Artículo

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" (2017) Molecular Psychiatry. 22(4):595-604
Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

Abstract:

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.

Registro:

Documento: Artículo
Título:Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism
Autor:Bello, E.P.; Casas-Cordero, R.; Galiñanes, G.L.; Casey, E.; Belluscio, M.A.; Rodríguez, V.; Noaín, D.; Murer, M.G.; Rubinstein, M.
Filiación:Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nac. de Investigaciones Cientificas y Tecnicas and Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Vuelta de Obligado 2490, Buenos Aires, 1428, Argentina
Instituto de Fisiología y Biofísica Bernardo Houssay, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
Palabras clave: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
Año:2017
Volumen:22
Número:4
Página de inicio:595
Página de fin:604
DOI: http://dx.doi.org/10.1038/mp.2016.105
Título revista:Molecular Psychiatry
Título revista abreviado:Mol. Psychiatry
ISSN:13594184
CODEN:MOPSF
CAS:Dopamine Antagonists; Receptors, Dopamine D1; Receptors, Dopamine D2
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_13594184_v22_n4_p595_Bello

Referencias:

  • Yin, H.H., Knowlton, B.J., The role of the basal ganglia in habit formation (2006) Nat Rev Neurosci, 7, pp. 464-476
  • Graybiel, A.M., Aosaki, T., Flaherty, A.W., Kimura, M., The basal ganglia and adaptive motor control (1994) Science, 265, pp. 1826-1831
  • Gerfen, C.R., Surmeier, D.J., Modulation of striatal projection systems by dopamine (2011) Annu Rev Neurosci, 34, pp. 441-466
  • Kravitz, A.V., Freeze, B.S., Parker, P.R.L., Kay, K., Thwin, M.T., Deisseroth, K., Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry (2010) Nature, 466, pp. 622-626
  • Ralph, R.J., Caine, S.B., Dopamine D1 and D2 agonist effects on prepulse inhibition and locomotion: Comparison of Sprague-Dawley rats to Swiss-Webster, 129X1/ SvJ, C57BL/6J, and DBA/2J mice (2005) J Pharmacol Exp Ther, 312, pp. 733-741
  • Thomsen, M., Ralph, R.J., Caine, S.B., Psychomotor stimulation by dopamine D1-like but not D2-like agonists in most mouse strains (2011) Exp Clin Psychopharmacol, 19, pp. 342-360
  • Maurice, N., D2 dopamine receptor-mediated modulation of voltage-dependent Na+ Channels reduces autonomous activity in striatal cholinergic interneurons (2004) J Neurosci, 24, pp. 10289-10301
  • Wang, Z., Kai, L., Day, M., Ronesi, J., Yin, H.H., Ding, J., Dopaminergic control of corticostriatal long-term synaptic depression in medium spiny neurons is mediated by cholinergic interneurons (2006) Neuron, 50, pp. 443-452
  • Bamford, N.S., Zhang, H., Schmitz, Y., Wu, N.-P., Cepeda, C., Levine, M.S., Heterosynaptic dopamine neurotransmission selects sets of corticostriatal terminals (2004) Neuron, 42, pp. 653-663
  • Bello, E.P., Mateo, Y., Gelman, D.M., Noaín, D., Shin, J.H., Low, M.J., Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors (2011) Nat Neurosci, 14, pp. 1033-1038
  • Ford, C.P., The role of D2-autoreceptors in regulating dopamine neuron activity and transmission (2014) Neuroscience, 282 C, pp. 13-22
  • Noaín, D., Pérez-Millán, M.I., Bello, E.P., Luque, G.M., Casas Cordero, R., Gelman, D.M., Central dopamine D2 receptors regulate growth-hormone-dependent body growth and pheromone signaling to conspecific males (2013) J Neurosci, 33, pp. 5834-5842
  • Holroyd, K.B., Adrover, M.F., Fuino, R.L., Bock, R., Kaplan, A.R., Gremel, C.M., Loss of feedback inhibition via D2 autoreceptors enhances acquisition of cocaine taking and reactivity to drug-paired cues (2015) Neuropsychopharmacology, 40, pp. 1495-1509
  • Perez Millan, M.I., Luque, G.M., Ramirez, M.C., Noain, D., Ornstein, A.M., Rubinstein, M., Selective disruption of dopamine D2 receptors in pituitary lactotropes increases body weight and adiposity in female mice (2014) Endocrinology, 155, pp. 829-839
  • Anzalone, A., Lizardi-Ortiz, J.E., Ramos, M., De Mei, C., Hopf, F.W., Iaccarino, C., Dual control of dopamine synthesis and release by presynaptic and postsynaptic dopamine D2 receptors (2012) J Neurosci, 32, pp. 9023-9034
  • Fujiwara, H., Comparative studies of sulpiride and classical neuroleptics on induction of catalepsy, locomotor activity, and brain dopamine metabolism in mice (1992) Pharmacol Biochem Behav, 41, pp. 301-308
  • Caroff, S.N., Hurford, I., Lybrand, J., Campbell, E.C., Movement disorders induced by antipsychotic drugs: Implications of the CATIE schizophrenia trial (2011) Neurol Clin, 29, pp. 127-148. , viii
  • Zhou, Q.Y., Palmiter, R.D., Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic (1995) Cell, 83, pp. 1197-1209
