Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry -: Implications for drug addiction, sleep and pain

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. (C) 2007 Elsevier Ltd. All rights reserved.