Changing the Actions of Neuroactive Drugs by Changing Brain Protein Synthesis

Abstract

Diminution of cerebral protein synthesis diminished the cerebral responses of mice to some neuroactive drugs, while an increase in synthesis increased the responses. Protein synthesis in whole brains (tested in vitro ) was diminished by giving living mice different inhibitors by different routes. The inhibitors tested (chloramphenicol, cycloheximide, and puromycin) diminished the behavioral responses of the mice to levodopa without affecting either its cerebral uptake or its conversion to dopamine. A diminution of the reactions of dopaminergic receptors was suggested by the diminished responses to the dopaminergic drug, apomorphine, while participation of cholinergic ones was suggested by experiments with oxotremorine. Proof that receptors had been specifically involved was secured on homogenized caudate nuclei from chloramphenicol-treated mice, in which the dopamine-activated production of cyclic AMP was markedly diminished. A stimulator of cerebral protein synthesis, the artificial double-stranded RNA, poly(I)·poly(C), increased the behavioral responses to these three drugs while it increased the dopamine-activated production of cyclic AMP. Since all these experimental increases or decreases in the responses to drugs required the lapse of only a few hours, proteins with rapid turnover rates must be critical in the activation of several kinds of cerebral receptors.

Stress and cancer.

“…It is plausible that the neurochemical consequences of these lesions were responsible for the altered immune status observed. Indeed, depletion of storage pool DA and NE by reserpine produced immunosuppression (Dukor et al, 1966); stimulating DA receptors appeared to enhance immune functioning Tang, Cotzias, & Dunn, 1974).…”

Cholinergic effects of molecular segments of apomorphine and dopaminergic effects of N,N-dialkylated dopamines

“…(V-Methyl-DA, a compound that showed no dopaminergic activity in mice (50-150 pg/g) and only a weak one in nigral-lesioned rats at lethal dosages (25 pg/g), stimulated cAMP as much as did DA under the same conditions. In contrast, 22 showed no dopaminergic effects in any of these tests.…”

“…After synthesizing a series of 1,2,3,4tetrahydroisoquinolines (19a-c) and piperidines we found that some of the former had central cholinergic activities. To preserve dopaminergic while eliminating cholinergic activity we synthesized and investigated N,Ndialkyl-substituted dopamines (DA) (9,(22)(23)(24)(25). When we found that three relatively nontoxic alkyl-substituted DA had dopaminergic activity in lesioned mice and rats, we deemed them worthy of testing on DA-activated adenylate cyclase in homogenized mouse caudate nuclei6•7 to confirm this activity.…”