Dopamine D2 mechanisms in canine narcolepsy

Abstract

Narcolepsy is a sleep disorder characterized by abnormal manifestations of rapid-eye-movement (REM) sleep and excessive daytime sleepiness. Using a canine model of the disease, we found that central D2 antagonists suppressed cataplexy, a form of REM-sleep atonia occurring in narcolepsy, whereas this symptom was aggravated by D2 agonists. The effect on cataplexy was stereospecific for the S(-) enantiomer of sulpiride (a D2 antagonist) and the R(+) enantiomer of 3-PPP (a D2 agonist). There was also a significant correlation between the in vivo pharmacological potency and in vitro drug affinity for D2 receptors (but not for D1 and α2 receptors) among the seven central D2 antagonists tested. Selective D1 compounds were also tested; however, the results were inconsistent because both antagonists and agonists generally suppressed cataplexy. Our current results demonstrate that central D2-type receptors are critically involved in the control of cataplexy and REM sleep. Furthermore, the finding that small doses of D2 antagonists suppressed cataplexy and induced behavioral excitation, while small doses of D2 agonists aggravated cataplexy and induced sedation, suggests that this effect is mediated presynaptically. However, considering the fact that selective dopamine reuptake inhibitors did not modify cataplexy and that our previous pharmacological results demonstrated a preferential involvement of the noradrenergic system in the control of cataplexy, we believe that the effect of D2 compounds on cataplexy is mediated secondarily via the noradrenergic systems.