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Raul R Gainetdinov - One of the best experts on this subject based on the ideXlab platform.
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Novel 1-Amidino-4-Phenylpiperazines as Potent Agonists at Human TAAR1 Receptor: Rational Design, Synthesis, Biological Evaluation and Molecular Docking Studies.
Pharmaceuticals (Basel Switzerland), 2020Co-Authors: Valeria Francesconi, Raul R Gainetdinov, Elena Cichero, Evgeny V. Kanov, Erik Laurini, Sabrina Pricl, Michele TonelliAbstract:Targeting trace amine-associated receptor 1 (TAAR1) receptor continues to offer an intriguing opportunity to develop innovative therapies in different pharmacological settings. Pursuing our endeavors in the search for effective and safe human TAAR1 (hTAAR1) ligands, we synthesized a new series of 1-amidino-4-phenylpiperazine derivatives (1-16) based on the application of a combined pharmacophore model/scaffold simplification strategy for an in-house series of biguanide-based TAAR1 Agonists. Most of the novel compounds proved to be more effective than their prototypes, showing nanomolar EC50 values in functional activity at hTAAR1 and low general cytotoxicity (CC50 > 80 µM) when tested on the Vero-76 cell line. In this new series, the main determinant for TAAR1 agonism ability appears to result from the appropriate combination between the steric size and position of the substituents on the phenyl ring rather than from their different electronic nature, since both electron-withdrawing and electron donor groups are permitted. In particular, the ortho-substitution seems to impose a more appropriate spatial geometry to the molecule that entails an enhanced TAAR1 potency profile, as experienced, in the following order, by compounds 15 (2,3-diCl, EC50 = 20 nM), 2 (2-CH3, EC50 = 30 nM), 6 (2-OCH3, EC50 = 93 nM) and 3 (2-Cl, EC50 = 160 nM). Apart from the interest in them as valuable leads for the development of promising hTAAR1 Agonists, these simple small molecules have further allowed us to identify the minimal structural requirements for producing an efficient hTAAR1 targeting ability.
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The Action of TAAR1 Agonist RO5263397 on Executive Functions in Rats.
Cellular and molecular neurobiology, 2019Co-Authors: A Dorotenko, Raul R Gainetdinov, Antonina Dolgorukova, M. A. Tur, Nikita Bortnikov, Irina V Belozertseva, Edwin Zvartau, I. SukhanovAbstract: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. The results of the present study demonstrated that the pretreatment with RO5263397 was able to increase attention and decrease cognitive flexibility in rats. The analysis of the RO5263397 action on impulsivity demonstrated that the TAAR1 activation failed to affect premature responding but was able to slightly modify impulsive choice. Problem solving was resistant to the pharmacological intervention.
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Rational design, chemical synthesis and biological evaluation of novel biguanides exploring species-specificity responsiveness of TAAR1 Agonists.
European journal of medicinal chemistry, 2018Co-Authors: Sara Guariento, Raul R Gainetdinov, Stefano Espinoza, Andrey S. Gerasimov, Michele Tonelli, Elena CicheroAbstract:The design of novel chemical classes acting towards several G-protein-coupled receptors (GPCRs) represents a leading strategy in drug discovery, aimed at deriving effective and safe candidates for further assessment. During the last years, TAAR1 arose as a promising druggable target in medicinal chemistry, being of interest in the treatment of several pathologies, such as neuropsychiatric disorders, type 2 diabetes and obesity. Nevertheless, the limited number of known potent and selective ligands and the species-specificity responsiveness exhibited by those derivatives nowadays available make the discovery of novel compounds a challenging task. Herein, we discuss the development of two quantitative-structure activity relationship (QSAR) models around the agonism ability experienced by different chemo-types toward murine and human TAAR1 (m/hTAAR1) with the aim at deciphering some clues involved in their species-specificity responsiveness. Qualitatively, these information were evaluated guiding for the synthesis of novel ligands, which proved to feature selective agonism ability with respect to the mTAAR1 and hTAAR1 orthologues.
