The Molecular Basis of the Amphetamine Action

Neurotransmitter:sodium symporters (NSS) share many structural and functional features. The main physiological function of NSS is to terminate the action of neurotransmitters at their respective pre- and postsynaptic receptors. NSS also encompass the family of monoamine transoprter; that is, the dopamine- and serotonin-transporter. These transporters are targets for widely prescribed antidepressant drugs and also drugs of abuse. The latter drugs comprise amphetamine and its congeners (i.e. ecstasy (methylene-dioximethamphetamine, MDMA) or speed (D- amphetamine). They elicit their action via a change in transport direction. By this means, the concentration of neurotransmitter is elevated in the synaptic cleft. The underlying molecular basis, however, remains enigmatic. Thus, the working hypothesis underlying the current grant proposal is based on the following assumptions: (i) the inward Na+ -current and the resulting membrane depolarization induced by amphetamines are prerequisites for efflux. (ii) distinct amino acid side chains line the pathways for substrate influx and efflux through the transporter. (iii) the homo-oligomeric structure of the transporters is a prerequisite for carrier-mediated efflux. Based on this working hypothesis the following aims can be defined: 1. to identify the ionic requirements of reverse transport. 2. to identify molecular determinants of SERT and DAT important for efflux. 3. to verify the functional significance of oligomer formation by monoamine transporters for ion fluxes mediated and, thus, reversal of the transport direction. The primary goal of the current grant application is to understand what amphetamines do to their primary targets (that is, how they act at the molecular level). It is important to note that amphetamines do not only elicit short-term effects (that is release dopamine, serotonin and noradrenaline and thus induce pleasant feelings ranging from euphoria to a "rush", suppress appetite and sleep etc). They also have long-term effects that are of clinical relevance, most notably they cause neurodegeneration upon repeated administration. It is conceivable that neurodegeneration and the currents induced by amphetamines are causally linked. Hence, insights generated during this project may, in the long run, have repercussions on the prevention and the treatment of abuse-related diseases.

Neurotransmitter:sodium symporters (NSS) share many structural and functional features. The main physiological function of NSS is to terminate the action of neurotransmitters at their respective pre- and postsynaptic receptors. NSS also encompass the family of monoamine transoprter; that is, the dopamine- and serotonin-transporter. These transporters are targets for widely prescribed antidepressant drugs and also drugs of abuse. The latter drugs comprise amphetamine and its congeners (i.e. ecstasy (methylene-dioximethamphetamine, MDMA) or speed (D- amphetamine). They elicit their action via a change in transport direction. By this means, the concentration of neurotransmitter is elevated in the synaptic cleft. The underlying molecular basis, however, remains enigmatic. Thus, the working hypothesis underlying the current grant proposal is based on the following assumptions: 1. the inward Na+-current and the resulting membrane depolarization induced by amphetamines are prerequisites for efflux. 2. distinct amino acid side chains line the pathways for substrate influx and efflux through the transporter. 3. the homo-oligomeric structure of the transporters is a prerequisite for carrier-mediated efflux. Based on this working hypothesis the following aims can be defined: 1. to identify the ionic requirements of reverse transport. 2. to identify molecular determinants of SERT and DAT important for efflux. 3. to verify the functional significance of oligomer formation by monoamine transporters for ion fluxes mediated and, thus, reversal of the transport direction. The primary goal of the current grant application is to understand what amphetamines do to their primary targets (that is, how they act at the molecular level). It is important to note that amphetamines do not only elicit short-term effects (that is release dopamine, serotonin and noradrenaline and thus induce pleasant feelings ranging from euphoria to a "rush", suppress appetite and sleep etc). They also have long-term effects that are of clinical relevance, most notably they cause neurodegeneration upon repeated administration. It is conceivable that neurodegeneration and the currents induced by amphetamines are causally linked. Hence, insights generated during this project may, in the long run, have repercussions on the prevention and the treatment of abuse-related diseases.