  • Kelly, M.A., Rubinstein, M., Phillips, T.J., Lessov, C.N., Burkhart-Kasch, S., Zhang, G., Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations (1998) J Neurosci, 18, pp. 3470-3479
  • Clifford, J.J., Usiello, A., Vallone, D., Kinsella, A., Borrelli, E., Waddington, J.L., Topographical evaluation of behavioural phenotype in a line of mice with targeted gene deletion of the D2 dopamine receptor (2000) Neuropharmacology, 39, pp. 382-390
  • Clifford, J.J., Kinsella, A., Tighe, O., Rubinstein, M., Grandy, D.K., Low, M.J., Comparative, topographically-based evaluation of behavioural phenotype and specification of D(1)-like:D(2) interactions in a line of incipient congenic mice with D(2) dopamine receptor 'knockout' (2001) Neuropsychopharmacology, 25, pp. 527-536
  • Hayashi, S., McMahon, A.P., Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: A tool for temporally regulated gene activation/ inactivation in the mouse (2002) Dev Biol, 244, pp. 305-318
  • Pascual, A., Hidalgo-Figueroa, M., Piruat, J.I., Pintado, C.O., Gómez-Díaz, R., López-Barneo, J., Absolute requirement of GDNF for adult catecholaminergic neuron survival (2008) Nat Neurosci, 11, pp. 755-761
  • Nguyen, M.V., Du, F., Felice, C.A., Shan, X., Nigam, A., Mandel, G., MeCP2 is critical for maintaining mature neuronal networks and global brain anatomy during late stages of postnatal brain development and in the mature adult brain (2012) J Neurosci, 32, pp. 10021-10034
  • Pelosi, B., Pratelli, M., Migliarini, S., Pacini, G., Pasqualetti, M., Generation of a Tph2 conditional knockout mouse line for time-and tissue-specific depletion of brain serotonin (2015) PLoS One, 10, p. e0136422
  • Bumaschny, V.F., Yamashita, M., Casas-Cordero, R., Otero-Corchón, V., De Souza, F.S., Rubinstein, M., Obesity-programmed mice are rescued by early genetic intervention (2012) J Clin Invest, 122, pp. 4203-4212
  • Hammond, C., Bergman, H., Brown, P., Pathological synchronization in Parkinson's disease: Networks, models and treatments (2007) Trends Neurosci, 30, pp. 357-364
  • Stein, E., Bar-Gad, I., Beta oscillations in the cortico-basal ganglia loop during parkinsonism (2013) Exp Neurol, 245, pp. 52-59
  • Mallet, N., Pogosyan, A., Sharott, A., Csicsvari, J., Bolam, J.P., Brown, P., Disrupted dopamine transmission and the emergence of exaggerated beta oscillations in subthalamic nucleus and cerebral cortex (2008) J Neurosci, 28, pp. 4795-4806
  • Connolly, A.T., Jensen, A.L., Bello, E.M., Netoff, T.I., Baker, K.B., Johnson, M.D., Modulations in oscillatory frequency and coupling in globus pallidus with increasing parkinsonian severity (2015) J Neurosci, 35, pp. 6231-6240
  • Costa, R.M., Lin, S.-C., Sotnikova, T.D., Cyr, M., Gainetdinov, R.R., Caron, M.G., Rapid alterations in corticostriatal ensemble coordination during acute dopaminedependent motor dysfunction (2006) Neuron, 52, pp. 359-369
  • Walters, J.R., Hu, D., Itoga, C.A., Parr-Brownlie, L.C., Bergstrom, D.A., Phase relationships support a role for coordinated activity in the indirect pathway in organizing slow oscillations in basal ganglia output after loss of dopamine (2007) Neuroscience, 144, pp. 762-776
  • Zold, C.L., Ballion, B., Riquelme, L.A., Gonon, F., Murer, M.G., Nigrostriatal lesion induces D2-modulated phase-locked activity in the basal ganglia of rats (2007) Eur J Neurosci, 25, pp. 2131-2144
  • Mallet, N., Pogosyan, A., Márton, L.F., Bolam, J.P., Brown, P., Magill, P.J., Parkinsonian beta oscillations in the external globus pallidus and their relationship with subthalamic nucleus activity (2008) J Neurosci, 28, pp. 14245-14258
  • Zold, C.L., Larramendy, C., Riquelme, L.A., Murer, M.G., Distinct changes in evoked and resting globus pallidus activity in early and late Parkinson's disease experimental models (2007) Eur J Neurosci, 26, pp. 1267-1279
  • Zold, C.L., Escande, M.V., Pomata, P.E., Riquelme, L.A., Murer, M.G., Striatal NMDA receptors gate cortico-pallidal synchronization in a rat model of Parkinson's disease (2012) Neurobiol Dis, 47, pp. 38-48
  • Mallet, N., Micklem, B.R., Henny, P., Brown, M.T., Williams, C., Bolam, J.P., Dichotomous organization of the external globus pallidus (2012) Neuron, 74, pp. 1075-1086
  • Levy, R., Hazrati, L.N., Herrero, M.T., Vila, M., Hassani, O.K., Mouroux, M., Re-evaluation of the functional anatomy of the basal ganglia in normal and Parkinsonian states (1997) Neuroscience, 76, pp. 335-343
  • Kühn, A.A., Williams, D., Kupsch, A., Limousin, P., Hariz, M., Schneider, G.-H., Event-related beta desynchronization in human subthalamic nucleus correlates with motor performance (2004) Brain, 127, pp. 735-746
