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Amphetamine elicits opposing actions on readily releasable and reserve pools for dopamine.

Covey DP, Juliano SA, Garris PA - PLoS ONE (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Illinois State University, Normal, Illinois, USA.

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.

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Experimental timeline.Three stimulation trains with different durations (0.4 s, 2 s, and 10 s), indicated by the horizontal line under each evoked response, were applied before and after psychostimulant administration at time 0 min. Note that evoked responses are on a second timescale, while the overall design is shown in minutes.
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pone-0060763-g001: Experimental timeline.Three stimulation trains with different durations (0.4 s, 2 s, and 10 s), indicated by the horizontal line under each evoked response, were applied before and after psychostimulant administration at time 0 min. Note that evoked responses are on a second timescale, while the overall design is shown in minutes.

Mentions: The experimental design is shown in Figure 1. Three durations of stimulus trains, short (0.4 s), intermediate (2 s), and long (10 s), were applied to each animal and repeated after administration of the saline control or drug treatment. A frequency of 60 Hz was used for all stimulations. Stimulus current was ±300 µA for long and intermediate trains, and ±125 µA for the short train. The lower current intensity was selected for the short train to elicit evoked responses mirroring the amplitude and dynamics of naturally occurring phasic dopamine transients [26]. As such, we refer to these responses as “phasic-like”. This short train is also reinforcing in the operant paradigm of intracranial self-stimulation [27]. Sufficient time was allowed between trains for evoked responses to recover (5 s per pulse; [28]). Extracellular dopamine was measured in urethane-anesthetized rats by fast-scan cyclic voltammetry (FSCV) at a carbon fiber microelectrode (CFM) implanted in the dorsal and ventral striatum, as described previously [12]. Vesicular dopamine release was resolved from dopamine uptake for all evoked responses [28], [29]. A low (1 mg/kg, i.p.) and high (10 mg/kg, i.p.) dose of AMPH was evaluated to assess dose-dependent effects. A high dose of cocaine (40 mg/kg i.p.) was evaluated for comparison.


Amphetamine elicits opposing actions on readily releasable and reserve pools for dopamine.

Covey DP, Juliano SA, Garris PA - PLoS ONE (2013)

Experimental timeline.Three stimulation trains with different durations (0.4 s, 2 s, and 10 s), indicated by the horizontal line under each evoked response, were applied before and after psychostimulant administration at time 0 min. Note that evoked responses are on a second timescale, while the overall design is shown in minutes.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3643976&req=5

pone-0060763-g001: Experimental timeline.Three stimulation trains with different durations (0.4 s, 2 s, and 10 s), indicated by the horizontal line under each evoked response, were applied before and after psychostimulant administration at time 0 min. Note that evoked responses are on a second timescale, while the overall design is shown in minutes.
Mentions: The experimental design is shown in Figure 1. Three durations of stimulus trains, short (0.4 s), intermediate (2 s), and long (10 s), were applied to each animal and repeated after administration of the saline control or drug treatment. A frequency of 60 Hz was used for all stimulations. Stimulus current was ±300 µA for long and intermediate trains, and ±125 µA for the short train. The lower current intensity was selected for the short train to elicit evoked responses mirroring the amplitude and dynamics of naturally occurring phasic dopamine transients [26]. As such, we refer to these responses as “phasic-like”. This short train is also reinforcing in the operant paradigm of intracranial self-stimulation [27]. Sufficient time was allowed between trains for evoked responses to recover (5 s per pulse; [28]). Extracellular dopamine was measured in urethane-anesthetized rats by fast-scan cyclic voltammetry (FSCV) at a carbon fiber microelectrode (CFM) implanted in the dorsal and ventral striatum, as described previously [12]. Vesicular dopamine release was resolved from dopamine uptake for all evoked responses [28], [29]. A low (1 mg/kg, i.p.) and high (10 mg/kg, i.p.) dose of AMPH was evaluated to assess dose-dependent effects. A high dose of cocaine (40 mg/kg i.p.) was evaluated for comparison.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Illinois State University, Normal, Illinois, USA.

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.

Show MeSH