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155. Administration of the metabotropic glutamate receptor subtype 5 allosteric modulator GET 73 with alcohol: A translational study in rats and humans

Author

Haass-Koffler, Carolina L, primary, Goodyear, Kimberly, additional, Loche, Antonella, additional, Long, Victoria M, additional, Lobina, Carla, additional, Tran, Harrison H, additional, Cacciaglia, Roberto, additional, Swift, Robert M, additional, Colombo, Giancarlo, additional, and Leggio, Lorenzo, additional

Published
2018
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160. Marked Differences in the Submandibular Salivary Proteome between Sardinian Alcohol-Preferring and Sardinian Alcohol-Non Preferring Rats Revealed by an Integrated Top-Down–Bottom-Up Proteomic Platform

Author

Cabras, Tiziana, primary, D’Alessandro, Alfredo, additional, Serrao, Simone, additional, Isola, Raffaella, additional, Iavarone, Federica, additional, Vincenzoni, Federica, additional, Colombo, Giancarlo, additional, Ekström, Jörgen, additional, Messana, Irene, additional, and Castagnola, Massimo, additional

Published
2017
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163. Potential of GABAB Receptor Positive Allosteric Modulators in the Treatment of Alcohol Use Disorder.

Author

Maccioni, Paola and Colombo, Giancarlo

Subjects
*GABA receptors, *ALLOSTERIC regulation, *ALCOHOL drinking, *ALCOHOL-induced disorders, *BACLOFEN, *NEURAL stimulation, *LIGANDS (Biochemistry)
Abstract

The orthosteric γ-aminobutyric acidB (GABAB) receptor agonist baclofen is currently considered a therapeutic option for alcohol use disorder (AUD); however, the safety profile of baclofen is a concern, thus arousing interest in the positive allosteric modulators (PAMs) of the GABAB receptor (GABAB PAMs), a new class of ligands expected to possess a better safety profile. The present paper summarizes the several lines of experimental evidence indicating the ability of GABAB PAMs to inhibit multiple alcohol-motivated behaviors in rodents. All GABAB PAMs tested to date have invariably been reported to reduce, or even suppress, excessive alcohol drinking, relapse- and binge-like drinking, operant oral alcohol self-administration, reinstatement of alcohol seeking, and alcohol-induced locomotor stimulation and conditioned place preference in rats and mice. The use of validated animal models of several aspects of AUD confers translational value to these findings. The reducing effects of GABAB PAMs on alcohol-motivated behaviors (1) occurred at doses largely lower than those inducing sedation, suggesting that GABAB PAMs may possess, if compared with baclofen, a higher therapeutic index and a more favorable safety profile, and (2) were often not associated with reductions on other non-drug consummatory behaviors. Additional findings with therapeutic potential were (1) the lack of tolerance, after repeated treatment, to the reducing effect of GABAB PAMs on alcohol drinking and self-administration; (2) the efficacy of GABAB PAMs after intragastric administration; and (3) the ability of GABAB PAMs to selectively potentiate the suppressing effect of baclofen on alcohol self-administration. The recent transition of the first GABAB PAMs to the initial steps of clinical testing makes investigation of the efficacy of GABAB PAMs in AUD patients a feasible option. [ABSTRACT FROM AUTHOR]

Published
2019
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164. Molecular organization, trafficking, and degradation of the GABA-B receptor

Author

Colombo, Giancarlo, Colombo, G ( Giancarlo ), Benke, Dietmar; https://orcid.org/0000-0003-1846-4711, Balakrishnan, Karthik, Zemoura, Khaled, Colombo, Giancarlo, Colombo, G ( Giancarlo ), Benke, Dietmar; https://orcid.org/0000-0003-1846-4711, Balakrishnan, Karthik, and Zemoura, Khaled

Published
2016

169. Low copulatory activity in selectively bred Sardinian alcohol-nonpreferring (sNP) relative to alcohol-preferring (sP) rats

Author

Karlsson, Oskar, Colombo, Giancarlo, Roman, Erika, Karlsson, Oskar, Colombo, Giancarlo, and Roman, Erika

