Adenosine A₁and A_2AReceptors in Mouse Prefrontal Cortex Modulate Acetylcholine Release and Behavioral Arousal

Abstract

During prolonged intervals of wakefulness brain adenosine levels rise within the basal forebrain and cortex. The view that adenosine promotes sleep is supported by the corollary that N-methylated xanthines such as caffeine increase brain and behavioral arousal by blocking adenosine receptors. The four subtypes of adenosine receptors are distributed heterogeneously throughout the brain, yet the neurotransmitter systems and brain regions through which adenosine receptor blockade causes arousal are incompletely understood. This study tested the hypothesis that adenosine A1 and A2A receptors in the prefrontal cortex contribute to the regulation of behavioral and cortical arousal. Dependent measures included acetylcholine (ACh) release in the prefrontal cortex, cortical electroencephalographic (EEG) power, and time to waking after anesthesia. Sleep and wakefulness were also quantified after microinjecting an adenosine A1 receptor antagonist into the prefrontal cortex. The results showed that adenosine A1 and A2A receptors in the prefrontal cortex modulate cortical ACh release, behavioral arousal, EEG delta power, and sleep. Additional dual microdialysis studies revealed that ACh release in the pontine reticular formation is significantly altered by dialysis delivery of adenosine receptor agonists and antagonists to the prefrontal cortex. These data, and early brain transection studies demonstrating that the forebrain is not needed for sleep cycle generation, suggest that the prefrontal cortex modulates EEG and behavioral arousal via descending input to the pontine brainstem. The results provide novel evidence that adenosine A1 receptors within the prefrontal cortex comprise part of a descending system that inhibits wakefulness.

Adenosine inhibits glutamatergic input to basal forebrain cholinergic neurons

“…Previous studies have shown that adenosine, through its action on A 1 receptors, inhibits the discharge of BF wakeactive neurons, reduces acetylcholine release in the cortex, and directly inhibits cholinergic MCPO/SI neurons (Alam et al 1999;Arrigoni et al 2006;Materi et al 2000;Thakkar et al 2003a;Van Dort et al 2009). In this study, we demonstrate that adenosine reduces the excitatory drive to BF cholinergic neurons, a finding that provides an additional putative inhibitory mechanism for adenosine on BF cholinergic neurons.…”

“…Adenosine is a purine nucleoside; it is a by-product of ATP hydrolysis and might represent a cellular signal for energy demand in the brain (Benington and Heller 1995;Chagoya de Sanchez et al 1993). Adenosine has been shown to promote slow-wave sleep and rapid eye movement (REM) sleep in cats and rats (Basheer et al 2004;PorkkaHeiskanen et al 2002;Radulovacki 1995;Radulovacki et al 1984) and more recently in mice (Coleman et al 2006;Oishi et al 2008;Urade et al 2003;Van Dort et al 2009). In the early 1990s it was hypothesized that adenosine accumulates in the extracellular space during waking where, on reaching sufficiently high extracellular levels, it could produce sleep through inhibition of wake-active neurons, in particular those of the basal forebrain (BF) (Rainnie et al 1994).…”

Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia

“…A variety of experimental approaches have been used to study the neural circuits that underlie anesthetic-induced unconsciousness and recovery of consciousness in rodents, including designer receptors exclusively activated by designer drugs (DREADDs) (35), genetic manipulations (36), local and systemic drug administration (10,(37)(38)(39), microdialysis (40,41), targeted brain lesions (42,43), and electrical stimulation (34). Optogenetics is a novel tool that provides distinct advantages over previous techniques used to study anesthetic-induced unconsciousness and recovery of consciousness in rodents.…”

Limiting Activity at β1-Subunit-Containing GABAA Receptor Subtypes Reduces Ataxia

“…Second, tracazolate levels at its AD 50 value are associated with 270% enhancement of ␣ 1 ␤ 1 ␥ 2 GABA A Rs, which may result from its opposing action mediated by adenosine A 1 and A 2 receptors (Daly et al, 1988). Tracazolate is an antagonist of adenosine A 1 and A 2 receptors, with micromolar potency where it is predicted to promote arousal and wakefulness (Van Dort et al, 2009). Therefore, greater stimulation of ␣ 1 ␤ 1 ␥ 2 GABA A Rs by tracazolate would be required for physiological antagonism of its actions at these adenosine receptor subtypes.…”