Differential control of dopamine ascending pathways by serotonin2B receptor antagonists: New opportunities for the treatment of schizophrenia.
Recent studies suggest that the central serotonin2B receptor (5-HT2BR) could be an interesting pharmacological target for treating neuropsychiatric disorders related to dopamine (DA) dysfunction, such as schizophrenia. Thus, the present study was aimed at characterizing the role of 5-HT2BRs in the control of ascending DA pathway activity. Using neurochemical, electrophysiological and behavioral approaches, we assessed the effects of two selective 5-HT2BR antagonists, RS 127445 and LY 266097, on in vivo DA outflow in DA-innervated regions, on mesencephalic DA neuronal firing, as well as in behavioral tests predictive of antipsychotic efficacy and tolerability, such as phencyclidine (PCP)-induced deficit in novel object recognition (NOR) test, PCP-induced hyperlocomotion and catalepsy. Both RS 127445 (0.16 mg/kg, i.p.) and LY 266097 (0.63 mg/kg, i.p.) increased DA outflow in the medial prefrontal cortex (mPFC). RS 127445, devoid of effect in the striatum, decreased DA outflow in the nucleus accumbens, and potentiated haloperidol (0.1 mg/kg, s.c.)-induced increase in mPFC DA outflow. Also, RS 127445 decreased the firing rate of DA neurons in the ventral tegmental area, but had no effect in the substantia nigra pars compacta. Finally, both RS 127445 and LY 266097 reversed PCP-induced deficit in NOR test, and reduced PCP-induced hyperlocomotion, without inducing catalepsy. These results demonstrate that 5-HT2BRs exert a differential control on DA pathway activity, and suggest that 5-HT2BR antagonists could represent a new class of drugs for improved treatment of schizophrenia, with an ideal profile of effects expected to alleviate cognitive and positive symptoms, without eliciting extrapyramidal symptoms.
Inserm U1215, Neurocentre Magendie, Physiopathology of Addiction Group, Bordeaux, F-33000, France; Université de Bordeaux, Bordeaux, F-33000, France. Electronic address: celine.devroye@inserm.fr.
Céline
C
Devroye
Inserm U1215, Neurocentre Magendie, Physiopathology of Addiction Group, Bordeaux, F-33000, France; Université de Bordeaux, Bordeaux, F-33000, France. Electronic address: adeline.cathala@inserm.fr.
Adeline
A
Cathala
Inserm U1208, Stem Cell and Brain Research Institute, 69500, Bron, France; Université Lyon 1, 69373, Lyon, France. Electronic address: nasser.haddjeri@inserm.fr.
Nasser
N
Haddjeri
Inserm U1208, Stem Cell and Brain Research Institute, 69500, Bron, France; Université Lyon 1, 69373, Lyon, France. Electronic address: renaud.rovera@wanadoo.fr.
Renaud
R
Rovera
Inserm U1215, Neurocentre Magendie, Physiopathology of Addiction Group, Bordeaux, F-33000, France; Université de Bordeaux, Bordeaux, F-33000, France. Electronic address: monique.vallee@inserm.fr.
Monique
M
Vallée
Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, 95125, Italy. Electronic address: fdrago@tin.it.
Filippo
F
Drago
Inserm U1215, Neurocentre Magendie, Physiopathology of Addiction Group, Bordeaux, F-33000, France; Université de Bordeaux, Bordeaux, F-33000, France. Electronic address: pier-vincenzo.piazza@inserm.fr.
Pier Vincenzo
PV
Piazza
Inserm U1215, Neurocentre Magendie, Physiopathology of Addiction Group, Bordeaux, F-33000, France; Université de Bordeaux, Bordeaux, F-33000, France. Electronic address: umberto.spampinato@inserm.fr.
Umberto
U
Spampinato
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*
D014150:Antipsychotic Agents; D011743:Pyrimidines; D058830:Serotonin 5-HT2 Receptor Antagonists; C121466:2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine; D004298:Dopamine
5-HT(2B) receptor; Catalepsy; Dopamine firing; Dopamine release; Locomotion; Novel object recognition