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Molecular Pharmacology, Vol 15, 246-256, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Depression of Some Drug-Induced in Vivo Changes of Cerebellar Guanosine 3',5'-Monophosphate by Control of Motor and Respiratory Responses

D. B. A. LUNDBERG 1, G. R. BREESE 1, R. B. MAILMAN 1, G. D. FRYE 1, and R. A. MUELLER 1

1 Departments of Anesthesiology, Psychiatry and Pharmacology, Biological Sciences Research Center, University of North Carolina, School of Medicine, Chapel Hill, North Carolina 27514

Paralysis of rats with d-tubocurarine and maintanence of normal arterial pH, CO2 and O2 tensions reduced cerebellar cGMP to values only one fourth to one third that of spontaneously roving animals. Since administration of d-tubocurarine intracisternally elevated rather than decreased cerebellar cGMP, the decrease in nucleotide content may be a result of decreased motor behavior and subsequent cerebellar afferent stimulation. In paralyzed rats an increasing mechanical distortion of the chest by increasing tidal volumes raised cerebellar cGMP when arterial gas tensions were held constant. The relative decreases in cerebellar cGMP produced by pentobarbital, ethanol, and halothane in spontaneously active rats were sharply reduced in paralyzed rats. The magnitude of cGMP elevation produced by some drugs (thyrotropin releasing hormone, apomorphine) is also reduced when secondary motor and respiratory effects of these drugs are prevented, whereas the increase produced by harmaline is not altered. Systematic variations of arterial CO2 and O2 tensions revealed a negative correlation between the log cGMP content with arterial CO2 tension and a positive correlation of the log arterial O2 tension with cerebellar cGMP content in hypercarbic rats. It is concluded that a significant portion of the drug-induced changes in cerebellar cGMP content produced in vivo may be secondary to altered motor and/or respiratory actions of these drugs.

Note:
ACKNOWLEDGMENTS The authors wish to acknowledge the advice of Dr. Alton Steiner and the use of his antibodies to cAMP and cGMP. The expert technical assistance of E. Hoke, C. Jones, D. Smith, M. Handschy, and G. King is greatly appreciated.

Submitted on May 18, 1978




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