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

Jiang Fan Chen, Rosario Moratalla, Francesco Impagnatiello, David Grandy, Beatriz Cuellar, Marcelo Rubinstein, Mark A. Beilstein, Elizabeth Hackett, J. Stephen Fink, Malcolm J. Low, Ennio Ongini, Michael A. Schwarzschild

    Research output: Contribution to journalArticle

    214 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)1970-1975
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume98
    Issue number4
    DOIs
    StatePublished - Feb 13 2001

    Fingerprint

    Adenosine A2A Receptors
    Dopamine D2 Receptors
    Knockout Mice
    Enkephalins
    Corpus Striatum
    Haloperidol
    Adenosine
    Adenosine A2 Receptor Agonists
    Adenosine A2 Receptor Antagonists
    Catalepsy
    Messenger RNA
    Genetic Models
    Amphetamine
    Locomotion
    Caffeine
    Basal Ganglia
    Synaptic Transmission
    Pharmacology
    Phenotype
    Neurons

    ASJC Scopus subject areas

    • Genetics
    • General

    Cite this

    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, Jiang Fan; Moratalla, Rosario; Impagnatiello, Francesco; Grandy, David; Cuellar, Beatriz; Rubinstein, Marcelo; Beilstein, Mark A.; Hackett, Elizabeth; Fink, J. Stephen; Low, Malcolm J.; Ongini, Ennio; Schwarzschild, Michael A.

    In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 4, 13.02.2001, p. 1970-1975.

    Research output: Contribution to journalArticle

    Chen, JF, Moratalla, R, Impagnatiello, F, Grandy, D, Cuellar, B, Rubinstein, M, Beilstein, MA, Hackett, E, Fink, JS, Low, MJ, Ongini, E & Schwarzschild, MA 2001, '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', Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 4, pp. 1970-1975. https://doi.org/10.1073/pnas.98.4.1970
    Chen, Jiang Fan ; Moratalla, Rosario ; Impagnatiello, Francesco ; Grandy, David ; Cuellar, Beatriz ; Rubinstein, Marcelo ; Beilstein, Mark A. ; Hackett, Elizabeth ; Fink, J. Stephen ; Low, Malcolm J. ; Ongini, Ennio ; Schwarzschild, Michael 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. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 4. pp. 1970-1975.
    @article{3e13825e4709443380c802ddf6b6ce6b,
    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",
    abstract = "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.",
    author = "Chen, {Jiang Fan} and Rosario Moratalla and Francesco Impagnatiello and David Grandy and Beatriz Cuellar and Marcelo Rubinstein and Beilstein, {Mark A.} and Elizabeth Hackett and Fink, {J. Stephen} and Low, {Malcolm J.} and Ennio Ongini and Schwarzschild, {Michael A.}",
    year = "2001",
    month = "2",
    day = "13",
    doi = "10.1073/pnas.98.4.1970",
    language = "English (US)",
    volume = "98",
    pages = "1970--1975",
    journal = "Proceedings of the National Academy of Sciences of the United States of America",
    issn = "0027-8424",
    number = "4",

    }

    TY - JOUR

    T1 - 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

    AU - Chen, Jiang Fan

    AU - Moratalla, Rosario

    AU - Impagnatiello, Francesco

    AU - Grandy, David

    AU - Cuellar, Beatriz

    AU - Rubinstein, Marcelo

    AU - Beilstein, Mark A.

    AU - Hackett, Elizabeth

    AU - Fink, J. Stephen

    AU - Low, Malcolm J.

    AU - Ongini, Ennio

    AU - Schwarzschild, Michael A.

    PY - 2001/2/13

    Y1 - 2001/2/13

    N2 - 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.

    AB - 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.

    UR - http://www.scopus.com/inward/record.url?scp=0035852721&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=0035852721&partnerID=8YFLogxK

    U2 - 10.1073/pnas.98.4.1970

    DO - 10.1073/pnas.98.4.1970

    M3 - Article

    C2 - 11172060

    AN - SCOPUS:0035852721

    VL - 98

    SP - 1970

    EP - 1975

    JO - Proceedings of the National Academy of Sciences of the United States of America

    JF - Proceedings of the National Academy of Sciences of the United States of America

    SN - 0027-8424

    IS - 4

    ER -