In vivo and in vitro effects of adrenocorticotrophic hormone on serotonin receptors in neonatal rat brain.
The molecular basis of the antimyoclonic and antiepileptic properties of ACTH is unknown. Direct actions at neurotransmitter receptors have been hypothesized. Abnormalities of serotonergic neurotransmission have been suggested in the ACTH-responsive disorder infantile spasms based on elevated blood or platelet serotonin (5-HT) levels and induction of infantile spasms in Down's syndrome by the 5-HT precursor 5-hydroxytryptophan. To pursue these and other clinical and basic links between ACTH and 5-HT, the activity of ACTH at 5-HT receptors was determined n vitro and in vivo. Neonatal rats were treated for 30 consecutive days with a pharmacologic dose (40 IU/kg) of lyophilized porcine ACTH1-39 reconstituted in normal saline or with saline alone. ACTH administration impaired the weight gain of rat pups. In saturation receptor binding studies of rats treated as neonates (n = 7/group), ACTH significantly reduced receptor density (Bmax) of 5-HT2 sites in the cortex (-13%) compared to controls without a change in receptor affinity. Regional 5-HT1 receptor sites and 5-HT and 5-HIAA levels were not altered. Cortical tryptophan concentrations were significantly decreased (-29%) in rats treated neonatally with ACTH. In competition experiments in vitro using naive 7- to 10-day-old neonatal rat forebrain, ACTH1-39 displaced 5-HT1 and 5-HT2 sites only with 100 micromolar IC50 values. The small effects of ACTH at 5-HT receptors even at a supraclinical dose may not explain its potent clinical antimyoclonic properties.
Pranzatelli
M R
MR
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, N.Y.
D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001923:Brain Chemistry / Q000187:drug effects*; D006897:Hydroxyindoleacetic Acid / Q000032:analysis; D007650:Ketanserin / Q000378:metabolism; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000032:analysis / Q000378:metabolism; D014364:Tryptophan / Q000032:analysis; D015430:Weight Gain / Q000187:drug effects
D011985:Receptors, Serotonin; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D014364:Tryptophan; D000324:Adrenocorticotropic Hormone; D007650:Ketanserin