Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry

Abstract

Adenosine A 2A receptors localized in the dorsal striatum are considered as a new target for the development of antiparkinsonian drugs. Co-administration of A 2A receptor antagonists has shown a significant improvement of the effects of L-DOPA. The present review emphasizes the possible application of A 2A receptor antagonists in pathological conditions other than parkinsonism, including drug addiction, sleep disorders and pain. In addition to the dorsal striatum, the ventral striatum (nucleus accumbens) contains a high density of A 2A receptors, which presynaptically and postsynaptically regulate glutamatergic transmission in the cortical glutamatergic projections to the nucleus accumbens. It is currently believed that molecular adaptations of the cortico-accumbens glutamatergic synapses are involved in compulsive drug seeking and relapse. Here we review recent experimental evidence suggesting that A 2A antagonists could become new therapeutic agents for drug addiction. Morphological and functional studies have identified lower levels of A 2A receptors in brain areas other than the striatum, such as the ventrolateral preoptic area of the hypothalamus, where adenosine plays an important role in sleep regulation. Although initially believed to be mostly dependent on A 1 receptors, here we review recent studies that demonstrate that the somnogenic effects of adenosine are largely mediated by hypothalamic A 2A receptors. A 2A receptor antagonists could therefore be considered as a possible treatment for narcolepsy and other sleep-related disorders. Finally, nociception is another adenosine-regulated neural function previously thought to mostly involve A 1 receptors. Although there is some conflicting literature on the effects of agonists and antagonists, which may partly be due to the lack of selectivity of available drugs, the studies in A 2A receptor knockout mice suggest that A 2A receptor antagonists might have some therapeutic potential in pain states, in particular where high intensity stimuli are prevalent.

An Update on Adenosine A2A-Dopamine D2 Receptor Interactions: Implications for the Function of G Protein-Coupled Receptors

“…Under some conditions, a synergistic A 2A -D 2 receptor interaction can also be detected [34,62], which seems to depend on the presence of an activator of G protein signaling (AGS3), which facilitates a synergistic interaction between G s/olf -and G i/o -coupled receptors on the activation of types II/IV adenylyl cyclase (ACII/IV) (reviewed in ref. 63). AGS3 binds preferentially to G i , and stabilizes the GDP-bound conformation of G i , thereby dampening the signaling of the receptor through G i -GTP, while simultaneously increasing the activity of G -regulated effectors [64].…”

“…AGS3 binds preferentially to G i , and stabilizes the GDP-bound conformation of G i , thereby dampening the signaling of the receptor through G i -GTP, while simultaneously increasing the activity of G -regulated effectors [64]. Upon co-activation of the G i -coupled D 2 receptor, unbound subunits released in the presence of AGS3 are free to transiently stimulate ACII/IV upon co-activation of the G olf -coupled A 2A receptor, leading to a paradoxical increase in cAMP-PKA signaling [63] (Fig. 2c).…”

“…Therefore, upregulation of AGS3, with the consequent dampening of G i signaling while simultaneously promotingdependent signaling of G s -coupled receptors, such as D 1 in the prefrontal cortex or in the nucleus accumbens [66], or A 2A in the nucleus accumbens [63], can be an important mechanism responsible for the pathophysiologic changes associated with different addictive drugs. Thus, we have postulated that A 2A receptor antagonists could be useful in the treatment of drug addiction and relapse during drug withdrawal [63].…”

Chronic methamphetamine treatment induces oxytocin receptor up-regulation in the amygdala and hypothalamus via an adenosine A2A receptor-independent mechanism

“…PVN projections to the reward centers of the brain). Similarly to the effect of OT, activation of A 2A receptors has a prominent role in modulating MAP behavioural effects including attenuation of MAPinduced hyperactivity (Shimazoe et al , 2000) and stimulus discrimination (Munzar et al , 2002), at least partly by inhibiting MAP-induced elevation in dopamine output in the striatum (Golembiowska andZylewska, 1998, Yoshimatsu et al , 2001 (Ferre et al , 2007, Ferre et al , 2008. As OTR and D 2 receptors have recently been…”

Genetic deletion of the adenosine A2A receptor prevents nicotine-induced upregulation of α7, but not α4β2* nicotinic acetylcholine receptor binding in the brain

“…Among them, adenosine A 2A receptors (A 2 ARs) have attracted much interest as potential modulators of the effects of nicotine, both because of their predominant localization in brain circuitries that are involved in reinforcement (Ferre et al, 2007), and due to the altered behavioural phenotype that A 2A R knockout (KO) mice exhibit in response to nicotine. For instance, nicotine-induced conditioned place preference and dopamine release in the nucleus accumbens are attenuated in mice with genetic ablation of the adenosine A 2A R gene, suggesting that A 2A Rs contribute to nicotine reward (Castane et al, 2006).…”