of L-carnitine using an inhibitor of its biosynthesis, mildronate (3-(2,2,2-trimethylhydrazinium)-propionate), would influence the sexual behavior or sperm quality in male rats. Mildronate treatment induced a significant decrease in carnitine concentration and an increase in gamma-butyrobetaine (GBB) concentration in both plasma and testes extracts.

Comparison of the mGluR1 antagonist A-841720 in rat models of pain and cognition.

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.

Effects of NAAG peptidase inhibitor 2-PMPA in model chronic pain - relation to brain concentration.

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.

Lowered brain stimulation reward thresholds in rats treated with a combination of caffeine and N-methyl-D-aspartate but not alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate or metabotropic glutamate receptor-5 receptor antagonists.

Previous studies suggested that adenosine A1 and A2A receptor agonists counteract behavioral effects of N-methyl-D-aspartate (NMDA) receptor antagonists while adenosine receptor antagonists may produce opposite effects enhancing the actions of NMDA receptor antagonists. To further evaluate the effects of combined administration of adenosine receptor antagonist caffeine and various NMDA and non-NMDA glutamate receptor antagonists on brain stimulation reward (discrete-trial threshold current intensity titration procedure), rats with electrodes implanted into the ventral tegmental area were tested after pretreatment with NMDA receptor channel blocker MK-801 (0.01-0.

Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests.

Drugs that act to reduce glutamatergic neurotransmission such as NMDA receptor antagonists exert antidepressant-like effects in a variety of experimental paradigms, but their therapeutic application is limited by undesired side effects. In contrast, agents that reduce glutamatergic tone by blocking type I metabotropic glutamate receptors have been suggested to have more a favorable side-effect profile. The present study aimed to compare the effects of mGluR1 antagonist (EMQMCM; JNJ16567083, 3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate, 0.

Effects of low-affinity NMDA receptor channel blockers in two rat models of chronic pain.

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.

Facilitation of aggressive and sexual behaviors by saccharin deprivation in rats.

The 'deprivation effect' (DE) phenomenon is expressed as an increase in the level of free choice consumption of drugs, alcohol, or saccharin following a period of forced abstinence in humans and in several species of laboratory animals. The DE may reflect relapse-like drinking and be relevant for modeling addictive behaviors. In humans, drug or alcohol abstinence is commonly associated with the increased physical and sexual abuse.

Facilitation of electrical brain self-stimulation behavior by abused solvents.

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.

[Study of pharmacological activation of the male sexual behavior].

The model of sexual exhaustion of male rats was used in the study. The specific aim was to compare the effects of cocaine on the mount latency, number of mounts, intromissions and ejaculations during the entire copulatory cycle with the same indices during the first 30 min of observation (the latter is most frequently used in laboratory settings). Experiments consisted of four 3-day test periods.

Effects of short-acting NMDA receptor antagonist MRZ 2/576 on morphine tolerance development in mice.

The present study sought to evaluate the ability of a short-acting glycineB site NMDA receptor antagonist, MRZ 2/576, to affect morphine tolerance development in mice. It was found that MRZ 2/576 (10 mg/kg, i.p.