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Benjamin J, Greenberg BD, Murphy DL. 
“Daily administration of m-chlorophenylpiperazine to healthy human volunteers rapidly attenuates many of its behavioral, hormonal, cardiovascular and temperature effects”. 
Psychopharmacology Berl. 1996 Sep 07;127(2):140-9.
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.
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