Functional Uncoupling of Adenosine A_2A Receptors and Reduced Response to Caffeine in Mice Lacking Dopamine D₂Receptors

Abstract

Dopamine D(2) receptors (Rs) and adenosine A(2A)Rs are coexpressed on striatopallidal neurons, where they mediate opposing actions. In agreement with the idea that D(2)Rs tonically inhibit GABA release from these neurons, stimulation-evoked GABA release was significantly greater from striatal/pallidal slices from D(2)R null mutant (D(2)R(-/-)) than from wild-type (D(2)R(+/+)) mice. Release from heterozygous (D(2)R(+/-)) slices was intermediate. However, contrary to predictions that A(2A)R effects would be enhanced in D(2)R-deficient mice, the A(2A)R agonist CGS 21680 significantly increased GABA release only from D(2)R(+/+) slices. CGS 21680 modulation was observed when D(2)Rs were antagonized by raclopride, suggesting that an acute absence of D(2)Rs cannot explain the results. The lack of CGS 21680 modulation in the D(2)R-deficient mice was also not caused by a compensatory downregulation of A(2A)Rs in the striatum or globus pallidus. However, CGS 21680 significantly stimulated cAMP production only in D(2)R(+/+) striatal/pallidal slices. This functional uncoupling of A(2A)Rs in the D(2)R-deficient mice was not explained by reduced expression of G(s), G(olf), or type VI adenylyl cyclase. Locomotor activity induced by the adenosine receptor antagonist caffeine was significantly less pronounced in D(2)R(-/-) mice than in D(2)R(+/+) and D(2)R(+/-) mice, further supporting the idea that D(2)Rs are required for caffeine activation. Caffeine increased c-fos only in D(2)R(-/-) globus pallidus. The present results show that a targeted disruption of the D(2)R reduces coupling of A(2A)Rs on striatopallidal neurons and thereby responses to drugs that act on adenosine receptors. They also reinforce the ideas that D(2)Rs and A(2A)Rs are functionally opposed and that D(2)R-mediated effects normally predominate.

Alternative transcripts and evidence of imprinting of GNAL on 18p11.2

“…In addition, G olf couples to G-protein-coupled receptors (GPCRs), namely the D1 and A2a receptors, that mediate dopaminergic transmission and psychostimulant drug actions in those regions. [22][23][24] Apparent functional differences between the isoforms would suggest that changes in the relative expression levels of G olf and XLG olf might alter the pharmacology of the GPCRs that couple to them. The quantitative assay we have established will enable the measurement of absolute expression levels of G olf and XLG olf in cells or tissues under different conditions, such as normal and disease states.…”

Adenosine receptor blockade reverses hypophagia and enhances locomotor activity of dopamine-deficient mice

“…For example, previous reports showed that adenosine receptor antagonists reversed hypoactivity in D 2 receptor-deficient mice with partial efficacy (4)(5)(6). In Th Ϫ/Ϫ ; Dbh Th/ϩ mice, however, a comparison could be made between the effects of adenosine receptor antagonism and dopamine restoration.…”

“…The model of striatal dopamine͞adenosine opposition is further supported by findings that parkinsonism-like motor deficits of D 2 receptor-deficient mice can be reversed by A 2A receptor antagonists and caffeine (4,5). Additionally, catalepsy induced by acute D 2 receptor antagonist treatment is attenuated in A 2A receptor-deficient mice (6).…”

Adenosine Signaling in Striatal Circuits and Alcohol Use Disorders

“…However, it is important to note that A2ARs can exert dopamine independent effects on neurotransmission. For example, caffeine, an A2A antagonist, is known to promote locomotor function in D2R KO mice (Zahniser et al, 2000). Due to the high concentration of A2AR-D2R heterodimers in the striatum, they may be able to be used as a specific target location in the treatment of addiction.…”