  • Brown, P., Abnormal oscillatory synchronisation in the motor system leads to impaired movement (2007) Curr Opin Neurobiol, 17, pp. 656-664
  • Devos, D., Defebvre, L., Chapter 22 Effect of deep brain stimulation and l-Dopa on electrocortical rhythms related to movement in Parkinson's disease (2006) Prog Brain Res, 159, pp. 331-349
  • Sharott, A., Magill, P.J., Harnack, D., Kupsch, A., Meissner, W., Brown, P., Dopamine depletion increases the power and coherence of beta-oscillations in the cerebral cortex and subthalamic nucleus of the awake rat (2005) Eur J Neurosci, 21, pp. 1413-1422
  • Amirnovin, R., Williams, Z.M., Cosgrove, G.R., Eskandar, E.N., Visually guided movements suppress subthalamic oscillations in Parkinson's disease patients (2004) J Neurosci, 24, pp. 11302-11306
  • McCarthy, M.M., Moore-Kochlacs, C., Gu, X., Boyden, E.S., Han, X., Kopell, N., Striatal origin of the pathologic beta oscillations in Parkinson's disease (2011) Proc Natl Acad Sci USA, 108, pp. 11620-11625
  • Miyamoto, S., Duncan, G.E., Marx, C.E., Lieberman, J.A., Treatments for schizophrenia: A critical review of pharmacology and mechanisms of action of antipsychotic drugs (2005) Mol Psychiatry, 10, pp. 79-104
  • Koeltzow, T.E., Xu, M., Cooper, D.C., Hu, X.T., Tonegawa, S., Wolf, M.E., Alterations in dopamine release but not dopamine autoreceptor function in dopamine D3 receptor mutant mice (1998) J Neurosci, 18, pp. 2231-2238
  • Xu, M., Koeltzow, T.E., Cooper, D.C., Tonegawa, S., White, F.J., Dopamine D3 receptor mutant and wild-type mice exhibit identical responses to putative D3 receptorselective agonists and antagonists (1999) Synapse, 31, pp. 210-215
  • Rubinstein, M., Phillips, T.J., Bunzow, J.R., Falzone, T.L., Dziewczapolski, G., Zhang, G., Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine (1997) Cell, 90, pp. 991-1001
  • Kelly, M.A., Rubinstein, M., Asa, S.L., Zhang, G., Saez, C., Bunzow, J.R., Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptordeficient mice (1997) Neuron, 19, pp. 103-113
  • Díaz-Torga, G., Feierstein, C., Libertun, C., Gelman, D., Kelly, M.A., Low, M.J., Disruption of the D2 dopamine receptor alters GH and IGF-I secretion and causes dwarfism in Male mice (2002) Endocrinology, 143, pp. 1270-1279
  • Susatia, F., Fernandez, H.H., Drug-induced parkinsonism (2009) Curr Treat Options Neurol, 11, pp. 162-169
  • Rocchetti, J., Isingrini, E., Dal Bo, G., Sagheby, S., Menegaux, A., Tronche, F., Presynaptic D2 dopamine receptors control long-term depression expression and memory processes in the temporal hippocampus (2015) Biol Psychiatry, 77, pp. 513-525
  • Cachope, R., Mateo, Y., Mathur, B.N., Irving, J., Wang, H.-L., Morales, M., Selective activation of cholinergic interneurons enhances accumbal phasic dopamine release: Setting the tone for reward processing (2012) Cell Rep, 2, pp. 33-41
  • Threlfell, S., Lalic, T., Platt, N.J., Jennings, K.A., Deisseroth, K., Cragg, S.J., Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons (2012) Neuron, 75, pp. 58-64
  • Barone, P., Davis, T.A., Braun, A.R., Chase, T.N., Dopaminergic mechanisms and motor function: Characterization of D-1 and D-2 dopamine receptor interactions (1986) Eur J Pharmacol, 123, pp. 109-114
  • Rubinstein, M., Gershanik, O., Stefano, F.J., Different roles of D-1 and D-2 dopamine receptors involved in locomotor activity of supersensitive mice (1988) Eur J Pharmacol, 148, pp. 419-426
  • Cui, G., Jun, S.B., Jin, X., Pham, M.D., Vogel, S.S., Lovinger, D.M., Concurrent activation of striatal direct and indirect pathways during action initiation (2014) Nature, 494, pp. 238-242
  • Yin, H.H., Mulcare, S.P., Hilário, M.R.F., Clouse, E., Holloway, T., Davis, M.I., Dynamic reorganization of striatal circuits during the acquisition and consolidation of a skill (2009) Nat Neurosci, 12, pp. 333-341
  • Schwab, R.S., Chafetz, M.E., Walker, S., Control of two simultaneous voluntary motor acts in normals and in parkinsonism (1954) AMA Arch Neurol Psychiatry, 72, pp. 591-598
  • Knowlton, B.J., Mangels, J.A., Squire, L.R., A neostriatal habit learning system in humans (1996) Science, 273, pp. 1399-1402
  • Faure, A., Haberland, U., Condé, F., El Massioui, N., Lesion to the nigrostriatal dopamine system disrupts stimulus-response habit formation (2005) J Neurosci, 25, pp. 2771-2780
  • Tseng, K.Y., Kasanetz, F., Kargieman, L., Riquelme, L.A., Murer, M.G., Cortical slow oscillatory activity is reflected in the membrane potential and spike trains of striatal neurons in rats with chronic nigrostriatal lesions (2001) J Neurosci, 21, pp. 6430-6439

