The role of the D2 dopamine receptor (D2R) in A2A adenosine receptor (A2AR)-mediated behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice

The A2AR is largely coexpressed with D2Rs and enkephalin mRNA in the striatum where it modulates dopaminergic activity. Activation of the A2AR antagonizes D2R-mediated behavioral and neurochemical effects in the basal ganglia through a mechanism that may involve direct A2AR-D2R interaction. However,...

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Autores principales:	Chen, J.-F., Moratalla, R., Impagnatiello, F., Grandy, D.K., Cuellar, B., Rubinstein, M., Beilstein, M.A., Hackett, E., Fink, J.S., Low, M.J., Ongini, E., Schwarzschild, M.A.
Formato:	JOUR
Materias:	8 (3 chlorostyryl)caffeine adenosine A2a receptor adenosine A2a receptor agonist adenosine A2a receptor antagonist adenosine receptor blocking agent amphetamine derivative caffeine dopamine 2 receptor dopamine 2 receptor blocking agent enkephalin haloperidol animal behavior animal experiment animal model article controlled study dopaminergic activity drug effect knockout mouse locomotion motor activity mouse nerve conduction neurotransmission nonhuman priority journal protein expression receptor down regulation Adenosine Amphetamines Animals Caffeine Catalepsy Corpus Striatum Dopamine Antagonists Enkephalins Gene Expression Haloperidol Mice Mice, Inbred C57BL Mice, Knockout Motor Activity Phenethylamines Receptor, Adenosine A2A Receptors, Dopamine D1 Receptors, Dopamine D2 Receptors, Purinergic P1 RNA, Messenger Animalia
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_00278424_v98_n4_p1970_Chen
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	todo:paper_00278424_v98_n4_p1970_Chen
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spelling	todo:paper_00278424_v98_n4_p1970_Chen2023-10-03T14:38:23Z The role of the D2 dopamine receptor (D2R) in A2A adenosine receptor (A2AR)-mediated behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice Chen, J.-F. Moratalla, R. Impagnatiello, F. Grandy, D.K. Cuellar, B. Rubinstein, M. Beilstein, M.A. Hackett, E. Fink, J.S. Low, M.J. Ongini, E. Schwarzschild, M.A. 8 (3 chlorostyryl)caffeine adenosine A2a receptor adenosine A2a receptor agonist adenosine A2a receptor antagonist adenosine receptor blocking agent amphetamine derivative caffeine dopamine 2 receptor dopamine 2 receptor blocking agent enkephalin haloperidol animal behavior animal experiment animal model article controlled study dopaminergic activity drug effect knockout mouse locomotion motor activity mouse nerve conduction neurotransmission nonhuman priority journal protein expression receptor down regulation Adenosine Amphetamines Animals Caffeine Catalepsy Corpus Striatum Dopamine Antagonists Enkephalins Gene Expression Haloperidol Mice Mice, Inbred C57BL Mice, Knockout Motor Activity Phenethylamines Receptor, Adenosine A2A Receptors, Dopamine D1 Receptors, Dopamine D2 Receptors, Purinergic P1 RNA, Messenger Animalia The A2AR is largely coexpressed with D2Rs and enkephalin mRNA in the striatum where it modulates dopaminergic activity. Activation of the A2AR antagonizes D2R-mediated behavioral and neurochemical effects in the basal ganglia through a mechanism that may involve direct A2AR-D2R interaction. However, whether the D2R is required for the A2AR to exert its neural function is an open question. In this study, we examined the role of D2Rs in A2AR-induced behavioral and cellular responses, by using genetic knockout (KO) models (mice deficient in A2ARs or D2Rs or both). Behavioral analysis shows that the A2AR agonist 2-4-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine reduced spontaneous as well as amphetamine-induced locomotion in both D2 KO and wild-type mice. Conversely, the nonselective adenosine antagonist caffeine and the A2AR antagonist 8-(3-chlorostyryl)caffeine produced motor stimulation in mice lacking the D2R, although the stimulation was significantly attentuated. At the cellular level, A2AR inactivation counteracted the increase in enkephalin expression in striatopallidal neurons caused by D2R deficiency. Consistent with the D2 KO phenotype, A2AR inactivation partially reversed both acute D2R antagonist (haloperidol)-induced catalepsy and chronic haloperidol-induced enkephalin mRNA expression. Together, these results demonstrate that A2ARs elicit behavioral and cellular responses despite either the genetic deficiency or pharmacological blockade of D2Rs. Thus, A2AR-mediated neural functions are partially independent of D2Rs. Moreover, endogenous adenosine acting at striatal A2ARs may be most accurately viewed as a facilitative modulator of striatal neuronal activity rather than simply as an inhibitory modulator of D2R neurotransmission. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00278424_v98_n4_p1970_Chen
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	8 (3 chlorostyryl)caffeine adenosine A2a receptor adenosine A2a receptor agonist adenosine A2a receptor antagonist adenosine receptor blocking agent amphetamine derivative caffeine dopamine 2 receptor dopamine 2 receptor blocking agent enkephalin haloperidol animal behavior animal experiment animal model article controlled study dopaminergic activity drug effect knockout mouse locomotion motor activity mouse nerve conduction neurotransmission nonhuman priority journal protein expression receptor down regulation Adenosine Amphetamines Animals Caffeine Catalepsy Corpus Striatum Dopamine Antagonists Enkephalins Gene Expression Haloperidol Mice Mice, Inbred C57BL Mice, Knockout Motor Activity Phenethylamines Receptor, Adenosine A2A Receptors, Dopamine D1 Receptors, Dopamine D2 Receptors, Purinergic P1 RNA, Messenger Animalia
