Elsevier

Progress in Neurobiology

Volume 83, Issue 5, December 2007, Pages 332-347
Progress in Neurobiology

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

https://doi.org/10.1016/j.pneurobio.2007.04.002Get rights and content

Abstract

Adenosine A2A receptors localized in the dorsal striatum are considered as a new target for the development of antiparkinsonian drugs. Co-administration of A2A receptor antagonists has shown a significant improvement of the effects of l-DOPA. The present review emphasizes the possible application of A2A 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 A2A 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 A2A antagonists could become new therapeutic agents for drug addiction. Morphological and functional studies have identified lower levels of A2A 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 A1 receptors, here we review recent studies that demonstrate that the somnogenic effects of adenosine are largely mediated by hypothalamic A2A receptors. A2A 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 A1 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 A2A receptor knockout mice suggest that A2A receptor antagonists might have some therapeutic potential in pain states, in particular where high intensity stimuli are prevalent.

Introduction

There is emerging evidence that A2A receptor antagonists might be useful clinically in treating Parkinson's disease. A2A receptor antagonists show promising results as an adjuvant to l-DOPA therapy (see Section 2.3). The dorsal striatum, which contains a high density of A2A receptors (Rosin et al., 1998), appears to be the site of action for the antiparkinsonian effects of A2A antagonists. The dorsal striatum receives its dopaminergic input from the substantia nigra (pars compacta), the predominant area of neurodegeneration in Parkinson's disease (Hirsch et al., 1988, Rinne, 1993). The ventral striatum, which receives its dopaminergic input from the ventral tegmental area (VTA; see Section 2.1), also contains the same density of A2A receptors (see Lillrank et al., 1999). The ventral striatum (nucleus accumbens) is implicated in drug addition. Here we review recent experimental evidence suggesting that A2A receptor antagonists could become new therapeutic agents for drug addiction.

It is commonly stated that A2A receptors are localized primarily in the striatum while A1 receptors are distributed much more widely (see Ferré et al., 1992, Ferré et al., 1997). Although the striatum contains the highest density of A2A receptors in the brain (Rosin et al., 1998), morphological and functional studies have identified lower levels of A2A receptors in other brain areas. A2A receptors appear to be involved in some adenosine-regulated brain functions previously thought to be mediated solely by A1 receptors. Adenosine is an endogenous sleep-promoting substance and it is currently believed that A1 receptors in the cholinergic basal forebrain mediate sleep-inducing mechanisms (recently reviewed in Basheer et al., 2004). Here we review evidence demonstrating a key role of hypothalamic A2A receptors in sleep regulation.

Nociception is another adenosine-regulated neural function previously thought to mostly involve A1 receptors (recently reviewed in Liu and Salter, 2005). Here, we review recent evidence demonstrating that A2A receptors in peripheral nerve endings also regulate nociception. Taken together, this review emphasizes the possible application of A2A receptor ligands in pathological conditions other than Parkinson's disease.

Section snippets

The ventral striatum in drug addiction

The striatum is functionally subdivided into dorsal and ventral striatum. The dorsal striatum receives glutamatergic input from sensoriomotor and association cortical areas and dopaminergic input from the substantia nigra pars compacta (Parent and Hazrati, 1995, Gerfen, 2004). The ventral striatum, mostly represented by the nucleus accumbens (with its two compartments “shell” and “core”), receives glutamatergic input from limbic and paralimbic cortices and the amygdala and hipoccampus, as well

Adenosine and its role in sleep

The concept of humoral, rather than neural, regulation of sleep dates as far back as almost 100 years ago when Kuniomi Ishimori and Henri Piéron demonstrated the presence of some endogenous sleep-promoting substance(s) that accumulated in the cerebrospinal fluid (CSF) of sleep-deprived dogs (Kubota, 1989). More than 30 so-called endogenous sleep substances in the brain, CSF, urine, and other organs and tissues of animals have been reported since then by numerous investigators. For example,

Adenosine and its role in pain

In considering the role of the A2A receptor in pain it should first be stressed that the evidence comes predominantly from experimental animal studies, and thus strictly speaking we are talking about the role of the A2A receptor in nociception (i.e. a response to a noxious stimulus). The description of pain requires verbalization and is thus exclusively a human phenomenon. Nevertheless, there has been clinical use of adenosine in pain and thus some aspects of adenosine receptor modulation can

Acknowledgements

This work has been supported by the National Institute on Drug Abuse Intramural Research Funds, by EC (LSHM-CT-2004-005166) and GlaxoSmithKline.

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