Elsevier

European Journal of Pharmacology

Volume 764, 5 October 2015, Pages 562-570
European Journal of Pharmacology

Review
Psychostimulants affect dopamine transmission through both dopamine transporter-dependent and independent mechanisms

https://doi.org/10.1016/j.ejphar.2015.07.044Get rights and content

Abstract

The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however, that these drugs produce their effects by enhancing dopamine neurotransmission in the brain, especially in limbic areas such as the nucleus accumbens, by inducing dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter. Here, we present the evidence that aside from dopamine transporter, non-dopamine transporter-mediated mechanisms also participate in psychostimulant-induced dopamine release and contribute to the behavioral effects of these drugs, such as locomotor activation and reward. Accordingly, psychostimulants could increase norepinephrine release in the prefrontal cortex, the latter then alters the firing pattern of dopamine neurons resulting in changes in action potential-dependent dopamine release. These alterations would further affect the temporal pattern of dopamine release in the nucleus accumbens, thereby modifying information processing in that area. Hence, a synaptic input to a nucleus accumbens neuron may be enhanced or inhibited by dopamine depending on its temporal relationship to dopamine release. Specific temporal patterns of dopamine release may also be required for certain forms of synaptic plasticity in the nucleus accumbens. Together, these effects induced by psychostimulants, mediated through a non-dopamine transporter-mediated mechanism involving norepinephrine and the prefrontal cortex, may also contribute importantly to the reinforcing properties of these drugs.

Introduction

Cocaine, and amphetamine-like psychostimulants, including methamphetamine and methylphenidate, modulate arousal and produce behavioral activation and reinforcing actions that are associated with significant abuse potential (dela Peña et al., 2013b, dela Peña et al., 2010, dela Peña et al., 2013a, dela Peńa et al., 2011; Heal et al., 2013; Kalivas, 2007; Wood et al., 2013). After the intake of a stimulant drug, temporally limited functional changes in the brain occur, which are believed to endure beyond the presence in the brain of the actual drug or metabolites in the brain (Ungless et al., 2001). Identifying the initial functional changes wrought by psychostimulants is critical in understanding further the corresponding homeostatic responses that are responsible for behavioral and subjective effects of the drug intake that outlast the presence of the drug in the brain (Koob and Le Moal, 1997, Müller et al., 2007). While previous studies have provided strong evidence that dopamine plays a key role in the reinforcing effects of psychostimulants, the precise mechanisms by which psychostimulants alter dopamine-mediated transmission remain to be fully defined. Understanding these processes will not only help explain the complex mechanism of psychostimulant addiction but also aid in the discovery of effective therapies to counteract addiction to these drugs.

Section snippets

Role of dopamine in the effects of psychostimulants

Many lines of evidence suggest that dopamine plays a central role in the above-mentioned effects of psychostimulants (for reviews see Nutt et al. (2015) and Wise, 2004, Wise, 2008). In humans, for example, blockade of dopamine receptors decreased the euphoria produced by intravenous amphetamine injection (Gunne et al., 1972, Jönsson et al., 1971). In animals, dopamine receptor blockade also attenuated the reinforcing properties of amphetamine and cocaine (Davis and Smith, 1975; Yokel and Wise,

Evidence for non-dopamine transporter mediated dopamine release

Aside from dopamine transporters, psychostimulants also bind to the norepinephrine and serotonin transporters. Studies with the human dopamine, serotonin, and norepinephrine transporters suggest that amphetamine has very high affinity for the norepinephrine transporter, whereas methylphenidate inhibits norepinephrine and dopamine transporters equally well (Han and Gu, 2006). Moreover, both amphetamine and methylphenidate display significantly weaker binding to the serotonin transporter, while

Involvement of norepinephrine and the prefrontal cortex in non-dopamine transporter-mediated dopamine release

In a landmark study, Darracq et al. (1998) showed that intra-nucleus accumbens dextroamphetamine (or d-amphetamine) injection did not produce behavioral activation in rats although it caused a dramatic increase in extracellular dopamine. Meanwhile, systemic administration of d-amphetamine induced an increase in locomotor activity despite producing a relatively small elevation in extracellular dopamine. Furthermore, Darracq et al. also showed that both dopamine release and locomotor activation

Prefrontal cortical regulation of dopamine neurons

The prefrontal cortex is highly developed in humans and primates and critical to the executive functions of brain, including decision making (Euston et al., 2012), learning and memory (Rugg et al., 1996, Tomita et al., 1999), social behavior (Avale et al., 2011, Forbes and Grafman, 2010) and emotional regulation (Davidson and Irwin, 1999, Kennis et al., 2013). Prefrontal cortical dysfunction has been implicated in a number of neuropsychiatric disorders, including drug addiction (Goldstein and

Importance of prefrontal cortex regulation of dopamine neurons in the effects of psychostimulants

Dopamine neurons in the ventral tegmental area receive synaptic information from many brain areas including inputs directly from the prefrontal cortex and from other areas that are under the control of the prefrontal cortex (e.g. hippocampus, amygdala, and ventral pallidum). Information from different inputs is processed and integrated in the dendrites and soma of dopamine neurons and then transmitted in the form of spike trains to axon terminals where action potentials would trigger Ca2+

Concluding remarks

It has long been believed that psychostimulants produce rewarding effects via dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter, thereby enhancing dopamine neurotransmission. The evidence presented in this paper indicates that in addition to dopamine transporter, non-dopamine transporter mediated mechanisms of dopamine release are also involved and appears to be critical for the behavioral effects of stimulant drugs such as

Acknowledgments

This research was supported, in part, by the National Institutes of Health, National Institute of Drug Abuse DA032857 and Loma Linda University School of Pharmacy.

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