Relationship between self-administration of amphetamine and monoamine receptors in brain: comparison with cocaine

Amphetamine and cocaine, commonly abused psychostimulants, often produce similar physiologic and behavioral effects in both animals and humans. We have shown previously that the reinforcing effects of cocaine can be correlated with drug binding to the mazindol and GBR 12935 binding sites on the dopamine transporter. In an attempt to identify the receptors associated with the reinforcing properties of amphetamine and related phenylethylamines, we have compared the potencies of these compounds in studies of drug reinforced behavior with their binding potencies at monoaminergic uptake sites and neurotransmitter receptor sites. The results of these experiments indicate that d-amphetamine exhibits a pharmacologically relevant micromolar affinity for dopamine, norepinephrine and serotonin uptake sites as well as for alpha-2 adrenergic receptor sites. Analysis of the data indicates that the reinforcing effects of phenylethylamines were not positively correlated with inhibition of ligand binding to any of the monoamine sites tested. However, the self-administration of amphetamine and related compounds may be inversely related to the inhibition of [3H]paroxetine binding to the serotonin transporter, suggesting that serotonin uptake inhibition opposes the reinforcing effects of amphetamine. This effect is not related to direct effects of drug binding at 5-HT2 receptor sites. Finally, amphetamine binding to alpha-2 adrenergic receptors suggests that these receptors could play a role in mediating the releasing or uptake inhibiting properties of the drug, and perhaps a role in some of its psychotomimetic effects.