spellingShingle	8 (3 chlorostyryl)caffeine adenosine A2a receptor adenosine A2a receptor agonist adenosine A2a receptor antagonist adenosine receptor blocking agent amphetamine derivative caffeine dopamine 2 receptor dopamine 2 receptor blocking agent enkephalin haloperidol animal behavior animal experiment animal model article controlled study dopaminergic activity drug effect knockout mouse locomotion motor activity mouse nerve conduction neurotransmission nonhuman priority journal protein expression receptor down regulation Adenosine Amphetamines Animals Caffeine Catalepsy Corpus Striatum Dopamine Antagonists Enkephalins Gene Expression Haloperidol Mice Mice, Inbred C57BL Mice, Knockout Motor Activity Phenethylamines Receptor, Adenosine A2A Receptors, Dopamine D1 Receptors, Dopamine D2 Receptors, Purinergic P1 RNA, Messenger Animalia Chen, J.-F. Moratalla, R. Impagnatiello, F. Grandy, D.K. Cuellar, B. Rubinstein, M. Beilstein, M.A. Hackett, E. Fink, J.S. Low, M.J. Ongini, E. Schwarzschild, M.A. The role of the D2 dopamine receptor (D2R) in A2A adenosine receptor (A2AR)-mediated behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice
topic_facet	8 (3 chlorostyryl)caffeine adenosine A2a receptor adenosine A2a receptor agonist adenosine A2a receptor antagonist adenosine receptor blocking agent amphetamine derivative caffeine dopamine 2 receptor dopamine 2 receptor blocking agent enkephalin haloperidol animal behavior animal experiment animal model article controlled study dopaminergic activity drug effect knockout mouse locomotion motor activity mouse nerve conduction neurotransmission nonhuman priority journal protein expression receptor down regulation Adenosine Amphetamines Animals Caffeine Catalepsy Corpus Striatum Dopamine Antagonists Enkephalins Gene Expression Haloperidol Mice Mice, Inbred C57BL Mice, Knockout Motor Activity Phenethylamines Receptor, Adenosine A2A Receptors, Dopamine D1 Receptors, Dopamine D2 Receptors, Purinergic P1 RNA, Messenger Animalia
description	The A2AR is largely coexpressed with D2Rs and enkephalin mRNA in the striatum where it modulates dopaminergic activity. Activation of the A2AR antagonizes D2R-mediated behavioral and neurochemical effects in the basal ganglia through a mechanism that may involve direct A2AR-D2R interaction. However, whether the D2R is required for the A2AR to exert its neural function is an open question. In this study, we examined the role of D2Rs in A2AR-induced behavioral and cellular responses, by using genetic knockout (KO) models (mice deficient in A2ARs or D2Rs or both). Behavioral analysis shows that the A2AR agonist 2-4-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine reduced spontaneous as well as amphetamine-induced locomotion in both D2 KO and wild-type mice. Conversely, the nonselective adenosine antagonist caffeine and the A2AR antagonist 8-(3-chlorostyryl)caffeine produced motor stimulation in mice lacking the D2R, although the stimulation was significantly attentuated. At the cellular level, A2AR inactivation counteracted the increase in enkephalin expression in striatopallidal neurons caused by D2R deficiency. Consistent with the D2 KO phenotype, A2AR inactivation partially reversed both acute D2R antagonist (haloperidol)-induced catalepsy and chronic haloperidol-induced enkephalin mRNA expression. Together, these results demonstrate that A2ARs elicit behavioral and cellular responses despite either the genetic deficiency or pharmacological blockade of D2Rs. Thus, A2AR-mediated neural functions are partially independent of D2Rs. Moreover, endogenous adenosine acting at striatal A2ARs may be most accurately viewed as a facilitative modulator of striatal neuronal activity rather than simply as an inhibitory modulator of D2R neurotransmission.
format	JOUR
author	Chen, J.-F. Moratalla, R. Impagnatiello, F. Grandy, D.K. Cuellar, B. Rubinstein, M. Beilstein, M.A. Hackett, E. Fink, J.S. Low, M.J. Ongini, E. Schwarzschild, M.A.
author_facet	Chen, J.-F. Moratalla, R. Impagnatiello, F. Grandy, D.K. Cuellar, B. Rubinstein, M. Beilstein, M.A. Hackett, E. Fink, J.S. Low, M.J. Ongini, E. Schwarzschild, M.A.
author_sort	Chen, J.-F.
title	The role of the D2 dopamine receptor (D2R) in A2A adenosine receptor (A2AR)-mediated behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice
title_short	The role of the D2 dopamine receptor (D2R) in A2A adenosine receptor (A2AR)-mediated behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice
title_full	The role of the D2 dopamine receptor (D2R) in A2A adenosine receptor (A2AR)-mediated behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice
title_fullStr	The role of the D2 dopamine receptor (D2R) in A2A adenosine receptor (A2AR)-mediated behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice
title_full_unstemmed	The role of the D2 dopamine receptor (D2R) in A2A adenosine receptor (A2AR)-mediated behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice
title_sort	role of the d2 dopamine receptor (d2r) in a2a adenosine receptor (a2ar)-mediated behavioral and cellular responses as revealed by a2a and d2 receptor knockout mice
url	http://hdl.handle.net/20.500.12110/paper_00278424_v98_n4_p1970_Chen
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The role of the D2 dopamine receptor (D2R) in A2A adenosine receptor (A2AR)-mediated behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice

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