Littleton H. Wade

Changes in locomotor activity, core temperature, and heart rate in response to repeated cocaine administration.

The effects of daily single injections of 20 mg/kg cocaine on locomotor activity, core temperature, and heart rate were determined by radiotelemetry. There was a progressive increase in locomotor activity over the 30-day treatment period. Cocaine-induced activity was 9-12-fold greater than that of saline-treated animals. Cocaine also caused increases in core temperature and heart rate. Tolerance did not develop to the locomotor, hyperthermic, and tachycardic responses resulting from repeated cocaine administration. Comparison of the time-course of the cocaine-induced responses revealed that, on Day 1 and 3, the peak locomotor activity was observed 15 min after cocaine administration, whereas the hyperthermic response peaked at 95 min on those days. The fact that the peak locomotor activity and the hyperthermic response occurred at different times suggests that different processes acting independently or interacting may be involved in these actions of cocaine.

Effects of calcium channel entry blockers on cocaine and amphetamine-induced motor activities and toxicities

The effects of calcium channel entry blockers on cocaine and amphetamine-induced behavioral responses were investigated. Cocaine and amphetamine produced dose-dependent increases in locomotor activity and stereotyped behavior with a maximum response at 40 and 1.2 mg/kg, respectively. The 1,4-dihydropyridine nimodipine and the benzothiazepine diltiazem were more effective in inhibiting cocaine (20 mg/kg)-induced responses than amphetamine (0.6 mg/kg)-induced responses. At doses of cocaine and amphetamine that caused seizures and death, nimodipine, nitrendipine and diltiazem did not offer any protection; rather, they potentiated the toxicities produced by these psychomotor stimulants.

Isolation, purification, and probable structural configuration of N-acetyl aspartyl glutamate in human brain ☆

Abstract An acetylated dipeptide composed of equimolar quantities of aspartic acid and glutamic acid has been isolated in pure form from human brain by a combination of ion exchange and paper chromatographic techniques. Hydrazinolysis and acid hydrolysis studies indicate that the peptide is N -acetyl aspartyl glutamate. Preliminary synthesis studies suggest that the peptide may be of the alpha rather than the beta structural configuration.

OCCURRENCE OF N‐ACETYL‐l‐GLUTAMIC ACID IN THE HUMAN BRAIN

A substance apparently identical with N‐acetyl‐l‐glutamic acid was isolated from an aqueous extract from human brain by a combination of paper and ion exchange chromatography. The isolated substance does not react with ninhydrin reagent but yields glutamic acid upon acid hydrolysis. Acetyl hydrazide was identified by paper chromatography of hydrazinolysates of the isolated substance and N‐acetyl‐l‐glutamic acid. The configuration was determined with l‐specific hog kidney acylase.

A NA + K-ACTIVATED MGATPASE IN RABBIT KIDNEY MITOCHONDRIA.

Abstract A concealed Na+K-activated MgATPase has been uncovered in rabbit kidney mitochondria. The Na+K-activated component but not the Mg component is inhibited by G-strophanthin. The enzyme apparently resides in the membrane structure of mitochondrion.

Evidence for the presence of N-Acetyl-α-l-aspartyl-l-glutamate in human brain

Abstract A peptide composed of equimolar quantities of glutamic and aspartic acids was isolated from a protein-free extract of human brain by a combination of ion-exchange and paper chromatography. Hydrazinolysis studies established that glutamic acid was C-terminal and that the amino group of the aspartyl residue was substituted with an acetyl group. To determine which aspartyl carboxyl group was linked to glutamic acid, N -acetyl-α- and N -acetyl-β-aspartyl glutamate were synthesized. When the partial acid hydrolyzates of the synthesized acetylated peptides were chromatographed on the amino acid analyzer, two distinct elution patterns were observed. The elution pattern of the brain dipeptide resembled the alpha rather than the beta derivative. When acetylated amino acids prepared from brain dipeptide were incubated with hog l -specific kidney acylase, aspartic and glutamic acids were liberated.

Nifedipine potentiates the toxic effects of cocaine in mice.

The calcium channel blockers (CCBs) have been shown to be effective in attenuating the behavioral effects of cocaine in rodents and subjective effects in cocaine-using volunteers. There have been reports indicating that, in the presence of toxic doses of cocaine, the CCBs could actually potentiate cocaine toxicity in rats. The present study was undertaken to make toxicological assessment of the potentiating effect of CCBs in mice. Nifedipine and nimodipine dose-dependently increased the lethalities produced by 80 mg/kg cocaine. In the presence of 40 mg/kg nifedipine, the LD50 of cocaine was decreased from 80.7 to 66.3 mg/kg. Nifedipine potentiated cocaine toxicities in both ICR and Swiss-Webster mice. The increased toxicity was not accompanied by alterations in blood electrolytes. The mechanism of increased cocaine toxicity by CCBs remains to be determined. However, our results corroborate previous findings in rats and suggest that the possibility of an antidote exacerbating the toxic effects of cocaine has to be taken into consideration when screening for therapeutic agents.

Effects of alpha-2-adrenoceptor agonists on induced diuresis in rats

The alpha-2 adrenoceptor agonists, clonidine, guanabenz, and guanfacine, injected subcutaneously produced a dose-related diuresis. The maximal effect occurred at 2h after administration of clonidine 192 micrograms/kg or 960 micrograms/kg of guanabenz and guanfacine. The alpha-2 antagonist, yohimbine, in doses of 1-8 mg/kg administered prior to the agonists caused a dose-dependent decrease in urine output. The action of the three agonists at alpha-2 adrenoceptors was supported by the observation that the alpha-1 adrenoceptor agonist, prazosin (0.61-2.5 mg/kg), administered prior to each agonist caused an inconsistent decrease in the elevated urinary output caused by clonidine, guanabenz and guanfacine. These results indicate that stimulation of alpha-2 adrenoceptors causes diuresis in the rat.

Isolation of N-acetylglutamine, pyroglutamic acid and the butyl ester of pyroglutamic acid from human brain.

N‐acetyl‐l‐glutamine, pyroglutamic acid, and the butyl ester of pyroglutamic acid were isolated in pure form from an aqueous extract of human brain. These compounds were isolated by combination of paper and ion exchange chromatography. The isolated substance identified as N‐acetyl‐l‐glutamine did not react with the ninhydrin reagent but yielded glutamic acid and ammonia upon acid hydrolysis. An acetyl hydrazide was identified by paper chromatography from hydrazinolysates of the isolated substance. The glutamic acid liberated by hydrolysis had the l‐configuration. The results of elementary analysis of the isolated compound were in full accord with the analysis calculated for synthetic N‐acetyl‐l‐glutamine. A large amount of pyroglutamic acid and a substance identical with the butyl ester of pyroglutamic acid were isolated in pure form. The results of our studies suggest that pyroglutamic and the butyl ester derivative were artifacts formed during the isolation and purification procedures.

Occurrence of N-acetylalanine in the human brain.

A substance identical with N‐acetyl‐l‐alanine was isolated from an aqueous extract of human brain by a combination of paper and ion‐exchange Chromatography. The isolated substance did not react with ninhydrin reagent but yielded alanine upon acid hydrolysis. An acetyl hydrazide was identified by paper chromatography of hydrazinolysates of the isolated substance and N‐acetyl‐l‐alanine. The unknown alanine had the l‐configuration. The results of elementary analysis of the isolated compound were in full accord with the analysis calculated for synthetic N‐acetyl‐l‐alanine.