Amphetamines are likely to become increasingly abused, due In part to the recent introduction of 'Ice', an inexpensive smokeable methamphetamine. Clinical approaches to amphetamine abuse have long been frustrated by a lack of understanding of Its mechanism of action, which apparently differs from that of cocaine. Although both produce psychostimulant and rewarding effects by increasing extraneuronal dopamine, cocaine acts by inhibiting the dopamine uptake transporter, while amphetamine both reduces uptake and increases dopamine release from intracellular stores. Since the fundamental actions of amphetamine and cocaine are apparently quite different, It is probable that clinical treatments for amphetamine abuse will require different approaches. Two recent advances may elucidate the action of amphetamine and related psychostimulants: 1) a novel mechanism (the weak base hypothesis) has been discovered which appears to explain the primary molecular basis for amphetamine effects, and 2) the development of an in vitro culture preparation using dissociated, Identified mesoaccumbens dopamine neurons now allows direct study of the cellular substrate for the rewarding effects of amphetamine and cocaine. Using these advances will further understanding of the mechanism of action amphetamine-like psychostimulants. Immunocytochemical, electron microscopic, biochemical techniques will be used to quantify the direct effects of amphetamine vesicle alkalinization and on uptake and release of neurotransmitter from synaptic cells. Electrophysiological analysis of cultured mesoaccumbens synapses promises to be useful for the study of amphetamine's pre- and post-synaptic effects In the pharmacologically appropriate neural circuit and for study of the roles of the presynaptic classical transmitter (dopamine) and the peptide cotransmitter (CCK8-S) in the reward pathway. The weak base model also suggests several important predictions, Including; 1) amphetamine should increase extracellular catecholamine, but not peptide cotransmitters; 2) psychostimulants could lead to changes In Ionic gradients that could help explain stimulant-- induced neurotoxicity; 3) changes in the pH gradient of synaptic vesicles should be an useful In vitro method to predict the behavioral efficacy of amphetamine-like stimulant drugs; and 4) animals should self-administer intracerebral injection of weak base drugs that do not normally cross the blood/brain barrier.
