Adenosinergic inhibition of basal forebrain wakefulness-active neurons: a simultaneous unit recording and microdialysis study in freely behaving cats.
The majority of neurons in the magnocellular basal forebrain are wakefulness-active with highest discharge activity during wakefulness and a marked reduction in activity just before and during the entry to non-rapid eye movement (REM) sleep. We have hypothesized that the reduction of discharge activity of wakefulness-active neurons and a consequent facilitation of the transition from wakefulness to sleep is due to an increase in the extracellular concentration of adenosine during wakefulness. To test the hypothesis, the present study employed microdialysis perfusion of adenosinergic pharmacological agents combined with single unit recording in freely moving cats, so as to determine: 1). if there were dose-dependent effects on behaviorally identified wakefulness-active neurons; 2). whether effects were mediated by the A1 receptor, as contrasted to the A2a receptor; and 3). if effects were specific to wakefulness-active neurons, and not present in sleep-active neurons, those preferentially discharging in nonREM sleep. Both adenosine and the A1 receptor-specific agonist N6-cyclo-hexyl-adenosine reduced the discharge activity of wakefulness-active neurons (n=16) in a dose-dependent manner but had no effect on sleep-active neurons (n=4). The A1 receptor antagonist 8-cyclopentyl-1-3-dimethylxanthine increased the discharge of wakefulness-active neurons (n=5), but the A2a receptor agonist, CGS-16284, had no effect (n=3). Recording sites were histologically localized to the cholinergic basal forebrain. These data support our hypothesis that adenosine acts via the A1 receptor to reduce the activity of wakefulness-promoting neurons, thus providing a cellular mechanism explaining why the increased adenosine concentrations observed in the basal forebrain following prolonged wakefulness act to induce sleep.
Thakkar
M M
MM
Department of Psychiatry, Harvard Medical School, Brockton VA Medical Center, 940 Belmont Street, Brockton, MA 02401, USA. mthakkar@hms.harvard.edu
Delgiacco
R A
RA
Strecker
R E
RE
McCarley
R W
RW
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000241:Adenosine / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D002415:Cats; D004305:Dose-Response Relationship, Drug; D008297:Male; D017551:Microdialysis / Q000379:methods; D009433:Neural Inhibition / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism*; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology*
D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D043682:Receptor, Adenosine A1; D000241:Adenosine