title: Cholinergic mechanisms in canine narcolepsy--I. Modulation of cataplexy via local drug administration into the pontine reticular formation.
abstract: Cataplexy in the narcoleptic canine has been shown to increase after systemic administration of cholinergic agonists. Furthermore, the number of cholinergic receptors in the pontine reticular formation of narcoleptic canines is significantly elevated. In the present study we have investigated the effects of cholinergic drugs administered directly into the pontine reticular formation on cataplexy, as defined by brief episodes of hypotonia induced by emotions, in narcoleptic canines. Carbachol and atropine were perfused through microdialysis probes implanted bilaterally in the pontine reticular formation of freely moving, narcoleptic and control Doberman pinschers. Cataplexy was quantified using the Food-Elicited Cataplexy Test, and analysed using recordings of electroencephalogram, electrooculogram and electromyogram. Cataplexy was characterized by a desynchronized electroencephalogram and a drop in electromyogram and electrooculogram activity. In narcoleptic canines, both unilateral and bilateral carbachol (10(-5) to 10(-3) M) produced a dose-dependent increase in cataplexy, which resulted in complete muscle tone suppression at the highest concentration. In control canines, neither bilateral nor unilateral carbachol (10(-5) to 10(-3) M) produced cataplexy, although bilateral carbachol, did produce muscle atonia at the highest dose (10(-3)). The increase in cataplexy after bilateral carbachol (10(-4) M) was rapidly reversed when the perfusion medium was switched to one containing atropine (10(-4) M). Bilateral atropine (10(-3) to 10(-2) M) alone did not produce any significant effects on cataplexy in narcoleptic canines; however, bilateral atropine (10(-2) M) did reduce the increase in cataplexy produced by systemic administration of physostigmine (0.05 mg/kg, i.v.). These findings demonstrate that cataplexy in narcoleptic canines can be stimulated by applying cholinergic agonists directly into the pontine reticular formation. The ability of atropine to inhibit locally and systemically stimulated cataplexy indicates that the pontine reticular formation is a critical component in cholinergic stimulation of cataplexy. Therefore, it is suggested that the pontine reticular formation plays a significant role in the cholinergic regulation of narcolepsy.
authors.affiliation: Stanford University Sleep Disorders Research Center, Palo Alto, CA 94304.
authors.forename: M S
authors.initials: MS
authors.lastname: Reid
authors.forename: M
authors.initials: M
authors.lastname: Tafti
authors.forename: J N
authors.initials: JN
authors.lastname: Geary
authors.forename: S
authors.initials: S
authors.lastname: Nishino
authors.forename: J M
authors.initials: JM
authors.lastname: Siegel
authors.forename: W C
authors.initials: WC
authors.lastname: Dement
authors.forename: E
authors.initials: E
authors.lastname: Mignot
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001285:Atropine / Q000008:administration & dosage / Q000494:pharmacology*; D002217:Carbachol / Q000008:administration & dosage / Q000494:pharmacology*; D002385:Cataplexy / Q000188:drug therapy / Q000503:physiopathology / Q000662:veterinary*; D004283:Dog Diseases; D004285:Dogs; D004569:Electroencephalography / Q000187:drug effects; D004576:Electromyography / Q000187:drug effects; D004585:Electrooculography / Q000187:drug effects; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D007839:Functional Laterality; D008297:Male; D009290:Narcolepsy / Q000503:physiopathology / Q000662:veterinary*; D010830:Physostigmine / Q000494:pharmacology; D012016:Reference Values; D012154:Reticular Formation / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D013238:Stereotaxic Techniques
chemical_list: D001285:Atropine; D002217:Carbachol; D010830:Physostigmine