Enabling role of adenosine A₁receptors in adenosine A_2Areceptor‐mediated striatal expression ofc‐fos

Abstract

When striatal neurons are strongly activated they produce adenosine, which activates nearby adenosine A1 receptors (A1Rs) and adenosine A2A receptors (A2ARs). Although the effects of A1R or A2AR activation on neural activity in the striatum have been examined separately, the effects of coactivating both receptors has not been investigated. Using c-Fos immunohistochemistry as an indicator of neural activity, we examined the effects of coactivation of A1Rs and A2ARs on neural activity and their mechanism of interaction in the caudate-putamen, nucleus accumbens (NAc) and prefrontal cortex in rats. Administration of a motor-depressant dose of the A2AR agonist CGS 21680 (0.5 mg/kg i.p.) did not significantly induce c-fos expression in any of these brain regions. Administration of a motor-depressant dose of the A1R agonist CPA (0.3 mg/kg, i.p.) produced a small but significant induction of c-fos expression only in the shell of the NAc. Coadministration of CGS 21680 and CPA produced a synergistic induction of c-fos expression in the caudate-putamen, cingulate cortex, and especially the NAc. In the shell of the NAc administration of CPA significantly decreased extracellular dopamine levels measured by in vivo microdialysis and blocked CGS 21680-induced increases in dopamine levels. Because it has been previously shown that activation of dopamine D2 receptors (D2Rs) by endogenous dopamine blocks A2AR-mediated c-fos expression, it is hypothesized that the enabling role of A1Rs in A2AR-mediated striatal c-fos expression is related to the A1R-mediated inhibition of dopamine release.

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

“…In a previous study it was shown that co-administration of the A 1 receptor agonist CPA and the A 2A receptor agonist CGS 21680 increases the expression of the immediate-early gene c-fos in the striatum (Karcz-Kubicha et al, 2003). In the present study, we demonstrate that this increase is selective for the GABAergic enkephalinergic neurons.…”

“…However, under normal conditions, the ability of A 2A receptors to activate the cAMP-PKA signaling pathway is restrained by the tonic inhibitory effect of D 2 receptors, which potently inhibit A 2A -receptor mediated adenylyl-cyclase activation (Agnati et al, 2003;Ferré et al, 2003Ferré et al, , 2004. We have shown that activation of adenosine A 1 receptors allows A 2A receptors to overcome the inhibitory effect of D 2 receptors and induce striatal expression of c-fos (Karcz-Kubicha et al, 2003). However, it remained to be demonstrated if this increase in c-fos expression takes place in GABAergic enkephalinergic neurons.…”

“…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. In fact, the systemic administration of A 2A receptor antagonists produces either no effect or a modest decrease in the striatal expression of c-fos or preproenkephalin (Le Moine et al, 1997;Pinna et al, 1997;Aoyama et al, 2002;Carta et al, 2002;Karcz-Kubicha et al, 2003;Wardas et al, 2003). It must also be pointed out that some studies suggest that A 2A and D 2 receptor can interact synergistically, with stimulation of D 2 receptors potentiating the effects of A 2A receptor stimulation.…”

“…The simultaneous analysis of the medial and lateral parts of the NAc might have diluted such a local effect of CPA. We have previously suggested that the inability of the A 2A receptor agonist CGS 21680 to induce an increase in the striatal expression of c-fos depends on its ability to produce striatal dopamine release (Karcz-Kubicha et al, 2003), which further stimulates D 2 receptors and, therefore, antagonizes the effects of A 2A receptor stimulation by the exogenous agonist. CPA administration was shown to decrease the striatal extracellular concentration of dopamine and to counteract CGS 21680-induced dopamine release (Karcz-Kubicha et al, 2003).…”

“…The NAc was chosen for the co-localization analysis since the present and previous studies (Karcz-Kubicha et al, 2003) showed that this is the striatal region with the largest increase in c-fos expression after co-administration of adenosine A 2A and A 1 receptor agonists. The simultaneous detection of c-Fos immunoreactivity and preproenkephalin or preprodynorphin transcripts in the NAc showed a significant increase in the number of c-Fos immunoreactive cells that co-express preproenkephalin in animals treated with CGS 21680 (0.5 mg/kg) plus CPA (0.3 mg/kg) when compared with control saline-treated animals (non-paired Student's t-test: po0.001; n ¼ 70 and 32 fields for the groups treated with CGS 21680 plus CPA and saline, respectively).…”