A closer look at amphetamine-induced reverse transport and trafficking of the dopamine and norepinephrine transporters

Abstract

Amphetamine (AMPH) and its derivatives are regularly used in the treatment of a wide array of disorders such as attention-deficit hyperactivity disorder (ADHD), obesity, traumatic brain injury, and narcolepsy (Prog Neurobiol 75:406-433, 2005; J Am Med Assoc 105:2051-2054, 1935; J Am Acad Child Adolesc Psychiatry 41:514-521, 2002; Neuron 43:261-269, 2004; Annu Rev Pharmacol Toxicol 47:681-698, 2007; Drugs Aging 21:67-79, 2004). Despite the important medicinal role for AMPH, it is more widely known for its psychostimulant and addictive properties as a drug of abuse. The primary molecular targets of AMPH are both the vesicular monoamine transporters (VMATs) and plasma membrane monoamine-dopamine (DA), norepinephrine (NE), and serotonin (5-HT)-transporters. The rewarding and addicting properties of AMPH rely on its ability to act as a substrate for these transporters and ultimately increase extracellular levels of monoamines. AMPH achieves this elevation in extracellular levels of neurotransmitter by inducing synaptic vesicle depletion, which increases intracellular monoamine levels, and also by promoting reverse transport (efflux) through plasma membrane monoamine transporters (J Biol Chem 237:2311-2317, 1962; Med Exp Int J Exp Med 6:47-53, 1962; Neuron 19:1271-1283, 1997; J Physiol 144:314-336, 1958; J Neurosci 18:1979-1986, 1998; Science 237:1219-1223, 1987; J Neurosc 15:4102-4108, 1995). This review will focus on two important aspects of AMPH-induced regulation of the plasma membrane monoamine transporters-transporter mediated monoamine efflux and transporter trafficking.

Figure 1. Schematic Representation of Transporter Mediated Monoamine Efflux

Transporters in the inward facing conformation are capable of mediating monoamine efflux by binding substrate and co-transported ions. Transporter reversal can be enhanced under certain conditions such as in the presence of AMPH or increased intracellular Na⁺. In addition to the slow exchange-like mechanism of efflux, AMPH can also induce efflux through a channel-like mode of the transporter.

Figure 2. AMPH-Induced DAT Efflux is Regulated by Second Messengers

A model of AMPH-induced regulation of DAT mediated DA efflux via intracellular signaling pathways. AMPH transport via DAT into the intracellular milieu results in an increase in both intracellular Na⁺ and Ca²⁺ levels. As a consequence, PKC and CaMKII activation initiates both phosphorylation of the N-terminus of DAT and enhancement of DAT/SYN1A association, shifting the transporter from a ‘reluctant’ to a ‘willing’ state for efflux.