Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism

Motor execution and planning are tightly regulated by dopamine D1 and D2 receptors present in basal ganglia circuits. Although stimulation of D1 receptors is known to enhance motor function, the global effect of D2 receptor (D2R) stimulation or blockade remains highly controversial, with studies sho...

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Autores principales:	Bello, E.P., Casas-Cordero, R., Galiñanes, G.L., Casey, E., Belluscio, M.A., Rodríguez, V., Noaín, D., Murer, M.G., Rubinstein, M.
Formato:	JOUR
Materias:	dopamine 2 receptor dopamine 1 receptor dopamine receptor blocking agent adult aged animal experiment animal model Article body posture catatonia controlled study gene mutation locomotion male motor coordination motor dysfunction motor learning mouse neurologic gait disorder nonhuman parkinsonism phenotype tremor ablation therapy animal basal ganglion corpus striatum drug effects genetics human knockout mouse learning metabolism motor activity motor performance pathophysiology physiology procedures Ablation Techniques Animals Basal Ganglia Corpus Striatum Dopamine Antagonists Humans Learning Locomotion Male Mice Mice, Knockout Motor Activity Motor Skills Parkinsonian Disorders Receptors, Dopamine D1 Receptors, Dopamine D2
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_13594184_v22_n4_p595_Bello
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	todo:paper_13594184_v22_n4_p595_Bello
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spelling	todo:paper_13594184_v22_n4_p595_Bello2023-10-03T16:10:33Z Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism Bello, E.P. Casas-Cordero, R. Galiñanes, G.L. Casey, E. Belluscio, M.A. Rodríguez, V. Noaín, D. Murer, M.G. Rubinstein, M. dopamine 2 receptor dopamine 1 receptor dopamine 2 receptor dopamine receptor blocking agent adult aged animal experiment animal model Article body posture catatonia controlled study gene mutation locomotion male motor coordination motor dysfunction motor learning mouse neurologic gait disorder nonhuman parkinsonism phenotype tremor ablation therapy animal basal ganglion corpus striatum drug effects genetics human knockout mouse learning locomotion metabolism motor activity motor performance parkinsonism pathophysiology physiology procedures Ablation Techniques Animals Basal Ganglia Corpus Striatum Dopamine Antagonists Humans Learning Locomotion Male Mice Mice, Knockout Motor Activity Motor Skills Parkinsonian Disorders Receptors, Dopamine D1 Receptors, Dopamine D2 Motor execution and planning are tightly regulated by dopamine D1 and D2 receptors present in basal ganglia circuits. Although stimulation of D1 receptors is known to enhance motor function, the global effect of D2 receptor (D2R) stimulation or blockade remains highly controversial, with studies showing increasing, decreasing or no changes in motor activity. Moreover, pharmacological and genetic attempts to block or eliminate D2R have led to controversial results that questioned the importance of D2R in motor function. In this study, we generated an inducible Drd2 null-allele mouse strain that circumvented developmental compensations found in constitutive Drd2 -/- mice and allowed us to directly evaluate the participation of D2R in spontaneous locomotor activity and motor learning. We have found that loss of D2R during adulthood causes severe motor impairments, including hypolocomotion, deficits in motor coordination, impaired learning of new motor routines and spontaneous catatonia. Moreover, severe motor impairment, resting tremor and abnormal gait and posture, phenotypes reminiscent of Parkinson's disease, were evident when the mutation was induced in aged mice. Altogether, the conditional Drd2 knockout model studied here revealed the overall fundamental contribution of D2R in motor functions and explains some of the side effects elicited by D2R blockers when used in neurological and psychiatric conditions, including schizophrenia, bipolar disorder, Tourette's syndrome, dementia, alcohol-induced delusions and obsessive-compulsive disorder. Fil:Bello, E.P. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Galiñanes, G.L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Belluscio, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Noaín, D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Rubinstein, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_13594184_v22_n4_p595_Bello
