ReviewPsychostimulants affect dopamine transmission through both dopamine transporter-dependent and independent mechanisms
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.
References (126)
- et al.
AMPA receptor synaptic plasticity induced by psychostimulants: the past, present, and therapeutic future
Neuron
(2010) - et al.
Amphetamine, cocaine, phencyclidine and nomifensine increase extracellular dopamine concentrations preferentially in the nucleus accumbens of freely moving rats
Neuroscience
(1989) - et al.
Effects of systemic and intracranial amphetamine injections on behavior in the open field: a detailed analysis
Pharmacol. Biochem. Behav.
(1987) - et al.
The functional neuroanatomy of emotion and affective style
Trends Cogn. Sci.
(1999) - et al.
Dopamine and drug addiction: the nucleus accumbens shell connection
Neuropharmacology
(2004) - et al.
Chronic d-amphetamine in nucleus accumbens: lack of tolerance or reverse tolerance of locomotor activity
Life Sci.
(1981) - et al.
The role of medial prefrontal cortex in memory and decision making
Neuron
(2012) The spike-timing dependence of plasticity
Neuron
(2012)- et al.
Burst firing induced in midbrain dopamine neurons by stimulation of the medial prefrontal and anterior cingulate cortices
Brain Res.
(1988) Nonlinear relationship between impulse flow and dopamine released by rat midbrain dopaminergic neurons as studied by in vivo electrochemistry
Neuroscience
(1988)