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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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Averaged effects of psychostimulants on dopamine transients.A. AMPH. B. Cocaine. Dopamine transients were analyzed in terms of frequency (left), amplitude (middle) and duration (right) in both the dorsal and ventral striatum (DS and VS, respectively). Data are transient characteristics compiled into 60-s bins and express as the mean ± SEM. Each histogram shows transient characteristics for the 10 minutes before, and the 65 minutes after drug injection (at time 0 min). Phasic dopamine transients were observed following AMPH in 3 of 7 animals in the dorsal striatum and 5 of 7 in the ventral striatum and following cocaine in 3 of 7 animals in the dorsal striatum and 1 of 7 animals in the ventral striatum.
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pone-0060763-g008: Averaged effects of psychostimulants on dopamine transients.A. AMPH. B. Cocaine. Dopamine transients were analyzed in terms of frequency (left), amplitude (middle) and duration (right) in both the dorsal and ventral striatum (DS and VS, respectively). Data are transient characteristics compiled into 60-s bins and express as the mean ± SEM. Each histogram shows transient characteristics for the 10 minutes before, and the 65 minutes after drug injection (at time 0 min). Phasic dopamine transients were observed following AMPH in 3 of 7 animals in the dorsal striatum and 5 of 7 in the ventral striatum and following cocaine in 3 of 7 animals in the dorsal striatum and 1 of 7 animals in the ventral striatum.

Mentions: To complement evoked phasic-like responses, we thus analyzed these dopamine transients to obtain a more physiological assessment of psychostimulant effects on phasic dopamine signaling. Figure 8 shows the time course of dopamine transients for high-dose AMPH (Panel A) and cocaine (Panel B) in the dorsal and ventral striatum (top and bottom, respectively) in the subset of animals where this phasic activity was observed (see legend for details). Transients were analyzed for frequency (left), amplitude (middle), and duration (right). Time 0 min is drug injection. The time when short, intermediate and long trains were applied during the post-drug period is demarcated by vertical dashed lines at 10, 12 and 22 min, respectively. High-dose AMPH and cocaine activated dopamine transients in both striatal subregions. Transients were rarely observed during pre-drug recording and were not observed after saline or low-dose AMPH. Both psychostimulants increased the frequency of dopamine transients to a greater extent in the ventral compared to the dorsal striatum, and AMPH was more effective than cocaine in both striatal subregions. The onset of dopamine transient activation was also slower for cocaine. A clear inhibition and rebound in transient frequency was observed following the long train in both the dorsal and ventral striatum after AMPH. This effect is most likely related to feedback inhibition by released dopamine [39], with the additional combination of AMPH and the long train depleting vesicular dopamine release in the dorsal striatum (Fig. 4). Overall, results for dopamine transients are consistent with those for evoked phasic-like responses and suggest that AMPH and cocaine activate phasic dopamine signaling.


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

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

Averaged effects of psychostimulants on dopamine transients.A. AMPH. B. Cocaine. Dopamine transients were analyzed in terms of frequency (left), amplitude (middle) and duration (right) in both the dorsal and ventral striatum (DS and VS, respectively). Data are transient characteristics compiled into 60-s bins and express as the mean ± SEM. Each histogram shows transient characteristics for the 10 minutes before, and the 65 minutes after drug injection (at time 0 min). Phasic dopamine transients were observed following AMPH in 3 of 7 animals in the dorsal striatum and 5 of 7 in the ventral striatum and following cocaine in 3 of 7 animals in the dorsal striatum and 1 of 7 animals in the ventral striatum.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0060763-g008: Averaged effects of psychostimulants on dopamine transients.A. AMPH. B. Cocaine. Dopamine transients were analyzed in terms of frequency (left), amplitude (middle) and duration (right) in both the dorsal and ventral striatum (DS and VS, respectively). Data are transient characteristics compiled into 60-s bins and express as the mean ± SEM. Each histogram shows transient characteristics for the 10 minutes before, and the 65 minutes after drug injection (at time 0 min). Phasic dopamine transients were observed following AMPH in 3 of 7 animals in the dorsal striatum and 5 of 7 in the ventral striatum and following cocaine in 3 of 7 animals in the dorsal striatum and 1 of 7 animals in the ventral striatum.
Mentions: To complement evoked phasic-like responses, we thus analyzed these dopamine transients to obtain a more physiological assessment of psychostimulant effects on phasic dopamine signaling. Figure 8 shows the time course of dopamine transients for high-dose AMPH (Panel A) and cocaine (Panel B) in the dorsal and ventral striatum (top and bottom, respectively) in the subset of animals where this phasic activity was observed (see legend for details). Transients were analyzed for frequency (left), amplitude (middle), and duration (right). Time 0 min is drug injection. The time when short, intermediate and long trains were applied during the post-drug period is demarcated by vertical dashed lines at 10, 12 and 22 min, respectively. High-dose AMPH and cocaine activated dopamine transients in both striatal subregions. Transients were rarely observed during pre-drug recording and were not observed after saline or low-dose AMPH. Both psychostimulants increased the frequency of dopamine transients to a greater extent in the ventral compared to the dorsal striatum, and AMPH was more effective than cocaine in both striatal subregions. The onset of dopamine transient activation was also slower for cocaine. A clear inhibition and rebound in transient frequency was observed following the long train in both the dorsal and ventral striatum after AMPH. This effect is most likely related to feedback inhibition by released dopamine [39], with the additional combination of AMPH and the long train depleting vesicular dopamine release in the dorsal striatum (Fig. 4). Overall, results for dopamine transients are consistent with those for evoked phasic-like responses and suggest that AMPH and cocaine activate phasic dopamine signaling.

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
Related in: MedlinePlus