Molecular Pharmacology, Vol 10, 146-154, Copyright © 1974 by the American Society for Pharmacology and Experimental Therapeutics

-Amanitin Inhibition of Mouse Brain Form II Ribonucleic Acid Polymerase and Passive Avoidance Retention

¹ Department of Pharmacology, Arizona Medical Center, University of Arizona, Tucson, Arizona 85724

Injection of -amanitin into a cerebral ventricle reduced the ability of male mice to retain a passive avoidance response without affecting spontaneous locomotor activity or performance of a previously learned task. -Amanitin inhibited the brain form II DNA-dependent RNA polymerase in a dose-dependent manner up to 10 µg, at which dose a maximum of 98% inhibition was observed as determined by assay of brain nuclei at the time of training. The effect observed on passive avoidance retention is only seen at maximal (98%) inhibition. Furthermore, the inhibition of brain form II polymerase is transient, indicating that -amanitin is effective in vivo only when virtually 100% inhibition of this enzyme is attained. The liver form II polymerase was also inhibited after cerebroventricular injection, indicating that a significant amount of the -amanitin reached peripheral circulation. A 50% inhibition of liver form II polymerase was measured within 15 min. However, intraperitoneal injection of 10 µg of -amanitin did not produce significant inhibition of brain form II polymerase, and retention of a passive avoidance response was not affected.

Note:
ACKNOWLEDGMENTS We thank Professor T. Wieland for a generous gift of -amanitin. The expert technical assistance of Sandra Burt , Royal Ellinger, Tony O'Malley, James Warren, Colleen Bentley, and Janet Neuberg is gratefully acknowledged. We thank Dr. Rubin Bressler for continued interest and support.

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