Abstract
Coffee and tea contain the stimulants caffeine and theophylline. These compounds act as antagonists of adenosine receptors. Adenosine promotes sleep and its extracellular concentration rises in association with prolonged wakefulness, particularly in the basal forebrain (BF) region involved in activating the cerebral cortex. However, the effect of adenosine on identified BF neurons, especially non-cholinergic neurons, is incompletely understood. Here we used whole-cell patch-clamp recordings in mouse brain slices prepared from two validated transgenic mouse lines with fluorescent proteins expressed in GABAergic or parvalbumin (PV) neurons to determine the effect of adenosine. Whole-cell recordings were made from BF cholinergic neurons and from BF GABAergic and PV neurons with the size (>20 μm) and intrinsic membrane properties (prominent H-currents) corresponding to cortically projecting neurons. A brief (2 min) bath application of adenosine (100 μM) decreased the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (EPSCs) in all groups of BF cholinergic, GABAergic, and PV neurons we recorded. In addition, adenosine decreased the frequency of miniature EPSCs in BF cholinergic neurons. Adenosine had no effect on the frequency of spontaneous inhibitory postsynaptic currents in cholinergic neurons or GABAergic neurons with large H-currents but reduced them in a group of GABAergic neurons with smaller H-currents. All effects of adenosine were blocked by a selective, adenosine A1 receptor antagonist, cyclopentyltheophylline (CPT, 1 μM). Adenosine had no postsynaptic effects. Taken together, our work suggests that adenosine promotes sleep by an A1 receptor-mediated inhibition of glutamatergic inputs to cortically projecting cholinergic and GABA/PV neurons. Conversely, caffeine and theophylline promote attentive wakefulness by inhibiting these A1 receptors in BF thereby promoting the high-frequency oscillations in the cortex required for attention and cognition.
Highlights
Caffeine and theophylline are widely used psychostimulants that are commonly found in coffee, tea, and “energy” drinks (Sun et al, 2006; Pomeranz et al, 2013)
EFFECT OF ADENOSINE ON PUTATIVE CHOLINERGIC NEURONS Adenosine presynaptically inhibits glutamatergic inputs to cholinergic neurons via A1 receptors but does not affect GABAergic inputs Putative cholinergic neurons in magnocellular preoptic area (MCPO)/horizontal limb of the diagonal band (HDB) (Figure 1A) were identified as GFP-negative neurons (Figure 1B) with intrinsic membrane properties similar to those previously reported for cholinergic neurons by us (McKenna et al, 2013) and others (e.g., Hawryluk et al, 2012)
Our data showed that the frequency of sEPSCs was significantly larger than that of mEPSCs, suggesting some of the glutamate release was due to the action potential firing of local glutamatergic neurons
Summary
Caffeine and theophylline are widely used psychostimulants that are commonly found in coffee, tea, and “energy” drinks (Sun et al, 2006; Pomeranz et al, 2013) These drugs act by inhibiting a group of highly conserved and widely expressed G-protein coupled proteins, adenosine receptors (Fredholm, 2010). There is a significant increase in the extracellular level of adenosine in basal forebrain (BF) and cortex (Porkka-Heiskanen et al, 1997, 2000; Kalinchuk et al, 2011) as well as in the mRNA and protein level of adenosine A1 receptors in BF (Basheer et al, 2001, 2007). The exact mechanisms by which adenosine modulates the BF neurons, especially the cortically projecting neurons, which in turn regulate the cortical activity, is still unclear
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