title: Studies on the mechanism of the sympatholytic effect of 8-OH DPAT: lack of correlation between inhibition of serotonin neuronal firing and sympathetic activity.
abstract: Previous studies indicate that the selective 5-HT1A agonist, 8-OH DPAT, acts in the central nervous system to inhibit sympathetic nerve activity. Based on the observations that: (1) 8-OH DPAT acts at serotonin (5-HT) autoreceptors to inhibit 5-HT neuronal firing; and (2) medullary 5-HT neurons provide a tonic excitatory input to sympathetic preganglionic neurons, we have hypothesized that 8-OH DPAT produces its sympatholytic effects by inhibiting medullary 5-HT neuronal firing and thereby removing an excitatory input to sympathetic preganglionic neurons. The present study was designed to critically test this hypothesis. The sympatholytic effects of 8-OH DPAT were compared in intact animals and in animals which received large electrolytic lesions in the midline area of the lower brainstem. These lesions extended from the obex rostral through the level of the facial motor nucleus and encompassed the brain stem from the dorsal to the ventral surface. The sympatholytic effect of 8-OH DPAT was identical in intact animals and in animals receiving the lesion. The inhibitory effects of 8-OH DPAT on activity recorded simultaneously from the inferior cardiac sympathetic nerve and from medullospinal 5-HT neurons were determined. Medullary 5-HT neurons were identified using criteria modeled after the electrophysiological and pharmacological characteristics previously described for dorsal raphe 5-HT neurons. Medullary 5-HT neuronal activity was more sensitive to the inhibitory effects of 8-OH DPAT than was sympathetic activity. Indeed, low doses of 8-OH DPAT completely suppressed the firing of medullary 5-HT neurons but had little effect on sympathetic nerve activity. These data fail to support the hypothesis that inhibition of 5-HT neuronal firing is responsible for the central sympatholytic effects of 8-OH DPAT. Rather, the data suggest that 8-OH DPAT acts postsynaptically on 5-HT1A receptors located on central sympathetic neurons to inhibit sympathetic nerve activity.
authors.affiliation: Cardiovascular Diseases Research, Upjohn Company, Kalamazoo, MI 49001.
authors.forename: R B
authors.initials: RB
authors.lastname: McCall
authors.forename: M E
authors.initials: ME
authors.lastname: Clement
authors.forename: L T
authors.initials: LT
authors.lastname: Harris
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000200:Action Potentials / Q000187:drug effects; D000320:Adrenergic Fibers / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001339:Autonomic Fibers, Preganglionic / Q000187:drug effects / Q000502:physiology*; D002415:Cats; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D008526:Medulla Oblongata / Q000502:physiology*; D009281:Naphthalenes / Q000494:pharmacology*; D012701:Serotonin / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
chemical_list: D009281:Naphthalenes; D013764:Tetrahydronaphthalenes; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin