Vol. 294, Issue 3, 1166-1174, September 2000

Acute and Chronic Administration of the Selective D₃ Receptor Antagonist SB-277011-A Alters Activity of Midbrain Dopamine Neurons in Rats: An In Vivo Electrophysiological Study

Charles R. Ashby, Jr., Yoshio Minabe, Geoff Stemp, Jim J. Hagan and Derek N. Middlemiss

Department of Pharmaceutical Health Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York (C.R.A.); Department of Psychiatry, Takamatsu Prefectural Hospital, Takamatsu, Ishikawa, Japan (Y.M.); and Discovery Chemistry (G.S.) and Neuroscience Research (J.J.H., D.N.M.), SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, United Kingdom

This study examined the effect of acute and repeated p.o. administration of the selective D₃ receptor antagonist SmithKline Beecham (SB)-277011-A (1, 3, or 10 mg/kg) on the activity of spontaneously active midbrain dopamine (DA) neurons in anesthetized, male Sprague-Dawley rats. This was accomplished with the technique of in vivo extracellular single-unit recording. A single administration of either 3 or 10 mg/kg SB-277011-A produced a significant increase in the number of spontaneously active substantia nigra pars compacta (or A9) DA neurons compared with vehicle-treated (2% methylcellulose) animals. The 10-mg/kg dose of SB-277011-A produced a significant increase in the number of spontaneously active A10 DA neurons compared with vehicle-treated animals. The acute administration of SB-277011-A produced a significantly greater alteration in the firing pattern of spontaneously active A10 DA neurons, particularly at the 3- and 10-mg/kg doses, compared with vehicle-treated animals. The i.v. administration of SB-277011-A (0.01-1.28 mg/kg) did not significantly alter the firing rate or firing pattern of either A9 or A10 DA neurons. The repeated p.o. administration of 1, 3, or 10 mg/kg SB-277011-A once a day for 21 days produced a significant decrease in the number of spontaneously active A10 DA neurons. The repeated administration of SB-277011-A produced a greater effect on the firing pattern of spontaneously active A10 DA neurons, particularly at the 3-mg/kg dose, compared with A9 DA neurons. Overall, our results indicate that SB-277011-A alters the activity of midbrain DA neurons in rats.