Effects of CB1 cannabinoid receptor blockade on ethanol preference after chronic alcohol administration combined with repeated re-exposures and withdrawals.

AIMS: The cannabinoid CB1 receptor antagonist, SR141716A, differentially affects the ethanol preference of chronically alcoholized rats when administered during cycles of ethanol exposure and withdrawal. In this study, ethanol preference was investigated in chronically alcoholized rats that underwent regular withdrawal periods during which the brain cannabinoid CB(1) receptor antagonist, SR141716A, was administered. METHODS: The cannabinoid receptor antagonist SR141716A, 3 or 10 mg/kg/day, was administered i.p. to Wistar rats at the conclusion of a 4-week period of chronic alcoholization, as they commenced a cycle of alcohol withdrawal for 10 days followed by a period of 10 days chronic ethanol exposure. In a second set of experiments, an additional cycle of ethanol withdrawal and re-exposure was given. Preference for ethanol versus water started at the end of the first or second chronic ethanol re-exposure for a period of at least 30 days. RESULTS: In rats pretreated with the higher dose of SR141716A, ethanol preference during free choice was significantly increased after two ethanol re-exposures. In contrast, pretreatment with the lower SR141716A dose induced no significant change in ethanol intake during the free choice followed by either one or two ethanol re-exposures. CONCLUSIONS: SR141716A, 10 mg/kg/day dose, induced a significant increase in ethanol preference which was dependent on both the number of ethanol withdrawals and chronic ethanol re-exposures, while 3 mg/kg/day had no significant effect on ethanol preference

Effects of CB1 cannabinoid receptor blockade on ethanol preference after chronic ethanol administration.

BACKGROUND: Chronic ethanol administration results in neurobiological alterations similar to those observed after chronic cannabinoid exposure. The purpose of this study was to investigate alcohol drinking and the withdrawal responses after pulmonary chronic alcoholization with intraperitoneal or oral administration of a cannabinoid CB1 receptor antagonist. METHODS: The cannabinoid receptor antagonist SR141716A, 1, 3 or 10 mg/kg/day intraperitoneally or orally, was administered to Wistar rats either during a 30-day chronic ethanol exposure or at the cessation of this procedure. Motility was recorded during 18 hr after the cessation of chronic alcoholization just before the beginning of the free-choice paradigm (water versus alcohol 10% v/v). RESULTS: A significant increase in ethanol preference was observed during the free-choice paradigm after chronic alcoholization with concurrent SR141716A administration (3 or 10 mg/kg/day). A significant decrease in withdrawal motility after administration of SR141716A was observed with only the highest dose (10 mg/kg/day). The administration of SR141716A, 3 or 10 mg/kg/day, after chronic pulmonary alcoholization significantly decreased the preference for alcohol. Finally, a significant decrease in ethanol preference was seen during the free-choice paradigm of nonalcoholized rats treated with SR141716A, 3 or 10 mg/kg/day, during 30 days before the free-choice paradigm. CONCLUSIONS: The concurrent administration of the CB1 antagonist together with the chronic alcoholization increases the preference for ethanol. Also, the administration of the CB1 antagonist after the chronic alcoholization or at the time of withdrawal drastically diminishes the ethanol preference

Altered neurotensin mrna expression in mice lacking the dopamine transporter.

Psychostimulants and antipsychotic drugs increase mRNA expression of the neuropeptide neurotensin (NT) in the striatum and nucleus accumbens. In the present study, we used mice lacking the dopamine transporter (DAT) to investigate the consequences of a chronic hyperdopaminergic state on NT gene expression. NT mRNA expression was examined under basal conditions and after administration of haloperidol or amphetamine using in situ hybridization with a digoxigenin-labeled NT cRNA probe. DAT-/- mice exhibited a striking increase in the number of NT mRNA-expressing perikarya in the substantia nigra and ventral tegmental area, as well as a less pronounced increase in the lateral septum compared with wild-type littermates. No changes were detected in other regions expressing NT mRNA. Acute administration of haloperidol (1 mg/kg) induced a significant increase in the number of NT mRNA-expressing neurons in the dorsomedial and dorsolateral striatum of wild-type mice but failed to stimulate NT gene expression in DAT mutants. In contrast, a higher dose of haloperidol (5 mg/kg) stimulated striatal NT mRNA expression both in DAT+/+ and DAT-/- mice. Amphetamine (10 mg/kg) increased the number of hybridized neurons in the nucleus accumbens shell and fundus striati of wild-type and DAT-/- mice, indicating that the drug acted through a target other than DAT, such as the serotonin or the norepinephrine transporters. The up-regulation of NT mRNA observed in DAT-/- mice may represent an adaptive mechanism in response to constitutive hyperdopaminergia. These results illustrate the profound alterations in the NT system induced by chronic stimulation of DA receptors and underscore the potential clinical relevance of NT/DA interactions in schizophrenia and drug abuse

