Comparative Psychotomimetic Effects of Stereoisomers of Amphetamine

Abstract

GRIFFITH'S demonstration in 1968 that amphetamine psychosis could be induced safely in non-psychotic human subjects made it feasible to study this psychosis in controlled experimental conditions¹, and later the clinical symptoms induced by large doses of amphetamine were identified^2,3. There were also attempts to investigate pathogenic factors in this condition, using pharmacological pretreatments which affected biogenic amines, and observing the effects on behavioural responses to amphetamine^3,4. Another approach to the study of possible pathogenic factors was suggested by recent reports^5,6 of differential biochemical and behavioural effects of d and l-amphetamine. The essence of these findings is that the d form of amphetamine was found to be ten times as potent as the l form in inhibiting accumulation of noradrenaline in synapto-somes from noradrenergic brain areas, while the two forms were equipotent in their effects on the accumulation of dopamine in synaptosomes from the striatum. Behavioural correlates in rats indicated a similar 10 to 1 potency for d against l-amphetamine for the induction of motor hyperactivity. The d isomer, however, proved only one to two times as potent as the l form in inducing stereotyped behaviour in rats. This suggested that the motor activity induced by amphetamine was noradrenergically mediated. The results with regard to stereotypy, however, suggested that dopaminergic, or other non-stereospecific mechanisms, were largely involved in the induction of behavioural stereotypy, but that noradrenergic mechanisms might also contribute since the potency of d to l-amphetamine was found to be between 1 and 2 to 1, not 1 to 1 as might be expected if only non-stereospecific mechanisms were involved. Moreover, these findings were consistent with biochemical and neuroanatomical studies^7–10 which suggested a critical role for dopaminergic mechanisms in the induction of behavioural stereotypies.