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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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Related in: MedlinePlus

Averaged psychostimulant-induced increases in tonic dopamine levels.A. Time course of the effects of AMPH and cocaine (COC) on tonic dopamine levels. Dopamine concentrations were determined using PCR and averaged across 10-s bins. The time period is the epoch immediately following drug injection and prior to the first post-drug. B. Dopamine levels from A. above but only shown at two-minute intervals. These data were used for statistical analysis. Data in the dorsal (left) and ventral (right) striatum are expressed as mean ± SEM. *, significantly different from other treatments (p<0.05).
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pone-0060763-g006: Averaged psychostimulant-induced increases in tonic dopamine levels.A. Time course of the effects of AMPH and cocaine (COC) on tonic dopamine levels. Dopamine concentrations were determined using PCR and averaged across 10-s bins. The time period is the epoch immediately following drug injection and prior to the first post-drug. B. Dopamine levels from A. above but only shown at two-minute intervals. These data were used for statistical analysis. Data in the dorsal (left) and ventral (right) striatum are expressed as mean ± SEM. *, significantly different from other treatments (p<0.05).

Mentions: Figure 6 shows the average effects of the four treatments on tonic dopamine signaling as determined by PCR analysis for the first 10 min of the FSCV recording after drug injection, which is just prior to the first stimulation of the post-drug period (see Fig. 1). This initial recording period was selected for analysis to avoid interactions between stimulation, psychostimulants, and tonic dopamine signaling. In the dorsal striatum (Fig. 6A), AMPH (10 mg/kg) elicited the fastest and largest increase in tonic dopamine levels. Statistical analysis revealed a significant effect of treatment (F3,22 = 3.38, p = 0.04), time (F4,22 = 11.99, p<0.001), and interaction (F12,22 = 2.13, p = 0.03). A post hoc comparison of the average change across the last two minutes of the time course (INSET) revealed that only 10 mg/kg AMPH significantly increased tonic dopamine levels compared to saline (p<0.01). In the ventral striatum (Fig. 6B) region, the effects of each psychostimulant were largely indistinguishable from each other and only slightly different than the saline control. Statistical analysis revealed a significant effect of only time (F4,22 = 3.90, p = 0.02). Overall, these results suggested that AMPH is more effective at increasing tonic dopamine signaling than cocaine and in the dorsal compared to the ventral striatum initially after drug injection.


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

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

Averaged psychostimulant-induced increases in tonic dopamine levels.A. Time course of the effects of AMPH and cocaine (COC) on tonic dopamine levels. Dopamine concentrations were determined using PCR and averaged across 10-s bins. The time period is the epoch immediately following drug injection and prior to the first post-drug. B. Dopamine levels from A. above but only shown at two-minute intervals. These data were used for statistical analysis. Data in the dorsal (left) and ventral (right) striatum are expressed as mean ± SEM. *, significantly different from other treatments (p<0.05).
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Related In: Results  -  Collection

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

pone-0060763-g006: Averaged psychostimulant-induced increases in tonic dopamine levels.A. Time course of the effects of AMPH and cocaine (COC) on tonic dopamine levels. Dopamine concentrations were determined using PCR and averaged across 10-s bins. The time period is the epoch immediately following drug injection and prior to the first post-drug. B. Dopamine levels from A. above but only shown at two-minute intervals. These data were used for statistical analysis. Data in the dorsal (left) and ventral (right) striatum are expressed as mean ± SEM. *, significantly different from other treatments (p<0.05).
Mentions: Figure 6 shows the average effects of the four treatments on tonic dopamine signaling as determined by PCR analysis for the first 10 min of the FSCV recording after drug injection, which is just prior to the first stimulation of the post-drug period (see Fig. 1). This initial recording period was selected for analysis to avoid interactions between stimulation, psychostimulants, and tonic dopamine signaling. In the dorsal striatum (Fig. 6A), AMPH (10 mg/kg) elicited the fastest and largest increase in tonic dopamine levels. Statistical analysis revealed a significant effect of treatment (F3,22 = 3.38, p = 0.04), time (F4,22 = 11.99, p<0.001), and interaction (F12,22 = 2.13, p = 0.03). A post hoc comparison of the average change across the last two minutes of the time course (INSET) revealed that only 10 mg/kg AMPH significantly increased tonic dopamine levels compared to saline (p<0.01). In the ventral striatum (Fig. 6B) region, the effects of each psychostimulant were largely indistinguishable from each other and only slightly different than the saline control. Statistical analysis revealed a significant effect of only time (F4,22 = 3.90, p = 0.02). Overall, these results suggested that AMPH is more effective at increasing tonic dopamine signaling than cocaine and in the dorsal compared to the ventral striatum initially after drug injection.

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