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J Neurophysiol 95: 2808-2820, 2006. First published February 1, 2006; doi:10.1152/jn.01210.2005
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Dopamine D1/5 Receptor Modulation of Firing Rate and Bidirectional Theta Burst Firing in Medial Septal/Vertical Limb of Diagonal Band Neurons In Vivo

Thomas E. Fitch1, Robert N. Sahr1, Brian J. Eastwood1, Feng C. Zhou2 and Charles R. Yang1

1Neuroscience Discovery, Eli Lilly & Company; and 2Indiana University, School of Medicine, Department of Anatomy and Cell Biology, Indianapolis, Indiana

Submitted 15 November 2005; accepted in final form 21 January 2006

The medial septum/vertical limb of diagonal band complex (MS/vDB) consists of cholinergic, GABAergic, and glutamatergic neurons that project to the hippocampus and functionally regulate attention, memory, and cognitive processes. Using tyrosine hydroxlase (TH) immunocytochemistry and dark-field light microscopy, we found that the MS/vDB is innervated by a sparse network of TH-immunoreactive (putative catecholaminergic) terminals. MS/vDB neurons are known to fire in rhythmic theta burst frequency of 3–7 Hz to pace hippocampal theta rhythm. Extracellular single-unit recording in theta and non-theta firing MS/vDB neurons and antidromically identified MS/vDB-hippocampal neurons were made in urethan-anesthetized rats. Tail-pinch noxious stimuli and ventral tegmental area (VTA) stimulation (20 Hz) evoked spontaneous theta burst firing in MS/vDB neurons. Systemic D1/5 antagonists SCH23390 or SCH39166 (0.1 mg/kg iv) alone suppressed the spontaneous theta bursts, suggesting a tonic facilitatory endogenous dopamine D1 "tone" that modulates theta bursts in vivo. Activation of D1/5 receptor by dihydrexidine (10 mg/kg iv) led to an increase in mean firing rate in 60% of all theta and non-theta MS/vDB neurons with an increase in the number of theta bursts and spikes/burst in theta cells. In strong theta firing MS/vDB neurons, D1/5 receptor stimulation suppressed the occurrence of theta burst firing, whereas the overall increase in spontaneous mean firing rate remained. In low baseline theta MS/vDB neurons D1/5 receptor stimulation increases the occurrence of theta bursts along with a net increase in mean firing rate. Atropine injection consistently disrupts theta burst pattern and reduced the time spent in theta firing. Collectively, these data suggest that dopamine D1/5 stimulation enhances the mean firing rate of most MS/vDB neurons and also provides a state-dependent bidirectional modulation of theta burst occurrence. Some of these MS/vDB neurons may be cholinergic or GABAergic that may indirectly regulate theta rhythm in the hippocampus.


Address for reprint requests and other correspondence: C. R. Yang, Neuroscience Discovery, Eli Lilly & Co., Lilly Corporate Ctr., Indianapolis, IN 46285-0510 (E-mail: cyang{at}lilly.com)




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