Daily administration of m-chlorophenylpiperazine to healthy human volunteers rapidly attenuates many of its behavioral, hormonal, cardiovascular and temperature effects.
The serotonergic agent meta-chlorophenylpiperazine (m-CPP) increases temperature and plasma ACTH and other hormones and decreases social interaction, locomotor activity and food intake in rats, most likely via stimulation of 5-HT2C receptors. Repeated daily administration of m-CPP to rats induces rapid tolerance to these effects of m-CPP. As m-CPP has been used in challenge tests and in preliminary treatment trials in humans, we evaluated the possible development of tolerance to m-CPP in ten healthy human volunteers using a double-blind, random assignment crossover study of placebo versus daily m-CPP infusions. Psychological and physical symptoms of anxiety, temperature, pupil size, diastolic blood pressure, and plasma ACTH, cortisol, and prolactin concentrations were increased by the first administration of m-CPP (0.08 mg/kg) compared to placebo. All of these responses were attenuated on m-CPP days 2 and 3. Plasma m-CPP levels did not differ across the 3 m-CPP days. Repeated m-CPP administration thus appears to induce rapid tolerance to its behavioral and physiological effects in humans. Further investigations of the mechanisms involved in the development of subsensitivity to m-CPP may contribute to increased understanding of the regulation of serotonin-mediated functions and of anxiety disorders.
Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD 20892-1264, USA.
J
J
Benjamin
B D
BD
Greenberg
D L
DL
Murphy
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D001007:Anxiety / Q000188:drug therapy; D001519:Behavior / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects*; D002319:Cardiovascular System / Q000187:drug effects*; D004311:Double-Blind Method; D004361:Drug Tolerance; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D011388:Prolactin / Q000097:blood; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*
D010879:Piperazines; D017366:Serotonin Receptor Agonists; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; C015068:1-(3-chlorophenyl)piperazine; D006854:Hydrocortisone