Dissociation of rat brain polyribosomesin vivo by amphetamines

Widelitz, Martin M.; Coryell, Marlene R.; Widelitz, Howard; Avadhani, Narayan G.

doi:10.1016/0006-8993(75)90263-2

Cited by 26 publications

(3 citation statements)

References 11 publications

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“…One interpretation of this phenomenon is that MDMA produces a reduction in the rate of translation of TPH mRNA to TPH protein. This explanation is supported by an earlier study showing that in vivo administration of amphetamine decreased protein synthesis in rat brain through a dissociation of polyribosomes (Widelitz et al, 1975). However, when Stone and coworkers (1987) measured TPH activity in the striatum, frontal cortex and hippocampus after repeated MDMA treatment (5 doses, every 6 h), they found that the decrease in TPH activity persisted for at least 110 days.…”

Section: Discussionmentioning

confidence: 81%

3,4-Methylenedioxymethamphetamine induces differential regulation of tryptophan hydroxylase 2 protein and mRNA levels in the rat dorsal raphe nucleus

Bonkale

Austin

2008

Neuroscience

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Previous investigations with 3,4-methylenedioxymethamphetamine (MDMA) have suggested that administration of this drug results in a degeneration of 5-HT nerve terminals and subsequent alterations in 5-HT neurotransmission. However, only limited investigations have examined the effects of MDMA on the dorsal raphe nucleus. The present study was designed to assess the effect of MDMA on the rate-limiting enzyme in 5-HT biosynthesis, tryptophan hydroxylase (TPH), by measuring TPH2 protein and mRNA levels in rat dorsal raphe (DR) nucleus. Rats were administered MDMA (20 mg/kg, s.c.) or saline twice daily for 4 days and killed 14 days later. Tissue sections of the DR were processed for quantitative immunoautoradiography and in situ hybridization histochemistry for measurements of the levels of TPH2-immunoreactivity (IR) and TPH2 mRNA. To assess 5-HT axon terminal integrity after MDMA treatment, the density of 5-HT transporter (SERT) binding sites was measured by quantitative autoradiography using [125I]RTI-55 ((-)-2beta-carbomethoxy-3 beta-(4-iodophenyl) tropane) ((125)I-RTI-55) as a ligand. TPH2-IR levels were significantly decreased by 45% in the mid DR and by 40% in the caudal DR in the MDMA-treated rats compared with saline-injected rats. In contrast, TPH2 mRNA levels were significantly increased by 24% in the mid DR and by 12% in the caudal DR. MDMA treatment significantly decreased (125)I-RTI-55 labeled SERT binding sites in the striatum, nucleus accumbens and cingulate cortex demonstrating a loss of 5-HT terminals. The increase in TPH2 mRNA levels in both the mid DR and caudal DR of MDMA-treated rats may reflect a compensatory mechanism in the injured 5-HT neurons to increase TPH2 protein synthesis. Taken together, our results suggest that a serious defect occurs in the biosynthesis of TPH2 in the DR following MDMA administration.

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Section: Discussionmentioning

confidence: 81%

3,4-Methylenedioxymethamphetamine induces differential regulation of tryptophan hydroxylase 2 protein and mRNA levels in the rat dorsal raphe nucleus

Bonkale

Austin

2008

Neuroscience

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“…30% of control activity, suggesting significant temporal and quantitative differences in the response of individual tissues to elevated temperatures. Brain glycogen levels after amphetamine administration were significantly lower under conditions of ambient temperature which resulted in more Amphetamine is one of several pharmacological agents demonstrated to cause reductions in brain protein synthesis as detected by analysis of polyribosome profiles or in vivo amino acid incorporation methods (Moskowitz et al, 1975;Widelitz et al, 1975;Holbrook and Brown, 1976;Roe1 et al, 1978). Although amphetamine can also directly inhibit in vitro translation systems (Loh et al, 1973;Baliga et al, 1976;Widelitz et al, 1976;Nowak et al, 1983), such effects require extremely high concentrations of the drug and could not account for actions on protein synthesis in vivo.…”

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confidence: 99%

Effects of Amphetamine on Protein Synthesis and Energy Metabolism in Mouse Brain: Role of Drug‐Induced Hyperthermia

Nowak

1988

Journal of Neurochemistry

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Changes in brain protein synthesis activity, and in brain levels of glucose, glycogen, and several high-energy phosphate metabolites, were evaluated under conditions of amphetamine-induced hyperthermia in mice. Protein synthesis showed a striking dependence on rectal temperature (TR), falling abruptly at TR above 40 degrees C. A similar result was obtained following direct heating of the animals. Protein synthesis activity in liver showed the same temperature dependence observed for brain. Increased synthesis of a protein with characteristics of the major mammalian stress protein, hsp 70, was demonstrated in both brain and liver following amphetamine administration. Brain protein synthesis showed significant recovery within 2 h after amphetamine administration whereas that of liver remained below 30% of control activity, suggesting significant temporal and quantitative differences in the response of individual tissues to elevated temperatures. Brain glycogen levels after amphetamine administration were significantly lower under conditions of ambient temperature which resulted in more severe drug-induced hyperthermia but did not correlate as strikingly as protein synthesis with the temperatures of individual animals. Brain glycogen also fell in animals whose temperatures were increased by brief exposure at high ambient temperature. Brain glucose levels did not consistently change with hyperthermia. Slight decreases in high-energy phosphates with increasing TR were likely the result of fixation artifact. These results demonstrate the fundamental role of hyperthermia in the reduction of protein synthesis in brain and other tissues by amphetamine, and suggest that temperature also constitutes a significant source of variability in the effects of this drug on brain energy metabolism, in particular glycogenolysis.

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“…It is known that a range of treatments causes a transient disaggregation of brain polysomes to monosomes and frequently a decreased incorporation of amino acid in vivo. These include excess phenylalanine (Aoki and Siegal, 1970;Taub and Johnson, 1975;Roberts and Morelos, 1976), 5-HTP (Weiss et al, 1973;Weiss et al, 1975) L-DOPA (Roe1 et al, 1974;Weiss et al, 1975) and damphetamine (Moskowitz et al, 1975;Widelitz et al, 1975). Physical treatments that result in breakdown of brain polysomes include electroconvulsive shock (Vesco and Giuditta, 1968;Wasterlain, 1972;Dunn, 1973) and intracranial hypertension (Wasterlain, 1974).…”

Section: Discussionmentioning

confidence: 99%

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

Cosgrove

Clark

Brown

1981

Journal of Neurochemistry

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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.

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Dissociation of rat brain polyribosomesin vivo by amphetamines

Cited by 26 publications

References 11 publications

3,4-Methylenedioxymethamphetamine induces differential regulation of tryptophan hydroxylase 2 protein and mRNA levels in the rat dorsal raphe nucleus

3,4-Methylenedioxymethamphetamine induces differential regulation of tryptophan hydroxylase 2 protein and mRNA levels in the rat dorsal raphe nucleus

Effects of Amphetamine on Protein Synthesis and Energy Metabolism in Mouse Brain: Role of Drug‐Induced Hyperthermia

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

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