Amphetamine Elicits Opposing Actions on Readily Releasable and Reserve Pools for Dopamine

Abstract

Amphetamine, a highly addictive drug with therapeutic efficacy, exerts paradoxical effects on the fundamental communication modes employed by dopamine neurons in modulating behavior. While amphetamine elevates tonic dopamine signaling by depleting vesicular stores and driving non-exocytotic release through reverse transport, this psychostimulant also activates phasic dopamine signaling by up-regulating vesicular dopamine release. We hypothesized that these seemingly incongruent effects arise from amphetamine depleting the reserve pool and enhancing the readily releasable pool. This novel hypothesis was tested using in vivo voltammetry and stimulus trains of varying duration to access different vesicular stores. We show that amphetamine actions are stimulus dependent in the dorsal striatum. Specifically, amphetamine up-regulated vesicular dopamine release elicited by a short-duration train, which interrogates the readily releasable pool, but depleted release elicited by a long-duration train, which interrogates the reserve pool. These opposing actions of vesicular dopamine release were associated with concurrent increases in tonic and phasic dopamine responses. A link between vesicular depletion and tonic signaling was supported by results obtained for amphetamine in the ventral striatum and cocaine in both striatal sub-regions, which demonstrated augmented vesicular release and phasic signals only. We submit that amphetamine differentially targeting dopamine stores reconciles the paradoxical activation of tonic and phasic dopamine signaling. Overall, these results further highlight the unique and region-distinct cellular mechanisms of amphetamine and may have important implications for its addictive and therapeutic properties.

Striatal dopamine neurotransmission: Regulation of release and uptake

“…In dopamine axons of the striatum, electrochemical recordings in acute striatal slices suggest similar actions of amphetamine in intact tissue [93,94], although contradictory findings have yet to be resolved. For example, Paul Garris and colleagues have shown that amphetamines indeed can enhance synaptic vesicle fusion in DA neurons in vivo , perhaps via a circuit mechanism [95]. Moreover, some of the decrease in evoked DA release may also be due to activation of a striatal circuit in the striatum (Jose Lizardi-Ortiz et al, ms. in preparation).…”

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease

“…However, these agents differ in their effect on tonic activation. For example, cocaine, but not AMPH, requires action potential-dependent mechanisms (for discussion, see Covey et al, 2013).…”

Illicit dopamine transients: Reconciling actions of abused drugs

“…Indeed, cocaine has been found to up-regulate vesicular dopamine release in several preparations, including brain-slice [ 53,54 ], anesthetized [ 55-57 ], and awake [ 58 ]. Up-regulation of dopamine release has more recently been extended to methylphenidate, a cocaine-like DAT-I [ 59 ], and surprisingly, even AMPH [ 42,55,56,60 ]. It should be emphasized that the evidence for up-regulated dopamine release by addictive DAT-Is is typically based on studies using a single dose administered non-contingently.…”

“…AMPH may similarly promote mobilization of the reserve pool [ 60 ] and vesicular trafficking [ 66 ] but also up-regulate vesicular dopamine release by distinct mechanisms. These include: (1) elevation of cytosolic dopamine levels by enhancing dopamine synthesis and inhibiting dopamine degradation [ 60 ], and selectively depleting the reserve pool [ 56 ]; (2) liberation of intracellular Ca 2+ stores [ 68 ]; (3) enhancing presynaptic membrane excitability as a DAT substrate [ 51 ]. Similar mechanisms may apply to AMPH analogs, such as methamphetamine, which also enhances membrane excitability [ 52 ] and alters vesicular dopamine trafficking [ 64 ].…”