Modification by L‐DOPA Methylester (H 19/61) of Amphetamine‐Induced Brain Catecholamine Changes, Thermal Responses and Toxicity in Developing Mice

Abstract

The effect of 150 mg/kg of L‐DOPA methylester on brain catecholamines was studied in adult and developing mice aged 3‐5 days and 13‐15 days. Noradrenaline was moderately increased in the developing brain but dopamine showed a manyfold increase. The increase of dopamine was less pronounced in adult brain. High doses of dl‐amphetamine (50‐160 mg/kg) injected to L‐DOPA pretreated mice further increased the dopamine levels in the developing brain. The adult brain catecholamines were remarkably depleted, provided the observation period was 4 hours after amphetamine. Amphetamine lowered the body temperature in mice aged 13‐15 days; the fall was dose‐dependent and potentiated by pretreatment with L‐DOPA. In adult mice amphetamine caused hyperthermia which was not modified by L‐DOPA. L‐DOPA did not change the mortality rates induced by amphetamine in developing mice, but infant mice pretreated with L‐DOPA showed a lower brain amphetamine concentration after death than the mice given amphetamine only. In adult mice GDOPA enhanced amphetamine toxicity. Special attention is paid to the importance of different turnover rates of catecholamines during development as well as to the complex action of amphetamine on enzymes regulating catecholamine turnover. It is assumed that the hypothermia of developing mice after amphetamine might result from the primary effect of amphetamine on dopaminergic mechanisms.

Levels of D‐ and L‐Amphetamine in Brain and Heart of Adult and Infant Mice

“…There is a striking similarity between the thermal responses of developing mice to amphetamine isomers and the previous finding with racemic amphetamine and L-DOPA (ALHAVA 1973). The response of young mice to the l-form corresponds well with that caused by the same dose of racemic amphetamine alone, while the temperature response produced by d-amphetamine is almost identical with that obtained with dl-amphetamine in L-DOPApretreated mice (ALHAVA 1973). This suggests a stronger action of d-amphetamine on central dopaminergic mechanisms when compared to I-amphetamine, i. e. compatible with the greater capacity of the d-form to increase striatal homovanillic acid in rats (JORI et al 1973).…”

Effects of Catecholamine Receptor Blocking Agents on Toxicity and Thermal Responses Induced by Amphetamine Isomers in Adult and Developing Mice

“…In contrast to the hyperthermia seen in adult mice, dl-amphetamine causes hypothermia in developing mice aged two weeks (ALHAVA 1973). This hypothermia is dose-dependent and potentiated by L-DOPA (ALHAVA 1973), which supports the concept concerning the stimulation of central dopamine (DA) neurons in the hypothermic response of the mouse (FUXE & SJOQVIST 1972). Hyperthermia, in turn, has been suggested to result from the stimulation of central noradrenaline (NA) neurons (FUXE & SJ~QVIST 1972).…”

“…cerning the role of thermoregulation in amphetamine toxicity (WOLF & BUNCE 1973). However, similar to the behavioural effects of the drug (WEISS-MAN et al 1966;HANSON 1967), there is evidence indicating the involvement of catecholaminergic mechanisms in the thermal action of amphetamine ( YEHUDA & W m m m 1972;ALHAVA 1973).…”

“…Whether the central or peripheral adrenergic system is of primary importance in amphetamine-induced toxicity and body temperature responses is obscure. It probably depends on the dosage of amphetamine and age of the mice (ALHAVA 1972(ALHAVA & 1973. The optical isomers of amphetamine exert different potencies in their central and peripheral as well as toxic action (MOORE 1963;TAYLOR & SNYDER 1970;JORI et al 1973;VOIGTLANDER & MOORE 1973), and the increasing effect of d-amphetamine on striatal homovanillic acid content has been reported to be stronger than that of l-amphetamine (JORI et al 1973).…”