Neurochemical and electrophysiological evidence that 5-HT4 receptors exert a state-dependent facilitatory control in vivo on nigrostriatal, but not mesoaccumbal, dopaminergic function.
In this study we investigated, using in vivo microdialysis and single unit recordings, the role of serotonin4 (5-HT4) receptors in the control of nigrostriatal and mesoaccumbal dopaminergic (DA) pathway activity. In freely moving rats, the 5-HT4 antagonist GR 125487 (1 mg/kg, i.p.), without effect on its own, significantly reduced the enhancement of striatal DA outflow induced by 0.01 (-35%) and 0.1 (-66%), but not 1 mg/kg, s.c. haloperidol (HAL). Intrastriatal infusion of GR 125487 (1 microM) had no influence on basal DA outflow, but attenuated (-49%) the effect of 0.01 mg/kg HAL. Systemic administration of GR 125487 modified neither basal nor 0.01 mg/kg HAL-stimulated accumbal DA outflow. In halothane-anaesthetized rats, 1 or 10 mg/kg GR 125487, without effect by itself, failed to modify the changes in accumbal and striatal DA outflow elicited by electrical stimulation (300 microA, 1 ms, 20 Hz, 15 min) of the dorsal raphe nucleus. Finally, GR 125487 (444 microg/kg, i.v.), whilst not affecting basal firing of DA neurons within either the substantia nigra or the ventral tegmental area, reduced HAL-stimulated (1--300 microg/kg, i.v.) impulse flow of nigrostriatal DA neurons only. These results indicate that 5-HT4 receptors exert a facilitatory control on both striatal DA release and nigral DA neuron impulse flow only when nigrostriatal DA transmission is under activated conditions. Furthermore, they indicate that the striatum constitutes a major site for the expression of the control exerted by 5-HT4 receptors on DA release. In contrast, 5-HT4 receptors have no influence on mesoaccumbal DA activity in either basal or activated conditions.
Laboratoire Neuropsychobiologie des Désadaptations, UMR-CNRS 5541, Université Victor Segalen Bordeaux 2, B.P. 31, 146 rue Léo-Saignat, 33077 Bordeaux Cedex, France.
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Lucas
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Di Matteo
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De Deurwaerdère
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G
Porras
R
R
Martín-Ruiz
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F
Artigas
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Esposito
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U
Spampinato
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005110:Extracellular Space / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009434:Neural Pathways / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D018492:Dopamine Antagonists; D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013449:Sulfonamides; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D006220:Haloperidol; D004298:Dopamine; C082871:GR 113808