Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport

Abstract

Whether amphetamine acts principally at the plasma membrane or at synaptic vesicles is controversial. We find that d-amphetamine injection into the Planorbis giant dopamine neuron causes robust dopamine release, demonstrating that specific amphetamine uptake is not required. Arguing for action at vesicles, whole-cell capillary electrophoresis of single Planorbis dopamine neurons shows that amphetamine reduces vesicular dopamine, while amphetamine reduces quantal dopamine release from PC12 cells by > 50% per vesicle. Intracellular injection of dopamine into the Planorbis dopamine neuron produces rapid nomifensine-sensitive release, showing that an increased substrate concentration gradient is sufficient to induce release. These experiments indicate that amphetamine acts at the vesicular level where it redistributes dopamine to the cytosol, promoting reverse transport, and dopamine release.

Randomized, placebo-controlled trial of bupropion for the treatment of methamphetamine dependence

“…Clinical imaging studies have also found significant deficits in dopaminergic function among chronic MA users, including reductions in DAT density (Volkow et al, 2001b) and DA receptor occupancy (Volkow et al, 2001a;Volkow et al, 2001c), which are thought to contribute to the dysphoric symptoms that accompany MA dependence and withdrawal. Chronic highdose MA exposure is thought to produce these neurotoxic effects by impairing the ability of synaptic vesicles to take up DA via disruption of the vesicular proton gradient necessary for VMAT-2 functioning (Sulzer et al, 1995;Sulzer and Rayport, 1990), resulting in accumulation of cytoplasmic DA and the subsequent production of harmful reactive oxygen species (Cubells et al, 1994;Fleckenstein et al, 1997). DA reuptake blockers such as bupropion increase vesicular dopamine uptake via enhancement of VMAT-2 function (Brown et al, 2001;Rau et al, 2005) suggesting that treatment with bupropion may counteract the MA-induced accumulation of cytosolic DA and reactive oxygen species thereby reducing the neurotoxic effects of MA.…”

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…This leads to an increase in the intracellular binding sites of DAT for dopamine, resulting in the exchange of extracellular amphetamine by intracellular dopamine, and leading to an increase in extracellular dopamine [289]. When present in higher extracellular concentrations, amphetamine may diffuse into the cell, due to its lipophilicity [290,291]. Amphetamine also interferes with VMATͲ2 function, impairing the active transport of the monoamines into synaptic vesicles, where they are stored.…”

Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs

“…At low concentrations, amphetamine is transported by the DAT to the cytosol and increases the intracellular binding sites of the DAT for dopamine, resulting in the exchange of extracellular amphetamine by intracellular dopamine, and leading to an increase in extracellular dopamine (Jones et al, 1999). When present at higher extracellular concentrations, amphetamine may diffuse into the cell, due to its lipophilicity (Sulzer et al, 1995;Kahlig et al, 2005).…”