Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes.

Abstract

Since high-affinity adenosine A2 receptors (A2u) are localized exclusively in dopamine-rich regions in the central nervous system and mediate inhibition of locomotor activity, we have examined the effect of A2 receptor activation on D1 and D2 receptor binding in membrane preparations of the rat striatum. The A2a agonist 2-p-(2-carboxyethyl)phen- ethylaminoJ-5'-N-ethylcarboxamidoadenosine (CGS 21680) Adenosine has been shown to function as a neuromodulator in many areas of the mammalian central nervous system (1-3). These actions of adenosine are mediated by receptors that can be subdivided into Al and A2 subtypes based on relative agonist and antagonist potencies (4, 5). Al activation inhibits and A2 activation stimulates adenylate cyclase (4, 6, 7). The A2 receptors have been further subclassified into high-affinity (A2a) and low-affinity (A2b) receptors, based on agonist potencies with regard to adenylate cyclase activation (4) and receptor binding (5). The A2b receptors are widely distributed in the brain and mediate the stimulatory action of high concentrations of adenosine agonists on cAMP formation, which could affect dopamine release and synthesis (8,9). In contrast, A2a receptors are exclusively localized to dopamine-innervated areas ofthe central nervous system (10, 11), with a postsynaptic distribution (12) similar to that of postsynaptic D1 and D2 receptors (13). By using in situ hybridization the recently cloned A2a receptors (14) have been found to be localized to striatal medium-sized neurons (15).Adenosine agonists inhibit, whereas adenosine antagonists, including caffeine, enhance spontaneous (16, 17) and dopamine-induced locomotor activity (16,(18)(19)(20). The potencies of adenosine agonists in producing hypomotility correlate with their affinities for Au adenosine receptors (21,22), suggesting that A2. receptors mediate most of the behavioral effects of adenosine agonists. The hypomotility induced by adenosine agonists resembles that induced by classical neuroleptics (22), which act by blocking postsynaptic D2 receptors (23). In fact, behavioral evidence for a negative interaction between postsynaptic A2. and D2 receptors has recently been obtained using acutely reserpinized mice (24,25). Since activation of postsynaptic D2 receptors seems to be a necessary step for locomotor behavior, a negative interaction between postsynaptic A2. and D2 receptors could explain the hypomotility induced by adenosine agonists and the enhancement of locomotor activity induced by adenosine antagonists, including caffeine (24,25).In contrast to the A2a receptor, the D2 receptor mediates an inhibition of adenylate cyclase (26

Reduced striatal ecto-nucleotidase activity in schizophrenia patients supports the “adenosine hypothesis”

“…We analyzed this cerebral region as some evidence points to the existence of striatal hyperdopaminergic activity secondary to hypofunction of the prefrontal dopamine system [32,33], whereas D 2 R and A 2A R are expressed mainly in medium-sized GABAergic spiny neurons [6]. Interestingly, a recent study showed that, in rodent, ecto-5′-nucleotidase is specifically expressed in this neuronal population, being responsible for most of the extracellular adenosine produced in the striatum [34].…”

“…A 1 Rs and A 2A R are the most expressed receptors in the brain. The modulation of A 1 Rs inhibits presynaptic glutamate release, while postsynaptic A 2A R activation can promote dopamine D 2 receptor signalling inhibition through the heterodimer A 2A R-D 2 R formation [6,7]. Interestingly, a hypoadenosinergic state has been proposed in SZ [8].…”

Stimulation of Adenosine Receptors Selectively Activates Gene Expression in Striatal Enkephalinergic Neurons

“…A 2A and D 2 receptors form heteromeric complexes with reciprocal antagonistic interactions that regulate the function of the GABAergic enkephalinergic neurons (Ferré et al, 1991(Ferré et al, , 1993(Ferré et al, , 1997Agnati et al, 2003;Canals et al, 2003;Kamiya et al, 2003;Ciruela et al, 2004;Woods and Ferré, 2005). Stimulation of A 2A receptors decreases the affinity of D 2 receptors for agonists by means of an intramembrane interaction (Ferré et al, 1991), while stimulation of D 2 receptors inhibits A 2A receptor-induced activation of adenylyl-cyclase (Kull et al, 1999;Hillion et al, 2002).…”

“…Stimulation of A 2A receptors decreases the affinity of D 2 receptors for agonists by means of an intramembrane interaction (Ferré et al, 1991), while stimulation of D 2 receptors inhibits A 2A receptor-induced activation of adenylyl-cyclase (Kull et al, 1999;Hillion et al, 2002). By means of the strong antagonistic D 2 -A 2A receptor interaction at the adenylyl cyclase level, and due to the existence of a tonic effect of dopamine on D 2 receptors, under normal conditions A 2A receptors are practically unable to activate the cAMP-PKA signaling pathway (Agnati et al, 2003;Ferré et al, 2003Ferré et al, , 2004.…”

Biphasic changes in locomotor behavior and in expression of mRNA for NGFI-A and NGFI-B in rat striatum following acute caffeine administration

“…Indeed the adenosine A,, receptors may be confined to pallidal-projecting GABAergic enkephalin-containing neurons, which also express dopamine D, receptors (Fink et al, 1992;Schiffmann et al, 1991). This is important because an interaction between A,, and D, receptors may play a critically important role for the psychostimulatory effects of caffeine (Ferre et al, 1991). Activation of A,, receptors increases intracellular levels of CAMP , whereas D, receptors mediate the opposite effect on intracellular CAMP levels (Senogles, 1994).…”