Abstract

Background. There is a growing consensus that similar neural mechanisms are involved in the reinforcing properties of natural rewards, like food and sex, and drugs of abuse. Rat lines selectively bred for high and low oral alcohol intake and preference have been useful for understanding factors contributing to excessive alcohol intake and may constitute proper animal models for investigating the neurobiological basis of natural rewarding stimuli. Methods. The present study evaluated copulatory behavior in alcohol and sexually naive Sardinian alcohol-preferring (sP) and -nonpreferring (sNP) male rats in three consecutive copulatory behavior tests. Results. The main finding was that, under the conditions used in this study, sNP rats were sexually inactive relative to sP rats. To gain more information about the sexual behavior in sP rats, Wistar rats were included as an external reference strain. Only minor differences between sP and Wistar rats were revealed. Conclusions. The reason behind the low copulatory activity of sNP rats remains to be elucidated, but may in part be mediated by innate differences in brain transmitter systems. The comparison between sP and Wistar rats may also suggest that the inherent proclivity to excessive alcohol drinking in sP rats may mainly be dependent on its anxiolytic properties, as previously proposed, and not changes in the reward system.

Published
2015
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171. Comparison of the effect of the GABAB receptor agonist, baclofen, and the positive allosteric modulator of the GABAB receptor, GS39783, on alcohol self-administration in three different lines of alcohol-preferring rats

Author

Maccioni, Paola, Zaru, Alessandro, Loi, Barbara, Lobina, Carla, Carai, Mauro A.M., Gessa, Gian Luigi, Capra, Alessandro, Mugnaini, Claudia, Pasquini, Serena, Corelli, Federico, Hyytiä, Petri, Lumeng, Lawrence, and Colombo, Giancarlo

Subjects
Male, Baclofen, Reinforcement Schedule, Alcohol Drinking, Ethanol, Self Administration, Cyclopentanes, Article, Rats, Pyrimidines, Allosteric Regulation, Species Specificity, GABA-B Receptor Agonists, Animals, GABA Modulators
Abstract

Administration of the GABA(B) receptor agonist, baclofen, and positive allosteric modulator, GS39783, has been repeatedly reported to suppress multiple alcohol-related behaviors, including operant oral alcohol self-administration, in rats. This study was designed to compare the effect of baclofen and GS39783 on alcohol self-administration in 3 lines of selectively bred, alcohol-preferring rats: Indiana alcohol-preferring (P), Sardinian alcohol-preferring (sP), and Alko Alcohol (AA).Rats of each line were initially trained to respond on a lever, on a fixed ratio (FR) 4 (FR4) schedule of reinforcement, to orally self-administer alcohol (15%, v/v) in daily 30-minute sessions. Once responding reached stable levels, rats were exposed to a sequence of experiments testing baclofen (0, 1, 1.7, and 3 mg/kg; i.p.) and GS39783 (0, 25, 50, and 100 mg/kg; i.g.) on FR4 and progressive ratio (PR) schedules of reinforcement. Finally, to assess the specificity of baclofen and GS39783 action, rats were slightly food-deprived and trained to lever-respond for food pellets.The rank of order of the reinforcing and motivational properties of alcohol was PsPAA rats. Under both FR and PR schedules of reinforcement, the rank of order of potency and efficacy of baclofen and GS39783 in suppressing alcohol self-administration was PsPAA rats. Only the highest dose of baclofen reduced lever-responding for food pellets; this effect was common to all 3 rat lines. Conversely, no dose of GS39783 altered lever-responding for food in any rat line.These results suggest that: (i) the strength of the reinforcing and motivational properties of alcohol differ among P, sP, and AA rats; (ii) the reinforcing and motivational properties of alcohol in P, sP, and AA rats are differentially sensitive to treatment with baclofen and GS39783; (iii) the heterogeneity in sensitivity to baclofen and GS39783 of alcohol self-administration in P, sP, and AA rats may resemble the differential effectiveness of pharmacotherapies among the different typologies of human alcoholics; and (iv) the GABA(B) receptor is part of the neural substrate mediating the reinforcing and motivational properties of alcohol.