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dopamine d2 receptor supersensitivity as a spectrum of neurotoxicity and status in psychiatric disorders
Journal of Pharmacology and Experimental Therapeutics, 2018Co-Authors: Richard M Kostrzewa, Karolina Wydra, Malgorzata Filip, Cynthia A Crawford, Sanders A Mcdougall, Russell W Brown, Dasiel O Borrotoescuela, Kjell Fuxe, Raul R GainetdinovAbstract:Abnormality of dopamine D2 receptor (D2R) function, often observed as D2R supersensitivity (D2RSS), is a commonality of schizophrenia and related psychiatric disorders in humans. Moreover, virtually all psychotherapeutic agents for schizophrenia target D2R in brain. Permanent D2RSS as a feature of a new animal model of schizophrenia was first reported in 1991, then behaviorally and biochemically characterized over the next 15-20 years. In this model of schizophrenia characterized by production of D2RSS in ontogeny, there are demonstrated alterations of signaling processes; as well as functional links between the biologic template of the animal model; and ability of pharmacotherapeutics to modulate or reverse biological and behavioral modalities towards normality. Another such animal model, featuring knockout of Trace Amine-Associated Receptor 1 (TAAR1), demonstrates D2RSS with an increase of the proportion of D2R in the high affinity state. Currently, TAAR1 Agonists are being explored as a therapeutic option for schizophrenia. There is likewise an overlay of D2RSS with substance use disorder. The aspect of adenosine A2A-D2 heteroreceptor complexes in substance use disorder is highlighted, and the association of A2AR antAgonists in discriminative and rewarding effects of psychostimulants is outlined. In summary, these new animal models of schizophrenia have face validity, construct validity and predictive validity, and with distinct advantages over earlier models. While the review summarizes elements of D2RSS in schizophrenia per se, and its interplay with substance use disorder, a major focus is on presumed new molecular targets attending D2RSS in schizophrenia and related clinical entities.
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Novel biguanide-based derivatives scouted as TAAR1 Agonists: Synthesis, biological evaluation, ADME prediction and molecular docking studies.
European journal of medicinal chemistry, 2016Co-Authors: Michele Tonelli, Raul R Gainetdinov, Stefano Espinoza, Elena CicheroAbstract:Trace amines (TAs) are endogenous neuromodulators that play a functional role in the synaptic transmission within central nervous system (CNS), targeting trace amine-associated receptors (TAARs). Starting from our previous computational studies on TAAR1 and TAAR5 interactions with the unselective ligand 3-iodothyronamine (T1AM), we investigated the functional activity at murine and human TAAR1 and murine TAAR5 receptors of twenty-seven biguanide-based derivatives, including six newly synthesized compounds. Phenyl (BIG2, BIG4, BIG8 and BIG22) or benzyl (BIG10-BIG16) biguanides were found to be selective murine and human TAAR1 Agonists with potencies in nanomolar or low micromolar range, respectively. In particular, compounds BIG2 and BIG12-BIG14 were the most promising and they could be considered valuable lead compounds worthy of further investigations. In addition to the interest for developing more effective human TAAR1 ligands, the disclosed here potent murine TAAR1 Agonists could offer suitable tools for studying the pharmacology of TAAR1 receptor.
Elena Cichero - One of the best experts on this subject based on the ideXlab platform.
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Novel 1-Amidino-4-Phenylpiperazines as Potent Agonists at Human TAAR1 Receptor: Rational Design, Synthesis, Biological Evaluation and Molecular Docking Studies.
Pharmaceuticals (Basel Switzerland), 2020Co-Authors: Valeria Francesconi, Raul R Gainetdinov, Elena Cichero, Evgeny V. Kanov, Erik Laurini, Sabrina Pricl, Michele TonelliAbstract:Targeting trace amine-associated receptor 1 (TAAR1) receptor continues to offer an intriguing opportunity to develop innovative therapies in different pharmacological settings. Pursuing our endeavors in the search for effective and safe human TAAR1 (hTAAR1) ligands, we synthesized a new series of 1-amidino-4-phenylpiperazine derivatives (1-16) based on the application of a combined pharmacophore model/scaffold simplification strategy for an in-house series of biguanide-based TAAR1 Agonists. Most of the novel compounds proved to be more effective than their prototypes, showing nanomolar EC50 values in functional activity at hTAAR1 and low general cytotoxicity (CC50 > 80 µM) when tested on the Vero-76 cell line. In this new series, the main determinant for TAAR1 agonism ability appears to result from the appropriate combination between the steric size and position of the substituents on the phenyl ring rather than from their different electronic nature, since both electron-withdrawing and electron donor groups are permitted. In particular, the ortho-substitution seems to impose a more appropriate spatial geometry to the molecule that entails an enhanced TAAR1 potency profile, as experienced, in the following order, by compounds 15 (2,3-diCl, EC50 = 20 nM), 2 (2-CH3, EC50 = 30 nM), 6 (2-OCH3, EC50 = 93 nM) and 3 (2-Cl, EC50 = 160 nM). Apart from the interest in them as valuable leads for the development of promising hTAAR1 Agonists, these simple small molecules have further allowed us to identify the minimal structural requirements for producing an efficient hTAAR1 targeting ability.
