Amphetamine Paradoxically Augments Exocytotic Dopamine Release and Phasic Dopamine Signals

Abstract

Drugs of abuse hijack brain reward circuitry during the addiction process by augmenting action potential-dependent phasic dopamine release events associated with learning and goal-directed behavior. One prominent exception to this notion would appear to be amphetamine (AMPH) and related analogs, which are proposed instead to disrupt normal patterns of dopamine neurotransmission by depleting vesicular stores and promoting non-exocytotic dopamine efflux via reverse transport. This mechanism of AMPH action, though, is inconsistent with its therapeutic effects and addictive properties - which are thought to be reliant on phasic dopamine signaling. Here we used fast-scan cyclic voltammetry in freely moving rats to interrogate principal neurochemical responses to AMPH in the striatum and relate these changes to behavior. First, we showed that AMPH dose-dependently enhanced evoked dopamine responses to phasic-like current pulse trains for up to two hours. Modeling the data revealed that AMPH inhibited dopamine uptake but also unexpectedly potentiated vesicular dopamine release. Second, we found that AMPH increased the amplitude, duration and frequency of spontaneous dopamine transients, the naturally occurring, non-electrically evoked, phasic increases in extracellular dopamine. Finally, using an operant sucrose reward paradigm, we showed that low-dose AMPH augmented dopamine transients elicited by sucrose-predictive cues. However, operant behavior failed at high-dose AMPH, which was due to phasic dopamine hyperactivity and the decoupling of dopamine transients from the reward predictive cue. These findings identify up-regulation of exocytotic dopamine release as a key AMPH action in behaving animals and support a unified mechanism of abused drugs to activate phasic dopamine signaling.

Cross-hemispheric dopamine projections have functional significance

“…We found spontaneous dopamine transients in the DMS of sham-lesioned animals that increased following AMPH administration (Fig. 5E), in agreement with previous studies (31). In the 6-OHDAlesioned animals, spontaneous dopamine transients in the DMS ipsilateral to the SN lesion were not present under vehicle administration, but were elicited by AMPH administration (Fig.…”

“…FSCV has been used to measure dopamine fluctuations in a number of studies; however, to date, all awake-animal measurements have been restricted to a single hemisphere (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(31)(32)(33)(34)(35). To investigate connectivity between hemispheres, we measured dopamine transients bilaterally in the NAc of freely moving rats.…”

Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal

“…Drugs of abuse increase dopaminergic transmission in the NAc (Cheer et al, 2007;Daberkow et al, 2013;Di Chiara and Imperato, 1988;Phillips et al, 2003;Volkow et al, 2007), which contributes to their acutely reinforcing properties. We used a dose of morphine that, when paired with precipitated withdrawal, generates rapid dependence in rats (Schulteis et al, 1999).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…5). Recently, it has become clear that, aside from these traditional mechanisms, amphetamines are also capable of modulating action potential-dependent neurotransmitter release (Branch and Beckstead, 2012;Daberkow et al, 2013). Furthermore, amphetamines regulate DA neurotransmission via inhibition of monoamine oxidase (MAO) and enhancement of tyrosine hydroxylase (TH) and have numerous other receptor targets, including the a2-adrenergic receptor, the sigma receptor, and the trace amine-associated receptor 1 (TA 1 ) receptor (Fung and Uretsky, 1982;Robinson, 1985;Ritz and Kuhar, 1989;Matsumoto et al, 2014;Reese et al, 2014).…”

“…One study that examined this demonstrated that AMPH at 10 mg/kg enhanced electrically evoked DA release measured 10 and 30 minutes after the initial injection. Additionally, it was shown that a low dose (1 mg/kg) of AMPH facilitated the DA release associated with a rewarding stimulus cue, suggesting that AMPH acts, at least in part, by altering the characteristics of action potential-dependent exocytotic DA release (Daberkow et al, 2013). Unlike AMPH, MPH was recently shown to decrease exocytotic DA release (Federici et al, 2014), which may help explain the differing subjective effects of this drug.…”