Effect of Intravenous Administration of d‐Lysergic Acid Diethylamide on Subsequent Protein Synthesis in a Cell‐Free System Derived from Brain

Abstract

An initiating cell-free protein synthesis system derived from brain was utilized to demonstrate that the intravenous injection of d-lysergic acid diethylamide (LSD) to rabbits induced a transient inhibition of translation following a brief stimulatory period. Subfractionation of the brain cell-free system into postribosomal supernatant (PRS) and microsome fractions demonstrated that LSD in vivo induced alterations in both of these fractions. In addition to the overall inhibition of translation in the cell-free system, differential effects were noted, i.e., greater than average relative decreases in in vitro labeling of certain brain proteins and relative increases in others. The brain proteins of molecular weights 75K and 95K, which were increased in relative labeling under conditions of LSD-induced hyperthermia, are similar in molecular weight to two of the major "heat shock" proteins reported in tissue culture systems. Injection of LSD to rabbits at 4 degrees C prevented LSD-induced hyperthermia but behavioral effects of the drug were still apparent. The overall decrease in cell-free translation was still observed but the differential labeling effects were not. LSD appeared to influence cell-free translation in the brain at two dissociable levels: (a) an overall decrease in translation that was observed even in the absence of LSD-induced hyperthermia and (b) differential labeling effects on particular proteins that were dependent on LSD-induced hyperthermia.

Cell‐Free Translation of Free and Membrane‐Bound Polysomes and Polyadenylated mRNA from Rabbit Brain Following Administration of d‐Lysergic Acid Diethylamide In Vivo

“…Recent studies in our laboratory have shown that the reduction in brain protein synthesis by either LSD or elevated ambient temperature treatment is accompanied by selective effects on the synthesis of particular brain proteins in both in vivo (Freedman et al, 1981) and homologous cell-free protein synthesis systems (Cosgrove et al, 1981). For example, LSD and direct heat treatment increased the relative labeling of a 75K and 95K brain protein and induced a decrease in the relative labeling of a 55K protein (Freedman et al, 1981;Cosgrove et al, 1981). These differential labeling effects on brain proteins appear to be caused by hyperthermia induced by either LSD or elevated ambient temperature.…”

Axonal transport of a heat shock protein in the rabbit visual system.

“…In previous reports, it has been shown that hyperthermia generated by elevation of ambient temperature or intravenous injection of LSD induces a transient inhibition of protein synthesis (19,20,(29)(30)(31)(32) and an induction of synthesis of a 74-kDa heat shock protein in various regions of the mammalian brain (8, 9, 11-13, 15, 16). In the visual system, the present results indicate that the 74-kDa heat shock protein undergoes axonal transport from neuronal cell bodies in the retina to synaptic termini in the superior colliculus, where maximal labeling of the protein was evident by 30 days after intraocular injection of [35S]methionine.…”

“…Animals that were injected with LSD exhibited rectal temperatures of 42.6 ± 0.4°C 1 hr after drug administration. When required, the hyperthermic response that was normally induced by LSD could be blocked by keeping rabbits in a cold room at 4°C (19,20). Under these conditions, body temperature remained at 39.6°C; however, the behavioral effects of the drug were still apparent.…”

“…Brown and coworkers have analyzed how intravenous injection of LSD into rabbits, at doses comparable to those causing distortioh of sensory perception in man (27,28), affects the biochemistry of brain cells. The drug binds to neurotransmitter receptors and rapidly induces a transient inhibition of protein synthesis in the brain via a lesion in reinitiation (19,20,(29)(30)(31)(32). LSD induces a rapid increase in body temperature due to an inhibitory action on heat loss mechanisms coupled with an excitatory action on heat production (33).…”

Characterization of an Initiating Cell‐Free Protein Synthesis System Derived from Rabbit Brain

“…This indicates that the system translates a wide spectrum of endogenous brain messenger RNAs. In the accompanying report (Cosgrove et al, 1981), data are presented that indicate that following intravenous administration of LSD, cell-free translation systems prepared from drugtreated animals exhibit a reduced capacity for protein synthesis. These results are similar to those obtained in vivo Brown, 1976, 1977;Freedman et al, 1981).…”