Published
2012

172. Innate difference in the endocannabinoid signaling and its modulation by alcohol consumption in alcohol-preferring sP rats

Author

Vinod, K. Yaragudri, Maccioni, Paola, García-Gutiérrez, María Salud, Femenía, Teresa, Xie, Shan, Carai, Mauro A. M., Manzanares, Jorge, Cooper, Thomas B., Hungund, Basalingappa L., Colombo, Giancarlo, National Institutes of Health (US), Instituto de Salud Carlos III, Red de Trastornos Adictivos (España), and Ministerio de Sanidad (España)

Abstract

The present study was undertaken to examine whether genetically predetermined differences in components of the endocannabinoid system were present in the brain of Sardinian alcohol-preferring (sP) and Sardinian alcohol-non-preferring (sNP) rats, a pair of rat lines selectively bred for opposite alcohol preference. The effects of acquisition and maintenance of alcohol drinking, alcohol withdrawal, and alcohol re-exposure on the endocannabinoid system was also assessed in the striatum of sP rats. The findings revealed significantly higher density of the CB1 receptors and levels of CB1 receptor mRNA, CB1 receptor-mediated G-protein coupling, and endocannabinoids in the cerebral cortex, hippocampus and striatum of alcohol-naive sP rats than sNP rats. A significantly lower expression of mFAAH enzyme was evident in the hippocampus of alcohol-naive sP rats. Alcohol drinking (during both acquisition and maintenance phases) in sP rats resulted in a significant reduction in striatal CB1 receptor-mediated G-protein coupling whereas alcohol withdrawal attenuated this effect. Alcohol consumption was also associated with markedly increased levels of endocannabinoids in the striatum. Co-administration of the CB1 receptor antagonist, rimonabant (SR141716A) reduced alcohol intake, and reversed alcohol-induced changes in CB1 receptor-mediated G-protein activation. These findings provided a new insight into a potential genetic basis of excessive alcohol consumption, suggesting innate differences in the endocannabinoid system might be associated with higher alcohol preference in sP rats. The data also indicate a modulation of CB1 receptor-mediated signaling following alcohol consumption, and further strengthen the potential of the endocannabinoid system as a target for the treatment of alcohol related behaviors., This study was supported by grants from NIH (AA015525) to BLH and RETICS (Red de Trastornos Adictivos; RD06/0001/1004, Spain) to JM. MSG was supported by a fellowship from the Spanish Ministry of Health.

Published
2012

178. Baclofen: preclinical data

Author

Carai, Mauro A.M., primary, Agabio, Roberta, additional, Addolorato, Giovanni, additional, Gessa, Gian L., additional, and Colombo, Giancarlo, additional

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179. Baclofen: clinical data

Author

Addolorato, Giovanni, primary, Abenavoli, Ludovico, additional, Leggio, Lorenzo, additional, DeLorenzi, Giosuè, additional, Ferrulli, Anna, additional, Caputo, Fabio, additional, Agabio, Roberta, additional, Gessa, Gian Luigi, additional, Colombo, Giancarlo, additional, and Gasbarrini, Giovanni, additional

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185. Supplementary material. Voluntary alcohol drinking enhances proopiomelanocortin gene expression in nucleus accumbens shell and hypothalamus of sardinian alcohol-preferring rats

Author

Zhou, Yan, Colombo, Giancarlo, Niikura, Keiichi, Carai, Mauro A. M., Femenía, Teresa, García-Gutiérrez, María Salud, Manzanares, Jorge, Ho, Ann, Gessa, Gian Luigi, Kreek, Mary Jeanne, Zhou, Yan, Colombo, Giancarlo, Niikura, Keiichi, Carai, Mauro A. M., Femenía, Teresa, García-Gutiérrez, María Salud, Manzanares, Jorge, Ho, Ann, Gessa, Gian Luigi, and Kreek, Mary Jeanne

Abstract

Data S1. Genetically determined differences between sP and sNP rats in voluntary alcohol drinking, and the effects on orexin and ppDyn in RNA levels in the lateral hypothalamus, and plasma prolactin levels, with methods.