Citas:

---------- APA ----------
Bello, E.P., Casas-Cordero, R., Galiñanes, G.L., Casey, E., Belluscio, M.A., Rodríguez, V., Noaín, D.,..., Rubinstein, M. (2017) . Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism. Molecular Psychiatry, 22(4), 595-604.
http://dx.doi.org/10.1038/mp.2016.105
---------- CHICAGO ----------
Bello, E.P., Casas-Cordero, R., Galiñanes, G.L., Casey, E., Belluscio, M.A., Rodríguez, V., et al. "Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism" . Molecular Psychiatry 22, no. 4 (2017) : 595-604.
http://dx.doi.org/10.1038/mp.2016.105
---------- MLA ----------
Bello, E.P., Casas-Cordero, R., Galiñanes, G.L., Casey, E., Belluscio, M.A., Rodríguez, V., et al. "Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism" . Molecular Psychiatry, vol. 22, no. 4, 2017, pp. 595-604.
http://dx.doi.org/10.1038/mp.2016.105
---------- VANCOUVER ----------
Bello, E.P., Casas-Cordero, R., Galiñanes, G.L., Casey, E., Belluscio, M.A., Rodríguez, V., et al. Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism. Mol. Psychiatry. 2017;22(4):595-604.
http://dx.doi.org/10.1038/mp.2016.105