Effect of acute and chronic administration of the selective 5-HT2C receptor antagonist SB-243213 on midbrain dopamine neurons in the rat: An in vivo extracellular single cell study

• Published in: Synapse (New York, N.Y.) Vol. 46; no. 3; pp. 129 - 139
• Main Authors: Blackburn, Thomas P., Minabe, Yoshio, Middlemiss, Derek N., Shirayama, Yukihiko, Hashimoto, Kenji, Ashby Jr, Charles R.
• Format: Journal Article
• Language: English
• Published: New York Wiley Subscription Services, Inc., A Wiley Company 01.12.2002
• Subjects: 2-Hydroxypropyl-beta-cyclodextrin; 5-HT2C receptors; Action Potentials - drug effects; Analysis of Variance; Animals; Apomorphine - pharmacology; beta-Cyclodextrins; Cell Count - methods; Clozapine - pharmacology; Cyclodextrins - pharmacology; Dopamine - metabolism; Dopamine Agonists - pharmacology; Dopamine Antagonists; dopamine neurons; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; electrophysiology; Haloperidol - pharmacology; Indoles - administration & dosage; Male; Neurons - classification; Neurons - drug effects; Neurons - metabolism; Pyridines - administration & dosage; Rats; Rats, Sprague-Dawley; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists - pharmacology; Substantia Nigra - cytology; Ventral Tegmental Area - cytology
• ISSN: 0887-4476; 1098-2396
• DOI: 10.1002/syn.10116

In this study, we examined the effect of the acute and chronic administration of the selective 5‐HT2C receptor antagonist SB‐243213 (SB) on the activity of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, albino, male Sprague‐Dawley rats. This was accomplished using the technique of in vivo extracellular single cell recording. The acute i.v. administration of SB‐243213 (0.025–3.2 mg/kg) did not significantly alter the basal firing rate or pattern of either spontaneously active SNC or VTA DA neurons compared to vehicle‐treated controls. The acute i.p. administration of either 1 or 10 mg/kg of SB‐243213 did not significantly alter the number of spontaneously active DA cells in the SNC or VTA compared to vehicle‐treated controls, whereas the 3 mg/kg dose only significantly decreased the number of spontaneously active VTA DA neurons. Overall, the 1 mg/kg dose of SB‐243213 did not significantly alter the firing pattern of either SNC or VTA DA neurons compared to vehicle‐treated controls. In contrast, the 3 mg/kg dose significantly altered the firing pattern of SNC DA neurons, whereas the 10 mg/kg dose altered the firing pattern of DA neurons in both the SNC and VTA. The repeated i.p. administration (21 days) of 1, 3, and 10 mg/kg of SB‐243213 or 20 mg/kg of clozapine produced a significant decrease in the number of spontaneously active DA cells in the VTA compared to vehicle‐treated controls. The decrease in the number of spontaneously active VTA DA cells was not reversed by the i.v. administration of (+)‐apomorphine (50 μg/kg). The repeated administration of either 1 or 3 mg/kg of SB‐243213 had minimal effects on the firing pattern of either SNC or VTA DA neurons. In contrast, the firing pattern of VTA DA neurons was significantly altered by 10 mg/kg dose of SB‐243213. Overall, our results indicate that antagonism of the 5‐HT2C receptor alters the activity of midbrain DA neurons in anesthetized rats and suggest that SB‐243213 has an atypical antipsychotic profile following chronic administration. Synapse 46:129–139, 2002. © 2002 Wiley‐Liss, Inc.