Opposite modulatory roles for adenosine A₁and A_2Areceptors on glutamate and dopamine release in the shell of the nucleus accumbens. Effects of chronic caffeine exposure

Abstract

Previous studies have demonstrated opposing roles for adenosine A 1 and A 2A receptors in the modulation of extracellular levels of glutamate and dopamine in the striatum. In the present study, acute systemic administration of motoractivating doses of the A 2A receptor antagonist MSX-3 significantly decreased extracellular levels of dopamine and glutamate in the shell of the rat nucleus accumbens (NAc) and counteracted both dopamine and glutamate release induced by systemic administration of motor-activating doses of either the A 1 receptor antagonist CPT or caffeine. Furthermore, exposure to caffeine in the drinking water (1 mg/mL, 14 days) resulted in tolerance to the effects of systemic injection of CPT or caffeine, but not MSX-3, on extracellular levels of dopamine and glutamate in the NAc shell. The present results show: first, the existence of opposite tonic effects of adenosine on extracellular levels of dopamine and glutamate in the shell of the NAc mediated by A 1 and A 2A receptors; second, that complete tolerance to caffeine's dopamine-and glutamatereleasing effects which develops after chronic caffeine exposure is attributable to an A 1 receptor-mediated mechanism. Development of tolerance to the dopamine-releasing effects of caffeine in the shell of the NAc may explain its weak addictive properties and atypical psychostimulant profile.

CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis

“…Because CD73 and the A 1 and A 2a AR subtypes are expressed on the choroid plexus, extracellular adenosine produced by CD73 at the choroid plexus can signal in an autocrine fashion. Because the A 1 and A 2a ARs are functionally antagonistic to each other and have different affinities for adenosine (44), the extracellular concentration of adenosine determines how a cell expressing the A 1 and A 2a receptors will respond, thus creating a mechanistic switch whereby low concentrations of adenosine activate the A 1 subtype and higher concentrations stimulate the A 2a subtype (45). In the CNS, there is evidence to suggest that this A 1 -A 2a interaction is important in mediating neuroinflammation, where A 1 signaling is protective and A 2a signaling promotes inflammation.…”

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

“…This contrasts with the neuroprotection based on the activation of A 1 Rs, which desensitises over time (see BLong-term desensitization of A 1 receptors and up-regulation of A 2A receptors by chronic noxious conditions^). In particular, long-term exposure of caffeine leads to a rapid A 1 R desensitization but maintenance of A 2A R-mediated responses [246]. Thus, the maintenance over long periods of the central effects of A 2A R antagonists, probably related to the stress-induced up-regulation of A 2A Rs (see BLong-term desensitization of A 1 receptors and up-regulation of A 2A receptors by chronic noxious conditions^), makes this receptor an attractive target for prolonged manipulation of brain injury.…”

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry

“…However, these effects of caffeine appear to be due to A 1 rather than A 2A receptor blockade (Kuzmin et al, 1999;Green and Schenk, 2002, Solinas et al, 2002, 2005Karcz-Kubicha et al, 2003;Quarta et al, 2004Quarta et al, 2005Antoniou et al, 2005). Thus, caffeine and selective A 1 receptor antagonists have many behavioral, subjective and biochemical similarities to other psychostimulants, including their ability to induce dopamine release in the nucleus accumbens (Solinas et al, 2002(Solinas et al, , 2005Karcz-Kubicha et al, 2003;Quarta et al, 2004aQuarta et al, , 2004bAntoniou et al, 2005). Nevertheless, we should distinguish between acute and chronic caffeine treatment.…”

“…We recently demonstrated that A 1 receptor antagonism plays a key role in the acute motor-activating, discriminative stimulus and dopamine-releasing effects of systemically administered caffeine in rats (Solinas et al, 2002(Solinas et al, , 2005Karcz-Kubicha et al, 2003;Quarta et al, 2004aQuarta et al, , 2004bAntoniou et al, 2005). However, the A 1 receptor antagonistic effects disappear with chronic treatment with caffeine, while A 2A receptor antagonistic effects remain (Karcz-Kubicha et al, 2003;Quarta et al, 2004a). Thus, although acute caffeine use can enhance the effects of addictive drugs, chronic caffeine use could be beneficial to avoid relapse.…”