D-amphetamine disaggregates brain polysomes via a dopaminergic mechanism.

Abstract

Brain polysomes are disaggregated in rats given moderate to large doses of d-amphetamine sulfate; this response is rapid in onset, lasts for at least 4-6 hr, and varies with the age of the animal. Pretreatment with a dopamine receptor blocking agent, haloperidol or pimozide, blocks the amphetamine-induced disaggregation.Rats treated with large single doses of i-dopa (a catecholamine precursor) exhibit a major disaggregation of brain polysomes (1) and a parallel decrease in the net rate of brain protein synthesis (2, 3). The L-dopa-induced disaggregation of brain polysomes is suppressed in animals pretreated with drugs that block the conversion of dopa to dopamine, or with drugs that block dopamine receptors (4, 5). Hence, the drug-induced polysome disaggregation may result from a direct action of dopamine on a receptor that controls the intracellular proteinsynthetic apparatus.Amphetamine, a sympathomimetic agent, acts on the central nervous system to affect locomotor activity (6-9), appetite (10), and thermoregulation (11-14); in high doses, it causes a psychotic reaction in humans that resembles paranoid schizophrenia (15). Catecholamine-containing brain neurons appear to mediate many of the behavioral and physiological effects of this drug (16). Relatively little information exists regarding effects of amphetamine on brain protein synthesis. We now report that large doses of d-amphetamine sulfate disaggregate brain polysomes in rats, and that this effect, like that of -dopa, appears to be mediated by dopamine receptors. MATERIALS AND METHODSMale albino rats of various ages (Charles River Laboratories, Wilmington, Mass.) were exposed to light from 9 a.m. to 9 p.m. and given free access to food and water. All animals were maintained at ambient temperatures ranging from 20-22'. Animals less than 26 days of age remained with the dam in litters of eight pups; older animals were caged in groups of four for 1 day prior to an experiment. All injections were administered intraperitoneally.Polysomes were prepared as described (1, 4). Briefly, the brains were removed, pooled two per sample, minced, and homogenized in an ice-cold 0.25 M sucrose medium containing 0.05 M Tris, HCl, 0.10 M KCl, and 0.012 M MgCl2, at pH 7.6. The homogenates were then centrifuged for 20 min at 21,000 X g; the post-mitochondrial supernatants were treated with sodium deoxycholate to a concentration of 1% and then layered over discontinuous sucrose gradients (0.5 M, 2.0 M). After this centrifugation, the pellets of ribosomes were again suspended and applied to a 10-40% continuous sucrose gradient. Absorbance profiles were recorded at 260 nm. The percentage of polysomes in the profile represents the fraction of total area attributable to polyribosomes (1, 4, 5). RESULTSIn the first experiment, 26-day-old animals received 0.9% (w/v) saline vehicle (1 ml/kg) or d-amphetamine sulfate (1.5, 10, 15, or 50 mg/kg, salt weight); they were decapitated 1 hr later. Doses of 10 mg/kg of d-amphetamine or larger disaggregated the brain polysomes; the m...

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

“…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.…”

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

“…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).…”

Neonatal Escherichia coli infection alters glial, cytokine, and neuronal gene expression in response to acute amphetamine in adolescent rats

“…On P40, rats received a single injection of D-amphetamine (Sigma, 15 mg/ml/kg) or saline vehicle. We used the d -amphetamine dose of Moskowitz et al, [19] that was shown to produce protein disaggregation adolescent rats but is lower than those that produce frank toxicity [27]. Each rat in a cage received the same drug treatment.…”