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

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.

Figure 1. Scheme of a dendritic spine of the GABAergic enkephalinergic neuron and the A_2A receptor-dependent mechanisms involved in drug addiction

Glutamatergic and dopaminergic inputs usually establish synaptic contact with the head and the neck of the dendritic spines. In the dendritic spines, A_2A receptors (A_2AR) are localized in the perisynaptic ring adjacent to the postsynaptic density, where they form heteromers with D₂. glutamate mGlu₅ and cannabinoid CB₁ receptors (D₂R, mGlu₅R and CB₁R, respectively). In the glutamatergic terminals A_2A receptors are found intrasynaptically, forming heteromers with adenosine A₁ receptors (A₁R). Involvement of A_2A receptors in drug-seeking behavior seems to be related to its modulation of CB₁ receptor signaling and its key role in both pre- and postsynaptic glutamatergic neurotransmission, including neuroadaptations such as upregulation of specific accessory proteins (RGS9-2 and AGS3) that dampen Gi/o protein-dependent signaling and promote A_2A receptor signaling (see text).

Figure 2. Time course of changes in NREM and REM sleep after caffeine (15 mg/kg) treatment in adenosine A_2A receptor wild-type (A_2AR WT, a) and knockout (A_2AR KO, b), and A₁ receptor wild-type (A₁R WT, c) and knockout (A₁R KO, d) mice

Each circle represents the hourly mean ± s.e.m. (n = 5-7). Open and closed circles stand for the baseline and experimental day profiles, respectively. The arrows indicate the injection time (9 a.m.). *, P < 0.05; **. P < 0.01, significantly different from the vehicle, by the paired t-test. Reprinted by permission from Macmillan Publishers Ltd: Nature Neuroscience, Huang et al., 2005).