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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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Representative effects of AMPH on phasic dopamine signaling in the ventral striatum.A. Pre-drug. B. Post-AMPH. Traces show 90 s of a recording with a short-duration (0.4 s) stimulation applied at 5 s (see line underneath). The color plot serially displaying all background-subtracted cyclic voltammograms is shown underneath. INSET. Time-expanded view. Individual background-subtracted voltammograms are shown at the top left and compare dopamine collected during the evoked phasic-like response (black line) to pre-drug baseline (A.) or a dopamine transient collected post-drug (B.) as indicated by vertical white line in the pseudocolot plot (red line).
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pone-0060763-g007: Representative effects of AMPH on phasic dopamine signaling in the ventral striatum.A. Pre-drug. B. Post-AMPH. Traces show 90 s of a recording with a short-duration (0.4 s) stimulation applied at 5 s (see line underneath). The color plot serially displaying all background-subtracted cyclic voltammograms is shown underneath. INSET. Time-expanded view. Individual background-subtracted voltammograms are shown at the top left and compare dopamine collected during the evoked phasic-like response (black line) to pre-drug baseline (A.) or a dopamine transient collected post-drug (B.) as indicated by vertical white line in the pseudocolot plot (red line).

Mentions: Increased [DA]max of phasic-like dopamine responses evoked by the short train (Figs. 2, 3, 4) suggests that both amphetamine and cocaine activate phasic dopamine signaling. These results are thus consistent with the two psychostimulants augmenting naturally occurring dopamine transients in awake, freely behaving animals [13], [36], [37]. While psychostimulant-induced burst firing of dopamine neurons is typically blunted under anesthesia [38] unless revealed by D2 antagonists [9], [10], dopamine transients are elicited by AMPH in a subset of animals in this preparation [14]. An example of this activation is shown in Figure 7. Before drug injection, the dopamine response evoked by the short train was small and no dopamine transients were observed (Fig. 7A). In sharp contrast, high-dose AMPH dramatically increased this evoked phasic-like signal, mediated by augmented vesicular dopamine release and inhibited dopamine uptake (Fig. 4 and Table 1), and transient frequency (Fig. 7B). To better view the presence or absence of dopamine transients, FSCV recordings are expanded in the INSET. These short-lived, non-electrically evoked deflections were identified as dopamine by the sequential voltammograms displayed in the pseudocolor plot below each trace and by the overlay of the individual voltammogram for the transients (black) with that obtained from the evoked signal established to be dopamine (red) to the left in the INSET.


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

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

Representative effects of AMPH on phasic dopamine signaling in the ventral striatum.A. Pre-drug. B. Post-AMPH. Traces show 90 s of a recording with a short-duration (0.4 s) stimulation applied at 5 s (see line underneath). The color plot serially displaying all background-subtracted cyclic voltammograms is shown underneath. INSET. Time-expanded view. Individual background-subtracted voltammograms are shown at the top left and compare dopamine collected during the evoked phasic-like response (black line) to pre-drug baseline (A.) or a dopamine transient collected post-drug (B.) as indicated by vertical white line in the pseudocolot plot (red line).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3643976&req=5

pone-0060763-g007: Representative effects of AMPH on phasic dopamine signaling in the ventral striatum.A. Pre-drug. B. Post-AMPH. Traces show 90 s of a recording with a short-duration (0.4 s) stimulation applied at 5 s (see line underneath). The color plot serially displaying all background-subtracted cyclic voltammograms is shown underneath. INSET. Time-expanded view. Individual background-subtracted voltammograms are shown at the top left and compare dopamine collected during the evoked phasic-like response (black line) to pre-drug baseline (A.) or a dopamine transient collected post-drug (B.) as indicated by vertical white line in the pseudocolot plot (red line).
Mentions: Increased [DA]max of phasic-like dopamine responses evoked by the short train (Figs. 2, 3, 4) suggests that both amphetamine and cocaine activate phasic dopamine signaling. These results are thus consistent with the two psychostimulants augmenting naturally occurring dopamine transients in awake, freely behaving animals [13], [36], [37]. While psychostimulant-induced burst firing of dopamine neurons is typically blunted under anesthesia [38] unless revealed by D2 antagonists [9], [10], dopamine transients are elicited by AMPH in a subset of animals in this preparation [14]. An example of this activation is shown in Figure 7. Before drug injection, the dopamine response evoked by the short train was small and no dopamine transients were observed (Fig. 7A). In sharp contrast, high-dose AMPH dramatically increased this evoked phasic-like signal, mediated by augmented vesicular dopamine release and inhibited dopamine uptake (Fig. 4 and Table 1), and transient frequency (Fig. 7B). To better view the presence or absence of dopamine transients, FSCV recordings are expanded in the INSET. These short-lived, non-electrically evoked deflections were identified as dopamine by the sequential voltammograms displayed in the pseudocolor plot below each trace and by the overlay of the individual voltammogram for the transients (black) with that obtained from the evoked signal established to be dopamine (red) to the left in the INSET.

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