Published
2013

186. 1337

Author

Carvalho, Fabricio, primary, Pessoa, Camila, additional, Rocha, Leonardo, additional, Colombo, Giancarlo, additional, Matos, Gustavo, additional, and Barbas, Carmen, additional

Published
2013
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187. Innate difference in the endocannabinoid signaling and its modulation by alcohol consumption in alcohol-preferring sP rats

Author

National Institutes of Health (US), Instituto de Salud Carlos III, Red de Trastornos Adictivos (España), Ministerio de Sanidad (España), Vinod, K. Yaragudri, Maccioni, Paola, García-Gutiérrez, María Salud, Femenía, Teresa, Xie, Shan, Carai, Mauro A. M., Manzanares, Jorge, Cooper, Thomas B., Hungund, Basalingappa L., Colombo, Giancarlo, National Institutes of Health (US), Instituto de Salud Carlos III, Red de Trastornos Adictivos (España), Ministerio de Sanidad (España), Vinod, K. Yaragudri, Maccioni, Paola, García-Gutiérrez, María Salud, Femenía, Teresa, Xie, Shan, Carai, Mauro A. M., Manzanares, Jorge, Cooper, Thomas B., Hungund, Basalingappa L., and Colombo, Giancarlo

Abstract

The present study was undertaken to examine whether genetically predetermined differences in components of the endocannabinoid system were present in the brain of Sardinian alcohol-preferring (sP) and Sardinian alcohol-non-preferring (sNP) rats, a pair of rat lines selectively bred for opposite alcohol preference. The effects of acquisition and maintenance of alcohol drinking, alcohol withdrawal, and alcohol re-exposure on the endocannabinoid system was also assessed in the striatum of sP rats. The findings revealed significantly higher density of the CB1 receptors and levels of CB1 receptor mRNA, CB1 receptor-mediated G-protein coupling, and endocannabinoids in the cerebral cortex, hippocampus and striatum of alcohol-naive sP rats than sNP rats. A significantly lower expression of mFAAH enzyme was evident in the hippocampus of alcohol-naive sP rats. Alcohol drinking (during both acquisition and maintenance phases) in sP rats resulted in a significant reduction in striatal CB1 receptor-mediated G-protein coupling whereas alcohol withdrawal attenuated this effect. Alcohol consumption was also associated with markedly increased levels of endocannabinoids in the striatum. Co-administration of the CB1 receptor antagonist, rimonabant (SR141716A) reduced alcohol intake, and reversed alcohol-induced changes in CB1 receptor-mediated G-protein activation. These findings provided a new insight into a potential genetic basis of excessive alcohol consumption, suggesting innate differences in the endocannabinoid system might be associated with higher alcohol preference in sP rats. The data also indicate a modulation of CB1 receptor-mediated signaling following alcohol consumption, and further strengthen the potential of the endocannabinoid system as a target for the treatment of alcohol related behaviors.

Published
2012

189. Potential efficacy of preparations derived from Phaseolus vulgaris in the control of appetite, energy intake, and carbohydrate metabolism

Author

Carai,Mauro, Fantini,Noemi, Loi,Barbara, Colombo,Giancarlo, Riva,Antonella, Morazzoni,Paolo, Carai,Mauro, Fantini,Noemi, Loi,Barbara, Colombo,Giancarlo, Riva,Antonella, and Morazzoni,Paolo

Abstract

Mauro AM Carai1, Noemi Fantini1, Barbara Loi1, Giancarlo Colombo1, Antonella Riva2, Paolo Morazzoni21C.N.R. Institute of Neuroscience, Cagliari, Italy; 2Indena SpA, Milan, ItalyAbstract: Preclinical data on extracts of and preparations derived from beans of Phaseolus vulgaris are reviewed as potential remedies for use in controlling food consumption, body weight, lipid accumulation, and glycemia. A growing body of evidence suggests that acute and chronic administration of P. vulgaris derivatives reduces food intake (including highly palatable foods), body weight, lipid deposit, and glycemia in rats exposed to multiple experimental procedures. Two possible lectin-mediated mechanisms of action have been proposed: (a) inhibition of α-amylase, resulting in a reduced carbohydrate metabolism and absorption; (b) phytohemoagglutinininduced modulation of the activity of cholecystokinin and glucagon-like peptides, resulting in a reduced appetite. Preliminary clinical data, as well as reports focusing on the use of several traditional medicines, apparently extend these findings to humans. Should these initial clinical data be confirmed by future surveys, P. vulgaris derivatives might constitute novel remedies for the treatment of obesity and metabolic syndrome. Future studies are also expected to identify active structures leading to the development of new pharmaceutical agents.Keywords: Phaseolus vulgaris extracts and derivatives, food intake, body weight, lipid accumulation, glycemia, obesity, diabetes, metabolic syndrome

