Serotonin2B receptor blockade in the rat dorsal raphe nucleus suppresses cocaine-induced hyperlocomotion through an opposite control of mesocortical and mesoaccumbens dopamine pathways

NEUROPHARMACOLOGY

卷:180

Article

Cathala, Adeline^1,2  Devroye, Celine^1,2,5  Robert, Elea^1,2  Vallee, Monique^1,2  Revest, Jean-Michel^1,2  Artigas, Francesc^3,4  Spampinato, Umberto^1,2 

[1] Neuroctr Magendie Physiopathol & Therapeut Approa, Inserm U1215, F-33000 Bordeaux, France

[2] Univ Bordeaux, F-33000 Bordeaux, France

[3] CSIC IDIBAPS, Inst Invest Biomed Barcelona, Dept Neurochem & Neuropharmacol, Rossello 161, Barcelona 08036, Spain

[4] Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain

[5] Ist Italiano Tecnol, Neurosci Area, Genet Cognit Lab, Via Morego 30, I-16163 Genoa, Italy

关键词: 5-HT2B receptor;    Cocaine;    Dopamine release;    Dorsal raphe nucleus;    Medial prefrontal cortex;    Rat;   

DOI  :  10.1016/j.neuropharm.2020.108309

来源: Elsevier

【 摘 要 】

Serotonin(2B) 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) 313 phosphorylation, a post -synaptic cellular marker of DA neurotransmission. Finally, in keeping with the location of 5-HT(2B)Rs on GABAergic interneurons in the dorsal raphe nucleus (DRN), the intra-DRN perfusion of the GABAAR antagonist bicuculline (100 mu M) prevented the effect of the systemic or local (1 mu M, intra-DRN) administration of RS 127445 on cocaine-induced mPFC DA outflow. Likewise, intra-DRN bicuculline injection (0.1 mu g/0.2 mu l) prevented the effect of the systemic RS 127445 administration on cocaine-induced hyperlocomotion and GSK313 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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