1-(m-chlorophenyl)piperazine (mCPP) dissociates in vivo serotonin release from long-term serotonin depletion in rat brain

Neuropsychopharmacology. 2001 May;24(5):492-501. doi: 10.1016/S0893-133X(00)00221-9.


Serotonin (5-HT) releasing agents such as d-fenfluramine are known to cause long-term depletion of forebrain 5-HT in animals, but the mechanism of this effect is unknown. In the present study, we examined the relationship between drug-induced 5-HT release and long-term 5-HT depletion in rat brain. The 5-HT-releasing actions of d-fenfluramine and a non-amphetamine 5-HT drug, 1-(m-chlorophenyl)piperazine (mCPP), were compared using in vivo microdialysis in the nucleus accumbens. The ability of d-fenfluramine and mCPP to interact with 5-HT transporters was tested using in vitro assays for [3H]5-HT uptake and radioligand binding. Local infusion of d-fenfluramine or mCPP (1-100 microM) increased extracellular 5-HT, with elevations in dopamine occurring at high doses. Intravenous injection of either drug (1-10 micromol/kg) produced dose-related increases in 5-HT without affecting dopamine. d-Fenfluramine and mCPP exhibited similar potency in their ability to stimulate 5-HT efflux in vivo and interact with 5-HT transporters in vitro. When rats received high-dose d-fenfluramine or mCPP (10 or 30 micromol/kg, i.p., every 2 h, 4 doses), only d-fenfluramine-treated rats displayed long-term 5-HT depletions. Thus, mCPP is a 5-HT releaser that does not appear to cause 5-HT depletion. Our data support the notion that 5-HT release per se may not be sufficient to produce the long-term 5-HT deficits associated with d-fenfluramine and other amphetamines.

MeSH terms

  • Animals
  • Brain / drug effects*
  • Brain / metabolism
  • Carrier Proteins / drug effects
  • Carrier Proteins / metabolism
  • Caudate Nucleus / drug effects
  • Caudate Nucleus / metabolism
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Dopamine / metabolism
  • Dopamine Plasma Membrane Transport Proteins
  • Dose-Response Relationship, Drug
  • Fenfluramine / pharmacology
  • Hydroxyindoleacetic Acid / metabolism
  • Male
  • Membrane Glycoproteins / drug effects
  • Membrane Glycoproteins / metabolism
  • Membrane Transport Proteins*
  • Microdialysis
  • Nerve Tissue Proteins*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Piperazines / pharmacology*
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Serotonin / deficiency*
  • Serotonin / metabolism*
  • Serotonin / pharmacokinetics
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Receptor Agonists / pharmacology
  • Time Factors
  • Tritium / pharmacokinetics


  • Carrier Proteins
  • Dopamine Plasma Membrane Transport Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Piperazines
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Receptor Agonists
  • Serotonin Uptake Inhibitors
  • Slc6a4 protein, rat
  • Tritium
  • Fenfluramine
  • Serotonin
  • Hydroxyindoleacetic Acid
  • 1-(3-chlorophenyl)piperazine
  • Dopamine