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opportunities and challenges in the design of selective TAAR1 Agonists an editorial
Expert Opinion on Therapeutic Patents, 2018Co-Authors: Elena CicheroAbstract:Nowadays, compounds targeting G-protein-coupled receptors (GPCRs) represent a large amount of clinically relevant drugs, depicting a leading role in the drug discovery panorama.Trace amine-associat...
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Rational design, chemical synthesis and biological evaluation of novel biguanides exploring species-specificity responsiveness of TAAR1 Agonists.
European journal of medicinal chemistry, 2018Co-Authors: Sara Guariento, Raul R Gainetdinov, Stefano Espinoza, Andrey S. Gerasimov, Michele Tonelli, Elena CicheroAbstract:The design of novel chemical classes acting towards several G-protein-coupled receptors (GPCRs) represents a leading strategy in drug discovery, aimed at deriving effective and safe candidates for further assessment. During the last years, TAAR1 arose as a promising druggable target in medicinal chemistry, being of interest in the treatment of several pathologies, such as neuropsychiatric disorders, type 2 diabetes and obesity. Nevertheless, the limited number of known potent and selective ligands and the species-specificity responsiveness exhibited by those derivatives nowadays available make the discovery of novel compounds a challenging task. Herein, we discuss the development of two quantitative-structure activity relationship (QSAR) models around the agonism ability experienced by different chemo-types toward murine and human TAAR1 (m/hTAAR1) with the aim at deciphering some clues involved in their species-specificity responsiveness. Qualitatively, these information were evaluated guiding for the synthesis of novel ligands, which proved to feature selective agonism ability with respect to the mTAAR1 and hTAAR1 orthologues.
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Novel biguanide-based derivatives scouted as TAAR1 Agonists: Synthesis, biological evaluation, ADME prediction and molecular docking studies.
European journal of medicinal chemistry, 2016Co-Authors: Michele Tonelli, Raul R Gainetdinov, Stefano Espinoza, Elena CicheroAbstract:Trace amines (TAs) are endogenous neuromodulators that play a functional role in the synaptic transmission within central nervous system (CNS), targeting trace amine-associated receptors (TAARs). Starting from our previous computational studies on TAAR1 and TAAR5 interactions with the unselective ligand 3-iodothyronamine (T1AM), we investigated the functional activity at murine and human TAAR1 and murine TAAR5 receptors of twenty-seven biguanide-based derivatives, including six newly synthesized compounds. Phenyl (BIG2, BIG4, BIG8 and BIG22) or benzyl (BIG10-BIG16) biguanides were found to be selective murine and human TAAR1 Agonists with potencies in nanomolar or low micromolar range, respectively. In particular, compounds BIG2 and BIG12-BIG14 were the most promising and they could be considered valuable lead compounds worthy of further investigations. In addition to the interest for developing more effective human TAAR1 ligands, the disclosed here potent murine TAAR1 Agonists could offer suitable tools for studying the pharmacology of TAAR1 receptor.
Guido Galley - One of the best experts on this subject based on the ideXlab platform.
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Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists.
ACS medicinal chemistry letters, 2016Co-Authors: Guido Galley, Annick Goergler, Angélica Beurier, Guillaume Décoret, Roman Hutter, Susanne Mohr, Axel Pähler, Philipp Schmid, Dietrich Türck, Robert UngerAbstract:2-Aminooxazolines were discovered as a novel structural class of TAAR1 ligands. Starting from a known adrenergic compound 1, structural modifications were made to obtain highly potent and selective TAAR1 ligands such as 12 (RO5166017), 18 (RO5256390), 36 (RO5203648), and 48 (RO5263397). These compounds exhibit drug-like physicochemical properties, have good oral bioavailability, and display in vivo activity in a variety of animal models relevant for psychiatric diseases and addiction.
