Strain-dependent serotonin neuron feedback control: role of serotonin 2C receptors.
We investigated the role of serotonin(2C) receptor-mediated feedback mechanisms in the response to citalopram in C57BL/6 and DBA/2 mice, which are respectively responders and non-responders to selective serotonin reuptake inhibitors in the forced swimming test. The microdialysis technique was used to assess changes in extracellular serotonin and GABA in the mouse dorsal raphé (DR). Citalopram (1.25-20 mg/kg) raised extracellular serotonin and GABA in the DR of both mouse strains. These effects were abolished by depleting brain serotonin with p-chlorophenylalanine (300 mg/kg × 3). Systemic and/or intra-DR infusion of the serotonin(2C) receptor antagonist 6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline (1 mg/kg and 0.1 μM, respectively) enhanced citalopram's effect on extracellular serotonin in the DR and medial prefrontal cortex and abolished the rise of GABA in the DR of DBA/2 mice but had no effect in C57BL/6 mice. The serotonin(2C) receptor agonist Ro60-0175 (0.03-3.0 mg/kg) reduced extracellular serotonin and raised GABA in the DR of DBA/2 mice but had much less effect in C57BL/6 mice. These findings show that the sensitivity of serotonin(2C) receptors determines the efficacy of augmentation strategies aimed at enhancing the effect of serotonin reuptake inhibitors on extracellular serotonin through the suppression of serotonin(2C) receptor-mediated feedback control of serotonin neurons.
Calcagno
Eleonora
E
Istituto di Ricerche Farmacologiche Mario Negri, Laboratory of Neurochemistry and Behavior, Department of Neuroscience, Milano, Italy.
Invernizzi
Roberto W
RW
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D015283:Citalopram / Q000494:pharmacology; D005021:Ethylamines / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D025461:Feedback, Physiological; D010134:Fenclonine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D017551:Microdialysis; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013045:Species Specificity; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000631:Aminopyridines; D015283:Citalopram; D005021:Ethylamines; D010134:Fenclonine; D007211:Indoles; D044405:Receptor, Serotonin, 5-HT2C; D012701:Serotonin; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D005680:gamma-Aminobutyric Acid; C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; C103848:Ro 60-0175