Published
2009

191. Synthesis and Pharmacological Characterization of 2-(Acylamino)thiophene Derivatives as Metabolically Stable, Orally Effective, Positive Allosteric Modulators of the GABAB Receptor

Author

Mugnaini, Claudia, primary, Pedani, Valentina, additional, Casu, Angelo, additional, Lobina, Carla, additional, Casti, Alberto, additional, Maccioni, Paola, additional, Porcu, Alessandra, additional, Giunta, Daniela, additional, Lamponi, Stefania, additional, Solinas, Maurizio, additional, Dragoni, Stefania, additional, Valoti, Massimo, additional, Colombo, Giancarlo, additional, Castelli, Maria Paola, additional, Gessa, Gian Luigi, additional, and Corelli, Federico, additional

Published
2013
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195. Hypoglycemic Effects of a Standardized Extract of Salvia miltiorrhiza Roots in Rats.

Author

Carai, Mauro A. M., Colombo, Giancarlo, Loi, Barbara, Zaru, Alessandro, Riva, Antonella, Cabri, Walter, and Morazzoni, Paolo

Subjects
*SALVIA miltiorrhiza, *PLANT roots, *HYPERGLYCEMIA treatment, *LABORATORY rats, *THERAPEUTICS, PHYSIOLOGICAL effects of hypoglycemic agents, THERAPEUTIC use of plant extracts
Abstract

Background and Aims: Salvia miltiorrhiza Bunge (Labiatae) is a Chinese medicinal plant, the dried roots of which (known as Dan-Shen) have been used for hundreds of years in the treatment of a series of ailments, including hyperglycemia. This study was designed to evaluate the hypoglycemic effect of a new, standardized extract of S. miltiorrhiza. Materials and Methods: S. miltiorrhiza extract (containing 21% total tanshinones and 3.7% tanshinone IIA) was administered acutely and intragastrically at the doses of 0, 50, 100, and 200 mg/kg to male, healthy, fasted Wistar rats 60 min before the intragastric infusion of a bolus of starch (3 g/kg; a semi-naturalistic experimental condition) (Experiment 1) or glucose (2 g/kg) (Experiment 2). Results: In both experiments, treatment with S. miltiorrhiza extract produced a dose-related decrease in glycemia, evidenced in terms of reduction of peak value and/or area under the curve of the time-course of glycemia. The effect of S. miltiorrhiza extract occurred at doses devoid of any behavioral toxicity in rats. Conclusion: The results of this study suggest that the hypoglycemic effect of S. miltiorrhiza extract was likely secondary to an action on carbohydrate metabolism. These results are consistent with several preclinical and clinical data and add further support to the hypothesis that S. miltiorrhiza extracts may act as effective anti-hyperglycemic remedies. [ABSTRACT FROM AUTHOR]

Published
2016
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198. Voluntary Alcohol Drinking Enhances Proopiomelanocortin Gene Expression in Nucleus Accumbens Shell and Hypothalamus of Sardinian Alcohol-Preferring Rats

Author

Zhou, Yan, primary, Colombo, Giancarlo, additional, Niikura, Keiichi, additional, Carai, Mauro A. M., additional, Femenía, Teresa, additional, García-Gutiérrez, Maria S., additional, Manzanares, Jorge, additional, Ho, Ann, additional, Gessa, Gian Luigi, additional, and Kreek, Mary Jeanne, additional

Published
2012
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200. Comparison of the Effect of the GABABReceptor Agonist, Baclofen, and the Positive Allosteric Modulator of the GABABReceptor, GS39783, on Alcohol Self-Administration in 3 Different Lines of Alcohol-Preferring Rats

Author

Maccioni, Paola, primary, Zaru, Alessandro, additional, Loi, Barbara, additional, Lobina, Carla, additional, Carai, Mauro A. M., additional, Gessa, Gian Luigi, additional, Capra, Alessandro, additional, Mugnaini, Claudia, additional, Pasquini, Serena, additional, Corelli, Federico, additional, Hyytiä, Petri, additional, Lumeng, Lawrence, additional, and Colombo, Giancarlo, additional

Published
2012
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