Serotonin2B receptor blockade in the rat dorsal raphe nucleus suppresses cocaine-induced hyperlocomotion through an opposite control of mesocortical and mesoaccumbens dopamine pathways.
Neuropharmacology. 2020-12-01; 180: 108309
DOI: 10.1016/j.neuropharm.2020.108309
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Cathala A(1), Devroye C(2), Robert É(3), Vallée M(4), Revest JM(5), Artigas F(6), Spampinato U(7).
Author information:
(1)Inserm U1215, Neurocentre Magendie Physiopathology and therapeutic Approaches
of Stress-related Diseases, Bordeaux, F-33000, France; Université de Bordeaux,
Bordeaux, F-33000, France. Electronic address: .
(2)Inserm U1215, Neurocentre Magendie Physiopathology and therapeutic Approaches
of Stress-related Diseases, Bordeaux, F-33000, France; Université de Bordeaux,
Bordeaux, F-33000, France. Electronic address: .
(3)Inserm U1215, Neurocentre Magendie Physiopathology and therapeutic Approaches
of Stress-related Diseases, Bordeaux, F-33000, France; Université de Bordeaux,
Bordeaux, F-33000, France. Electronic address: .
(4)Inserm U1215, Neurocentre Magendie Physiopathology and therapeutic Approaches
of Stress-related Diseases, Bordeaux, F-33000, France; Université de Bordeaux,
Bordeaux, F-33000, France. Electronic address: .
(5)Inserm U1215, Neurocentre Magendie Physiopathology and therapeutic Approaches
of Stress-related Diseases, Bordeaux, F-33000, France; Université de Bordeaux,
Bordeaux, F-33000, France. Electronic address: .
(6)Department of Neurochemistry and Neuropharmacology, Institut d’Investigacions
Biomèdiques de Barcelona, CSIC-IDIBAPS, Rosselló 161, 08036, Barcelona, Spain;
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain.
Electronic address: .
(7)Inserm U1215, Neurocentre Magendie Physiopathology and therapeutic Approaches
of Stress-related Diseases, Bordeaux, F-33000, France; Université de Bordeaux,
Bordeaux, F-33000, France. Electronic address: .
Serotonin2B receptor (5-HT2BR) antagonists inhibit cocaine-induced
hyperlocomotion independently of changes of accumbal dopamine (DA) release.
Given the tight relationship between accumbal DA activity and locomotion, and
the inhibitory role of medial prefrontal cortex (mPFC) DA on subcortical DA
neurotransmission and DA-dependent behaviors, it has been suggested that the
suppressive effect of 5-HT2BR antagonists on cocaine-induced hyperlocomotion may
result from an activation of mPFC DA outflow which would subsequently inhibit
accumbal DA neurotransmission. Here, we tested this hypothesis by means of the
two selective 5-HT2BR antagonists, RS 127445 and LY 266097, using a combination
of neurochemical, behavioral and cellular approaches in male rats. The
intraperitoneal (i.p.) administration of RS 127445 (0.16 mg/kg) or LY 266097
(0.63 mg/kg) potentiated cocaine (10 mg/kg, i.p.)-induced mPFC DA outflow. The
suppressant effect of RS 127445 on cocaine-induced hyperlocomotion was no longer
observed in rats with local 6-OHDA lesions in the mPFC. Also, RS 127445 blocked
cocaine-induced changes of accumbal glycogen synthase kinase (GSK) 3β
phosphorylation, a postsynaptic cellular marker of DA neurotransmission.
Finally, in keeping with the location of 5-HT2BRs on GABAergic interneurons in
the dorsal raphe nucleus (DRN), the intra-DRN perfusion of the GABAAR antagonist
bicuculline (100 μM) prevented the effect of the systemic or local (1 μM,
intra-DRN) administration of RS 127445 on cocaine-induced mPFC DA outflow.
Likewise, intra-DRN bicuculline injection (0.1 μg/0.2 μl) prevented the effect
of the systemic RS 127445 administration on cocaine-induced hyperlocomotion and
GSK3β phosphorylation. These results show that DRN 5-HT2BR blockade suppresses
cocaine-induced hyperlocomotion by potentiation of cocaine-induced DA outflow in
the mPFC and the subsequent inhibition of accumbal DA neurotransmission.
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