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	dopamine 2 receptor dopamine 1 receptor dopamine 2 receptor dopamine receptor blocking agent adult aged animal experiment animal model Article body posture catatonia controlled study gene mutation locomotion male motor coordination motor dysfunction motor learning mouse neurologic gait disorder nonhuman parkinsonism phenotype tremor ablation therapy animal basal ganglion corpus striatum drug effects genetics human knockout mouse learning locomotion metabolism motor activity motor performance parkinsonism pathophysiology physiology procedures Ablation Techniques Animals Basal Ganglia Corpus Striatum Dopamine Antagonists Humans Learning Locomotion Male Mice Mice, Knockout Motor Activity Motor Skills Parkinsonian Disorders Receptors, Dopamine D1 Receptors, Dopamine D2
spellingShingle	dopamine 2 receptor dopamine 1 receptor dopamine 2 receptor dopamine receptor blocking agent adult aged animal experiment animal model Article body posture catatonia controlled study gene mutation locomotion male motor coordination motor dysfunction motor learning mouse neurologic gait disorder nonhuman parkinsonism phenotype tremor ablation therapy animal basal ganglion corpus striatum drug effects genetics human knockout mouse learning locomotion metabolism motor activity motor performance parkinsonism pathophysiology physiology procedures Ablation Techniques Animals Basal Ganglia Corpus Striatum Dopamine Antagonists Humans Learning Locomotion Male Mice Mice, Knockout Motor Activity Motor Skills Parkinsonian Disorders Receptors, Dopamine D1 Receptors, Dopamine D2 Bello, E.P. Casas-Cordero, R. Galiñanes, G.L. Casey, E. Belluscio, M.A. Rodríguez, V. Noaín, D. Murer, M.G. Rubinstein, M. Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
topic_facet	dopamine 2 receptor dopamine 1 receptor dopamine 2 receptor dopamine receptor blocking agent adult aged animal experiment animal model Article body posture catatonia controlled study gene mutation locomotion male motor coordination motor dysfunction motor learning mouse neurologic gait disorder nonhuman parkinsonism phenotype tremor ablation therapy animal basal ganglion corpus striatum drug effects genetics human knockout mouse learning locomotion metabolism motor activity motor performance parkinsonism pathophysiology physiology procedures Ablation Techniques Animals Basal Ganglia Corpus Striatum Dopamine Antagonists Humans Learning Locomotion Male Mice Mice, Knockout Motor Activity Motor Skills Parkinsonian Disorders Receptors, Dopamine D1 Receptors, Dopamine D2
description	Motor execution and planning are tightly regulated by dopamine D1 and D2 receptors present in basal ganglia circuits. Although stimulation of D1 receptors is known to enhance motor function, the global effect of D2 receptor (D2R) stimulation or blockade remains highly controversial, with studies showing increasing, decreasing or no changes in motor activity. Moreover, pharmacological and genetic attempts to block or eliminate D2R have led to controversial results that questioned the importance of D2R in motor function. In this study, we generated an inducible Drd2 null-allele mouse strain that circumvented developmental compensations found in constitutive Drd2 -/- mice and allowed us to directly evaluate the participation of D2R in spontaneous locomotor activity and motor learning. We have found that loss of D2R during adulthood causes severe motor impairments, including hypolocomotion, deficits in motor coordination, impaired learning of new motor routines and spontaneous catatonia. Moreover, severe motor impairment, resting tremor and abnormal gait and posture, phenotypes reminiscent of Parkinson's disease, were evident when the mutation was induced in aged mice. Altogether, the conditional Drd2 knockout model studied here revealed the overall fundamental contribution of D2R in motor functions and explains some of the side effects elicited by D2R blockers when used in neurological and psychiatric conditions, including schizophrenia, bipolar disorder, Tourette's syndrome, dementia, alcohol-induced delusions and obsessive-compulsive disorder.
format	JOUR
author	Bello, E.P. Casas-Cordero, R. Galiñanes, G.L. Casey, E. Belluscio, M.A. Rodríguez, V. Noaín, D. Murer, M.G. Rubinstein, M.
author_facet	Bello, E.P. Casas-Cordero, R. Galiñanes, G.L. Casey, E. Belluscio, M.A. Rodríguez, V. Noaín, D. Murer, M.G. Rubinstein, M.
author_sort	Bello, E.P.
title	Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
title_short	Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
title_full	Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
title_fullStr	Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
title_full_unstemmed	Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
title_sort	inducible ablation of dopamine d2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
url	http://hdl.handle.net/20.500.12110/paper_13594184_v22_n4_p595_Bello
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Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism

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