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a new perspective for schizophrenia TAAR1 Agonists reveal antipsychotic and antidepressant like activity improve cognition and control body weight
Molecular Psychiatry, 2013Co-Authors: Florent G Revel, Danièle Buchy, Sylvie Chaboz, Jl Moreau, Bruno Pouzet, Roland Mory, Amyaouch Bradaia, Veit Metzler, Groebke K Zbinden, Guido GalleyAbstract:Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger serious side effects that precipitate treatment discontinuation. Here, we show that activation of the trace amine-associated receptor 1 (TAAR1), a modulator of monoaminergic neurotransmission, represents a novel therapeutic option. In rodents, activation of TAAR1 by two novel and pharmacologically distinct compounds, the full agonist RO5256390 and the partial agonist RO5263397, blocks psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties. TAAR1 Agonists do not induce catalepsy or weight gain; RO5263397 even reduced haloperidol-induced catalepsy and prevented olanzapine from increasing body weight and fat accumulation. Finally, TAAR1 activation promotes vigilance in rats and shows pro-cognitive and antidepressant-like properties in rodent and primate models. These data suggest that TAAR1 Agonists may provide a novel and differentiated treatment of schizophrenia as compared with current medication standards: TAAR1 Agonists may improve not only the positive symptoms but also the negative symptoms and cognitive deficits, without causing adverse effects such as motor impairments or weight gain.
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Optimization of Imidazole Compounds as Selective TAAR1 Agonists: Discovery of RO5073012.
ChemInform, 2012Co-Authors: Guido Galley, Henri Stalder, Annick Goergler, Marius C. Hoener, Roger David NorcrossAbstract:Based on 2-benzylimidazoline screening hits, low molecular weight imidazole compounds are identified as potent, selective, and drug-like TAAR1 Agonists.
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Optimisation of imidazole compounds as selective TAAR1 Agonists: discovery of RO5073012.
Bioorganic & medicinal chemistry letters, 2012Co-Authors: Guido Galley, Henri Stalder, Annick Goergler, Marius C. Hoener, Roger David NorcrossAbstract:A series of imidazole compounds has been identified which affords potent and selective partial and full Agonists of the TAAR1 receptor. Starting from 2-benzyl-imidazoline screening hits, a series of structurally related 2-benzyl- and 4-benzyl-imidazoles was investigated first, but it proved highly challenging to obtain compounds having sufficient selectivity against the adrenergic alpha 2 receptor. This issue could be successfully addressed by modification of the linker region and SAR exploration led to the discovery of highly selective isopropyl-substituted 4-aminomethyl-imidazole compounds. The work culminated in the identification of the selective TAAR1 partial agonist RO5073012 (4-chlorophenyl)-(1H-imidazol-4-ylmethyl)-isopropyl-amine, 24), which has a good pharmacokinetic profile after oral administration in rodents. RO5073012 has been found to be active in a behavioural rat model which is considered indicative for schizophrenia.
A Dorotenko - One of the best experts on this subject based on the ideXlab platform.
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The Action of TAAR1 Agonist RO5263397 on Executive Functions in Rats.
Cellular and molecular neurobiology, 2019Co-Authors: A Dorotenko, Raul R Gainetdinov, Antonina Dolgorukova, M. A. Tur, Nikita Bortnikov, Irina V Belozertseva, Edwin Zvartau, I. SukhanovAbstract: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. The results of the present study demonstrated that the pretreatment with RO5263397 was able to increase attention and decrease cognitive flexibility in rats. The analysis of the RO5263397 action on impulsivity demonstrated that the TAAR1 activation failed to affect premature responding but was able to slightly modify impulsive choice. Problem solving was resistant to the pharmacological intervention.
