EFFECT OF LSD AND HYPERTHERMIA ON THE PROTEIN SYNTHESIS APPARATUS OF THE MAMMALIAN BRAIN

The main objectives of this study were (a) to examine the involvement of stress and hyperthermia in the LSD-induced disaggregation of brain polysomes and (b) to examine the effect of LSD and hyperthermia on the fate and relative abundance of polysomal mRNA. This study has revealed a synergistic interaction of LSD and physiological stress at the level of rabbit brain polysomes. The application of stress markedly accentuated the disaggregation of rabbit brain polysomes to monosomes induced by LSD (1-25 (mu)g/kg) whereas no shift of polysomes to monosomes was found with stress treatment alone.;The preceding studies utilized an unfractionated polysome preparation consisting of free and membrane-bound polysomes in a ratio of 4 to 1. In order to examine the effect of LSD and direct heat treatment on these two classes of polysomes a free and membrane-bound polysome isolation method was adapted to rabbit brain. The administration of LSD (25-100 (mu)g/kg) or direct heat treatment resulted in the disaggregation of both free and membrane-bound polysomes via a non-ribonuclease mechanism. Free polysomes displayed a greater sensitivity to drug-induced disaggregation as compared to the membrane-bound polysome fraction. The degree of LSD and direct heat-induced hyperthermia was also correlated with the extent of disaggregation of both free and membrane-bound polysomes. Polysomal polyadenylated mRNA was conserved in each polysome class but relocalized from polysomes to the monosome region.;Since total brain protein synthesis is depressed by LSD or direct heat, it was of interest to determine whether these treatments had any selective effect on the relative abundance of polysomal mRNAs. Utilizing a mRNA-dependent cell-free protein synthesis assay, the translation products of free and membrane-bound polysomes were compared. Electrophoretic analysis of the translation products revealed that while most of the proteins were common to both free and membrane-bound polysomes, qualitative and quantitative differences were observed. Analysis of the translational products of free and membrane-bound polysomes isolated from LSD and direct heat treated animals revealed the appearance of a 74,000 dalton protein. The molecular weight of this heat-induced 74K brain protein is similar to certain 'heat shock' proteins found in tissue culture.;LSD-induced hyperthermia is implicated in the LSD-induced disaggregation of rabbit brain polysomes. Both LSD-induced hyperthermia and brain polysome disaggregation increased under conditions which accentuated the effect of the drug on brain protein synthesis such as increasing LSD dose, raising the ambient temperature to 33(DEGREES)C or stressing the animal after drug administration. Pretreatment with neurotransmitter receptor blockers or placing the animal at an ambient temperature of 4(DEGREES)C after LSD administration prevented both hyperthermia and brain polysome disaggregation. LSD-induced hyperthermia was also correlated with brain polysome disaggregation at specific stages of prenatal and postnatal development. Direct elevation of the body temperature to levels similar to that found after LSD was achieved by placing the animals at an ambient temperature of 37-38(DEGREES)C or by bacterial pyrogen injection. Under these conditions an organ-specific disaggregation of brain polysomes resulted which was not due to ribonuclease. After either LSD, bacterial pyrogen or direct heat treatment, the brain polysome shift was associated with a relocalization of polyadenylated mRNA from polysomes to monosomes. The finding that these hyperthermic treatments induced the accumulation of a monosome complex consisting of 40S and 60S ribosomal subunits plus intact mRNA suggests that brain protein synthesis is inhibited primarily at the initiation stage. Since polysome disaggregation was only found in brain, it appears that the brain may be more sensitive to elevations in body temperature compared to other organs.