Microdialysis elevation of adenosine in the basal forebrain produces vigilance impairments in the rat psychomotor vigilance task

Abstract

Study objective: The inhibitory neuromodulator adenosine has been proposed as a homeostatic sleep factor that acts potently in the basal forebrain (BF) to increase sleepiness. Here 300 microM of adenosine was dialyzed in the BF of rats, and the effect on vigilance was determined in the rat Psychomotor Vigilance Task (rPVT).

Design: Rats experienced all experimental conditions in a repeated-measures, cross-over design.

Patients or participants: Twelve young adult male Fischer-Norway rats.

Interventions: Sustained attention performance in the rPVT was evaluated following 2 hours of bilateral microdialysis perfusion of vehicle, adenosine (300 microM), or codialysis of 300 microM of adenosine with the A1 receptor antagonist 8-cyclopentyltheophylline.

Measurements and results: During rPVT performance, response latencies and performance lapses increased significantly after adenosine dialysis when compared with baseline (no dialysis) or vehicle dialysis sessions. The codialysis of 8-cyclopentyltheophylline with adenosine completely blocked the effects produced by adenosine alone, resulting in performance equivalent to that of the vehicle sessions.

Conclusions: Pharmacologic elevation of BF adenosine in rats produced vigilance impairments resembling the effect of sleep deprivation on vigilance performance in both man and rats. This effect of exogenous adenosine was completely blocked by codialysis with an adenosine A1 receptor antagonist. The results are consistent with the hypothesis that sleep loss induces elevations of BF adenosine that, acting via A1 receptors, lead to increased sleepiness and impaired vigilance.

Figure 1

Rat Psychomotor Vigilance Task. Response latencies are slowed (Panel A), and the mean number of lapses, including omissions, increased significantly (Panel B) after a 300-μM adenosine (AD) infusion into the basal forebrain (BF), compared with baseline and artificial cerebrospinal fluid (aCSF) controls. These behavior effects are reversed by codialysis of 300 μM of adenosine with 1 μM of 8-cyclopentyltheophyline (CPT, an adenosine A₁ receptor antagonist) in comparison with the 300-μM adenosine-only condition (Panels A & B). The number of premature errors per session decreased after the 300-μM adenosine infusion into the CBF, compared with baseline and aCSF control, but this reduction was reversed after codialysis of 300 μM of adenosine with 1 μM of CPT (Panel C). *P < 0.05, **P < 0.025, ***P < 0.01, ****P < 0.005. Base refers to nondialysis baseline. Error bars ± SEM.