The influence of brain catecholamines on 'drug taking behaviour' relative to oral self-administration of d-amphetamine by rats.

Oral administration of 5 mg/kg of d-amphetamine to adult Wistar rats caused brain NE to decrease to approx. 80% of the control level during 4-24 h after acute treatment and slowly further to 65% after 24 days of self-administration via drinking water. The norepinephrine (NE)-reducing effect was first recognized at 1 mg/kg and appeared to peak at 5 mg/kg of d-amphetamine. Brain dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were only shortly affected. Neither iprindole nor desipramine altered the effect of amphetamine on brain NE. DA was decreased by both inhibitors depending on the duration of pre-treatment. Iproniazid and alpha-methyl-p-tyrosine antagonized and potentiated respectively the amphetamine effect on NE- and DA-concentration after 4 days of simultaneous treatment. In the free choice experiment (water vs. 0.005% d-amphetamine solution) rats developed an aversion to amphetamine. The number of rats taking the drug and the consumption by rats still drinking it declined gradually from 100% and approx. 3 mg/kg/day to 50% and approx. 1.5 mg/kg/day, respectively, during 18 days. The time course of the developing aversive reaction to oral amphetamine ran approximately parallel to that of NE-depletion. Iprindole and desipramine intensified, iproniazid and propranolol weakened, while alpha-methyl-p-tyrosine and haloperidol hardly influenced the aversive effect of amphetamine. It is concluded that the development of aversive behaviour in response to oral d-amphetamine is mediated not only through the depleting effect of amphetamine on NE stores but also by its direct stimulation at beta-adrenergic receptors in the CNS.