Influence of radiative heating on a Martian orbiter

A computational platform was developed to study radiation of high-temperature gases during atmospheric reentries. This platform includes a 2-D axisymmetrical Navier–Stokes solver and a radiative heat transfer solver based on a Monte Carlo method. In this paper, only gas radiation occurring during entries in the Martian atmosphere is considered. Gas radiative properties are obtained using a statistical narrowband model for CO and CO2 molecules in high-temperature and low-pressure conditions. Computations on a test case related to the Mars sample return orbiter enabled us to set up a calculation methodology that includes a loose coupling of aerothermodynamics and radiative transfer. Monte Carlo band model calculations are validated against line-by-line calculation and a ray-tracing method. Results show that radiative fluxes on the rear part are important in comparison with convective fluxes. They are mostly due to CO2 infrared radiation. The effects of radiative transfer on the flow structure and temperature fields in both the front shield and the wake regions are discussed

RAPID COMMUNICATION Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors

Abstract SR 141716, a selective central CB1 cannabinoid receptor antagonist, markedly and selectively reduces sucrose feeding and drinking as well as neuropeptide Y-induced sucrose drinking in rats. SR 141716 also decreases ethanol consumption in C57BL / 6 mice. In contrast, blockade of CB1 receptors only marginally a¤ects regular chow intake or water drinking. The active doses of SR 141716 (0.33 mg / kg) are in the range known to antagonize the characteristic e¤ects induced by cannabinoid receptor agonists. These results suggest for the Þrst time that endogenous cannabinoid systems may modulate the appetitive value of sucrose and ethanol, perhaps by a¤ecting the activity of brain reward systems

Machine Learning‐Based Prediction of Immunomodulatory Properties of Polymers: Toward a Faster and Easier Development of Anti‐Inflammatory Biomaterials

In biomaterials development, creating materials with desirable properties can be a time‐consuming and resource‐intensive process, often relying on serendipitous discoveries. A potential route to accelerate this process is to employ artificial intelligence methodologies such as machine learning (ML). Herein, the possibility to predict anti‐inflammatory properties of the polymers by using a simplified model of inflammation and a restrained dataset is explored. Cellular assays with 50 different polymers are conducted using the murine macrophage cell line RAW 264.7 as a model. These experiments generate a dataset which is used to develop a ML model based on Bayesian logistic regression. After conducting a Bayesian logistic regression analysis, two ML models, K‐nearest neighbors (KNN) and Naïve Bayes, are employed to predict anti‐inflammatory polymers properties. The study finds that the probability of a polymer having anti‐inflammatory properties is multiplied by three if it is a polycation, and that nitric oxide secretion is a good indicator in determining the anti‐inflammatory properties of a polymer, which in this work are defined by tumor necrosis factor alpha expression decrease. Overall, the study suggests that with appropriate dataset design, ML techniques can provide valuable information on functional polymer properties, enabling faster and more efficient biomaterial development

The striatal neurotensin receptor modulates striatal and pallidal glutamate and GABA release: functional evidence for a pallidal glutamate–GABA interaction via the pallidal–subthalamic nucleus loop

In the present study, we used dual-probe microdialysis to investigate the effects of intrastriatal perfusion with neurotensin (NT) on striatal and pallidal glutamate and GABA release. The role of the pallidal GABAA receptor in the intrastriatal NTinduced increase in pallidal glutamate release was also investigated. Intrastriatal NT (100 and 300 nM) increased striatal glutamate and GABA (100 nM, 155 6 9 and 141 6 6%, respectively; 300 nM, 179 6 8 and 166 6 11%, respectively) release, as well as pallidal glutamate and GABA (100 nM, 144 6 8 and 130 6 5%; 300 nM, 169 6 9 and 157 6 8%, respectively) release. These effects were dose-dependently antagonized by the NT receptor antagonist 2-[(1-(7-chloro-4-quinolinyl)- 5-(2,6-dimethoxy-phenyl)pyrazol-3-yl)carboxylamino]tricyclo) 3.3.1.1.3.7)-decan-2-carboxylic acid (SR48692). Intrasubthalamic injection of the GABAA receptor antagonist (2)-bicuculline (10 pmol/100 nl, 30 sec) rapidly increased pallidal glutamate release, whereas the intrastriatal NT-induced increase in pallidal glutamate release was counteracted by intrapallidal perfusion with (2)-bicuculline, suggesting that an increase in striopallidal GABA-mediated inhibition of the GABAergic pallidal–subthalamic pathway results in an increased glutamatergic drive in the subthalamic–pallidal pathway. These results demonstrate a tonic pallidal GABA-mediated inhibition of excitatory subthalamic–pallidal neurons and strengthen the evidence for a functional role of NT in the regulation of glutamate and GABA transmission in the basal ganglia. The ability of intrastriatal SR48692 to counteract the NT-induced increase in both striatal and pallidal glutamate and GABA release suggests that blockade of the striatal NT receptor may represent a possible new therapeutic strategy in the treatment of those hypokinetic disorders implicated in disorders of the indirect pathway mediating motor inhibitio