title: The role of the D(2) dopamine receptor (D(2)R) in A(2A) adenosine receptor (A(2A)R)-mediated behavioral and cellular responses as revealed by A(2A) and D(2) receptor knockout mice.
abstract: The A(2A)R is largely coexpressed with D(2)Rs and enkephalin mRNA in the striatum where it modulates dopaminergic activity. Activation of the A(2A)R antagonizes D(2)R-mediated behavioral and neurochemical effects in the basal ganglia through a mechanism that may involve direct A(2A)R-D(2)R interaction. However, whether the D(2)R is required for the A(2A)R to exert its neural function is an open question. In this study, we examined the role of D(2)Rs in A(2A)R-induced behavioral and cellular responses, by using genetic knockout (KO) models (mice deficient in A(2A)Rs or D(2)Rs or both). Behavioral analysis shows that the A(2A)R agonist 2-4-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine reduced spontaneous as well as amphetamine-induced locomotion in both D(2) KO and wild-type mice. Conversely, the nonselective adenosine antagonist caffeine and the A(2A)R antagonist 8-(3-chlorostyryl)caffeine produced motor stimulation in mice lacking the D(2)R, although the stimulation was significantly attenuated. At the cellular level, A(2A)R inactivation counteracted the increase in enkephalin expression in striatopallidal neurons caused by D(2)R deficiency. Consistent with the D(2) KO phenotype, A(2A)R inactivation partially reversed both acute D(2)R antagonist (haloperidol)-induced catalepsy and chronic haloperidol-induced enkephalin mRNA expression. Together, these results demonstrate that A(2A)Rs elicit behavioral and cellular responses despite either the genetic deficiency or pharmacological blockade of D(2)Rs. Thus, A(2A)R-mediated neural functions are partially independent of D(2)Rs. Moreover, endogenous adenosine acting at striatal A(2A)Rs may be most accurately viewed as a facilitative modulator of striatal neuronal activity rather than simply as an inhibitory modulator of D(2)R neurotransmission.
authors.affiliation: Molecular Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. chenjf@helix.mgh.harvard.edu
authors.forename: J F
authors.initials: JF
authors.lastname: Chen
authors.forename: R
authors.initials: R
authors.lastname: Moratalla
authors.forename: F
authors.initials: F
authors.lastname: Impagnatiello
authors.forename: D K
authors.initials: DK
authors.lastname: Grandy
authors.forename: B
authors.initials: B
authors.lastname: Cuellar
authors.forename: M
authors.initials: M
authors.lastname: Rubinstein
authors.forename: M A
authors.initials: MA
authors.lastname: Beilstein
authors.forename: E
authors.initials: E
authors.lastname: Hackett
authors.forename: J S
authors.initials: JS
authors.lastname: Fink
authors.forename: M J
authors.initials: MJ
authors.lastname: Low
authors.forename: E
authors.initials: E
authors.lastname: Ongini
authors.forename: M A
authors.initials: MA
authors.lastname: Schwarzschild
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D002110:Caffeine / Q000031:analogs & derivatives / Q000494:pharmacology; D002375:Catalepsy / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004745:Enkephalins / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression; D006220:Haloperidol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology*; D010627:Phenethylamines / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D017447:Receptors, Dopamine D1 / Q000096:biosynthesis; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis / Q000502:physiology*; D018047:Receptors, Purinergic P1 / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D000662:Amphetamines; D018492:Dopamine Antagonists; D004745:Enkephalins; D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C081320:8-(3-chlorostyryl)caffeine; D002110:Caffeine; D006220:Haloperidol; D000241:Adenosine