Does tolerance develop to low doses of d- and l-amphetamine on locomotor activity in rats?

An observational study of the behavioural effects of chronic regimens of d- and l-amphetamine was designed to investigate possible mechanisms underlying any parallel behavioural changes: (1) Accumulation of p-hydroxynorephedrine in noradrenergic nerve terminals; (2) Altered sensitivity of dopaminergic receptors. The study revealed that locomotor activity seen with low doses of both isomers (2.0 mg/kg d- and 6.0 mg/kg l-) decreased with chronic once daily treatment. However, this was accompanied by an increase in directed sniffing activity and the behaviour came to resemble that seen with higher doses of amphetamine (8.0 mg/kg d- and 16.0 mg/kg l-). Nonsignificant decreases in locomotor activity and increases in directed sniffing to apomorphine administration were observed during chronic amphetamine treatment. These findings suggest that (1) p-hydroxynorephedrine, a metabolite of d- but not 1- amphetamine, does not play an important role in these alterations in behaviour with chronic treatment and (2) the tolerance to amphetamine observed under these conditions is due to an increased, rather than decreased, sensitivity of the rats to amphetamine.