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      Trace Amine-Associated Receptor 1 Modulates the Locomotor and Sensitization Effects of Nicotine

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          Abstract

          Trace amine-associated receptor 1 (TAAR1) has emerged as a promising target for addiction treatments because it affects dopamine transmission in the mesolimbic pathway. TAAR1 is involved in the effects of addictive drugs, such as amphetamines, cocaine and ethanol, but the impact of TAAR1 on the effects of nicotine, the psychoactive drug responsible for the development and maintenance of tobacco smoking, has not yet been studied. This study was performed to investigate the possible modulatory action of TAAR1 on the effects of nicotine on locomotor behaviors in rats and mice. Pretreatment with the TAAR1 agonist RO5263397 dose-dependently decreased nicotine-induced hyperlocomotion in rats habituated to locomotor boxes, prevented the development of nicotine sensitization and blocked hypermotility in nicotine-sensitized rats at the highest tested dose (10 mg/kg). The lack of TAAR1 failed to affect the effects of nicotine on the locomotion of mutant mice. Based on the results of the present study, TAAR1 activation attenuates the locomotion-stimulating effects of nicotine on rats. These results further support the previously proposed hypothesis that TAAR1 is a promising target for the prevention and treatment of drug addiction. Further studies aimed at analyzing the effects of TAAR1 agonists on animal models of nicotine addiction are warranted.

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          Most cited references 56

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          Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study

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              Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies.

              Repeated exposure to many drugs of abuse results in a progressive and enduring enhancement in the motor stimulant effect elicited by a subsequent drug challenge. This phenomenon, termed behavioral sensitization, is thought to underlie certain aspects of drug addiction. Behavioral sensitization is the consequence of drug-induced neuroadaptive changes in a circuit involving dopaminergic and glutamatergic interconnections between the ventral tegmental area, nucleus accumbens, prefrontal cortex and amygdala. The literature was critically reviewed in an effort to discern the relative roles of glutamate and dopamine transmission in the induction and expression of sensitization to amphetamine, cocaine and mu-opioids. In addition, the literature was reviewed to evaluate distinctions between these drugs in the involvement of the relevant brain nuclei listed above. The common substrates between sensitizing drugs are glutamate transmission, especially at the NMDA receptor, and an action in the ventral tegmental area. In contrast, a role for dopamine is only clearly seen in amphetamine sensitization and critical involvement of nuclei outside the ventral tegmental area is found for cocaine and morphine. While enhanced dopamine transmission is associated with sensitization by all three drugs, a role for glutamate is clearly identified only with cocaine sensitization. Accordingly, glutamatergic cortical and allocortical brain regions such as the prefrontal cortex appear more critical for cocaine sensitization. The distinctions between drugs in the induction and expression of sensitization indicate that behavioral sensitization can arise from multiple neuroadaptations in multiple brain nuclei. This is not only the result of distinct molecular targets for the drugs, but may also include a differential involvement of learned associations. It is postulated that the relatively more robust pharmacological capacity of amphetamine to release dopamine may induce a form of sensitization that is more dependent on adaptations in mesoaccumbens dopamine transmission compared with cocaine and morphine sensitization.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                06 April 2018
                2018
                : 9
                Affiliations
                1Laboratory of Behavioral Pharmacology, Valdman Institute of Pharmacology, Pavlov First Saint Petersburg State Medical University , Saint Petersburg, Russia
                2Laboratory of Neurochemical Pharmacology, Neuroscience and Brain Technologies, Fondazione Istituto Italiano di Technologia , Genoa, Italy
                3Institute of Translational Biomedicine, Saint Petersburg State University , Saint Petersburg, Russia
                4Skolkovo Institute of Science and Technology, Skolkovo Innovation Center , Moscow, Russia
                Author notes

                Edited by: George Panagis, University of Crete, Greece

                Reviewed by: Styliani Vlachou, Dublin City University, Ireland; David Pubill, Universitat de Barcelona, Spain

                *Correspondence: Ilya Sukhanov, ilia.sukhanov@ 123456gmail.com

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2018.00329
                5898227
                Copyright © 2018 Sukhanov, Dorofeikova, Dolgorukova, Dorotenko and Gainetdinov.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 58, Pages: 10, Words: 0
                Funding
                Funded by: Russian Foundation for Basic Research 10.13039/501100002261
                Award ID: 17-04-01714
                Funded by: Russian Science Foundation 10.13039/501100006769
                Award ID: 14-50-00069
                Categories
                Pharmacology
                Original Research

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