Differential control of dopamine ascending pathways by serotonin2B receptor antagonists: New opportunities for the treatment of schizophrenia

Céline Devroye, Adeline Cathala, Nasser Haddjeri, Renaud Rovera, Monique Vallée, Filippo Drago, Pier Vincenzo Piazza, Umberto Spampinato
Neuropharmacology. 2016-10-01; 109: 59-68
DOI: 10.1016/j.neuropharm.2016.05.024

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Devroye C(1), Cathala A(2), Haddjeri N(3), Rovera R(4), Vallée M(5), Drago F(6), Piazza PV(7), Spampinato U(8).

Author information:
(1)Inserm U1215, Neurocentre Magendie, Physiopathology of Addiction Group,
Bordeaux, F-33000, France; Université de Bordeaux, Bordeaux, F-33000, France.
Electronic address: .
(2)Inserm U1215, Neurocentre Magendie, Physiopathology of Addiction Group,
Bordeaux, F-33000, France; Université de Bordeaux, Bordeaux, F-33000, France.
Electronic address: .
(3)Inserm U1208, Stem Cell and Brain Research Institute, 69500, Bron, France;
Université Lyon 1, 69373, Lyon, France. Electronic address:
.
(4)Inserm U1208, Stem Cell and Brain Research Institute, 69500, Bron, France;
Université Lyon 1, 69373, Lyon, France. Electronic address:
.
(5)Inserm U1215, Neurocentre Magendie, Physiopathology of Addiction Group,
Bordeaux, F-33000, France; Université de Bordeaux, Bordeaux, F-33000, France.
Electronic address: .
(6)Department of Biomedical and Biotechnological Sciences, Section of
Pharmacology, University of Catania, Catania, 95125, Italy. Electronic address:
.
(7)Inserm U1215, Neurocentre Magendie, Physiopathology of Addiction Group,
Bordeaux, F-33000, France; Université de Bordeaux, Bordeaux, F-33000, France.
Electronic address: .
(8)Inserm U1215, Neurocentre Magendie, Physiopathology of Addiction Group,
Bordeaux, F-33000, France; Université de Bordeaux, Bordeaux, F-33000, France.
Electronic address: .

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.