The central serotonin 2B receptor: a new pharmacological target to modulate the mesoaccumbens dopaminergic pathway activity.
The function of the serotonin(2B) receptor (5-HT(2B)R) in the mammalian brain is poorly characterized, especially with regard to its influence on dopamine (DA) neuron activity. Here, we assessed this issue by evaluating effects of 5-HT(2B)Rs ligands in the control of striatal and accumbal DA outflow, using in vivo microdialysis in halothane-anesthetized rats, and amphetamine-induced hyperlocomotion in vigil rats. The selective 5-HT(2B)R antagonist 1-[(2-chloro-3,4-dimethoxyphenyl)methyl]-2,3,4,9-tetrahydro-6-methyl-1H-pyrido[3,4-B]indole (LY 266097; 0.16 mg/kg, i.p.) had no influence on basal accumbal and striatal DA outflow but reduced significantly accumbal DA outflow when injected at 0.63 mg/kg. A significant reduction of basal DA outflow in the nucleus accumbens was also observed after i.p. administration of 0.16 mg/kg 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine, another selective 5-HT(2B)R antagonist. In contrast, the 5-HT(2B)R agonist alpha-methyl-5-(2-thienylmethoxy)-1H-indole-3-ethanamine (3 mg/kg, s.c.) had no influence on basal DA outflow in either brain region. The increase in striatal and accumbal DA outflow induced by the 5-HT(2C)R inverse agonist 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f] indole (5 mg/kg, i.p.) was unaltered by LY 266097 (0.63 mg/kg) pre-treatment. Conversely, LY 266097 (0.63 mg/kg) significantly diminished the increase in DA outflow induced by haloperidol (0.01 mg/kg, s.c.) or amphetamine (0.5 mg/kg, i.p.) in the nucleus accumbens, but not in the striatum. Amphetamine-induced hyperlocomotion (1 mg/kg) was also attenuated by LY 266097 (0.63 mg/kg). These findings demonstrate that 5-HT(2B)Rs exert a facilitatory control on mesoaccumbens DA pathway activity, and suggest that they may constitute a new target for improved treatment of DA-related neuropsychiatric disorders.
Division of Neurobiology 2, Centre de Recherche Pierre Fabre, Castres, France.
Agnès L
AL
Auclair
Adeline
A
Cathala
Frédéric
F
Sarrazin
Ronan
R
Depoortère
Pier Vincenzo
PV
Piazza
Adrian
A
Newman-Tancredi
Umberto
U
Spampinato
D000818:Animals; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D016503:Drug Delivery Systems / Q000639:trends*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044403:Receptor, Serotonin, 5-HT2B / Q000502:physiology*; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D044403:Receptor, Serotonin, 5-HT2B; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D004298:Dopamine