Effect of a 5-HT2C serotonin agonist, dexnorfenfluramine, on amyloid precursor protein metabolism in guinea pigs

• Published in: Brain research Vol. 951; no. 1; pp. 135 - 140
• Main Authors: ARJONA, Anibal A, POOLER, Amy M, LEE, Robert K, WURTMAN, Richard J
• Format: Journal Article
• Language: English
• Published: London Elsevier 27.09.2002; Amsterdam; New York, NY
• Subjects: Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Medical sciences; Neurology; Nervous system diseases; Agonist; Alzheimer disease; Rodentia; Metabolism; Amyloid precursor protein; Cerebral disorder; Vertebrata; Mammalia; Guinea pig; Animal; Central nervous system disease; Degenerative disease; 5-HT2C serotonin receptor
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(02)03153-0

Stimulation of serotonin receptor subtypes 5-HT2A or 5-HT2C in stably transfected 3T3 cells by dexnorfenfluramine (DEXNOR) or serotonin increases secretion of the APP metabolite APPs. It is not known whether activation of these receptors can also affect APP metabolism in vivo. We examined the effects of a single intraperitoneal (i.p.) injection of DEXNOR on APPs levels in cerebrospinal fluid (CSF) of guinea pigs. These levels were significantly (P0.05) increased by a single dose of DEXNOR (1-4 mg/kg); those of the APP metabolites A beta 1-40 and A beta 1-42 were unaffected. The DEXNOR-induced (1 mg/kg) increases in CSF APPs were suppressed by ritanserin (1 mg/kg) but not by ketanserin (2 mg/kg). When given alone, ritanserin did not affect CSF levels of APPs, A beta 1-40, or A beta 1-42. Chronic treatment with DEXNOR for 9 days (1 mg /kg bid, i.p.) increased CSF APPs levels, measured 2 h after the last injection (P0.05), and decreased those of CSF A beta 1-42 (P0.05). Neither hippocampal nor cortical levels of the APP holoprotein (APPh), nor body weight, were affected by DEXNOR. Chronic administration of mCPP (1-(m-chlorophenyl)piperazine) (2 mg/kg bid, i.p.), a 5-HT2B/2C agonist, for 9 days also increased CSF APPs levels (P0.5) when measured 2 h after the drug's last administration; hippocampal and cortical APPh levels were unaffected. However, mCPP also caused a significant decrease in body weight gain. These data indicate that the pharmacological activation of 5-HT2C receptors can stimulate CSF APPs secretion and reduce A beta production in vivo. Hence 5-HT2C receptors, which apparently are localized to the brain, may represent useful targets for the development of treatments for Alzheimer's disease.