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activation of trace amine associated receptor 1 attenuates schedule induced polydipsia in rats
Neuropharmacology, 2019Co-Authors: I. Sukhanov, Antonina Dolgorukova, A Dorotenko, Anton BespalovAbstract:Trace Amine Associated Receptor 1 (TAAR1) is a novel pharmacological target. TAAR1 are well-documented to play a modulatory role in the dopaminergic system. In spite of a growing number of studies of TAAR1 effects, little is still known about the behavioral pharmacology of TAAR1 ligands, including effects of repeated TAAR1 agonist administration. The present study appears to be the first that estimated the action of TAAR1 Agonists on schedule-induced polydipsia, a type of adjunctive behavior, which is considered to be useful for evaluating certain aspects of obsessive-compulsive and related disorders (OCD) and schizophrenia. Our results have demonstrated that the wide range of RO5263397, the highly selective partial TAAR1 agonist, doses (1-10 mg/kg) attenuated the polydipsia induced by two different schedules of food delivery in rats. The effect remained unchanged for the 7 days of repeated treatment. However, the highest tested doses of RO5263397 (6 and 10 mg/kg) decreased the vertical locomotor activity of the animals and the volume of water intake of thirsty rats following the acute treatment. Also, though, the repeated RO5263397 administration is exhibited to diminish the volume of consumed water and weight of rats without SIP, on the other hand, the tolerance was observed to these drug effects. In general, the RO5263397 decreases specifically the adjunctive drinking and this effect is maintained with repeated drug administration without the development of tolerance. The interpretation of these results as an evidence for the RO5263397 anticompulsive-like action, however, should be taken with caution because the drug also influenced the drinking behavior and only weakly affected the other parameters of SIP used to reveal the potential anticompulsive-like effects of drugs.
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trace amine associated receptor 1 modulates the locomotor and sensitization effects of nicotine
Frontiers in Pharmacology, 2018Co-Authors: I. Sukhanov, Mariia Dorofeikova, Antonina Dolgorukova, A DorotenkoAbstract: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.
I. Sukhanov - One of the best experts on this subject based on the ideXlab platform.
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The Action of TAAR1 Agonist RO5263397 on Executive Functions in Rats.
Cellular and molecular neurobiology, 2019Co-Authors: A Dorotenko, Raul R Gainetdinov, Antonina Dolgorukova, M. A. Tur, Nikita Bortnikov, Irina V Belozertseva, Edwin Zvartau, I. SukhanovAbstract: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. The results of the present study demonstrated that the pretreatment with RO5263397 was able to increase attention and decrease cognitive flexibility in rats. The analysis of the RO5263397 action on impulsivity demonstrated that the TAAR1 activation failed to affect premature responding but was able to slightly modify impulsive choice. Problem solving was resistant to the pharmacological intervention.
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activation of trace amine associated receptor 1 attenuates schedule induced polydipsia in rats
Neuropharmacology, 2019Co-Authors: I. Sukhanov, Antonina Dolgorukova, A Dorotenko, Anton BespalovAbstract:Trace Amine Associated Receptor 1 (TAAR1) is a novel pharmacological target. TAAR1 are well-documented to play a modulatory role in the dopaminergic system. In spite of a growing number of studies of TAAR1 effects, little is still known about the behavioral pharmacology of TAAR1 ligands, including effects of repeated TAAR1 agonist administration. The present study appears to be the first that estimated the action of TAAR1 Agonists on schedule-induced polydipsia, a type of adjunctive behavior, which is considered to be useful for evaluating certain aspects of obsessive-compulsive and related disorders (OCD) and schizophrenia. Our results have demonstrated that the wide range of RO5263397, the highly selective partial TAAR1 agonist, doses (1-10 mg/kg) attenuated the polydipsia induced by two different schedules of food delivery in rats. The effect remained unchanged for the 7 days of repeated treatment. However, the highest tested doses of RO5263397 (6 and 10 mg/kg) decreased the vertical locomotor activity of the animals and the volume of water intake of thirsty rats following the acute treatment. Also, though, the repeated RO5263397 administration is exhibited to diminish the volume of consumed water and weight of rats without SIP, on the other hand, the tolerance was observed to these drug effects. In general, the RO5263397 decreases specifically the adjunctive drinking and this effect is maintained with repeated drug administration without the development of tolerance. The interpretation of these results as an evidence for the RO5263397 anticompulsive-like action, however, should be taken with caution because the drug also influenced the drinking behavior and only weakly affected the other parameters of SIP used to reveal the potential anticompulsive-like effects of drugs.
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trace amine associated receptor 1 modulates the locomotor and sensitization effects of nicotine
Frontiers in Pharmacology, 2018Co-Authors: I. Sukhanov, Mariia Dorofeikova, Antonina Dolgorukova, A DorotenkoAbstract: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.
