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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 psychostimulant- and stimulation-dependent effects on evoked dopamine dynamics in the dorsal striatum.A. Saline. B. 1 mg/kg AMPH. C. 10 mg/kg AMPH. D. 40 mg/kg cocaine (COC). AMPH and cocaine altered the amplitude of evoked dopamine signals in the dorsal striatum, while saline had no effect. In contrast to cocaine, there was an inverse relationship between stimulus duration and evoked dopamine amplitude following AMPH. Application of the stimulus train is indicated by the solid line underneath each representative response for short (left), intermediate (middle) and long (right) durations.
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pone-0060763-g002: Representative psychostimulant- and stimulation-dependent effects on evoked dopamine dynamics in the dorsal striatum.A. Saline. B. 1 mg/kg AMPH. C. 10 mg/kg AMPH. D. 40 mg/kg cocaine (COC). AMPH and cocaine altered the amplitude of evoked dopamine signals in the dorsal striatum, while saline had no effect. In contrast to cocaine, there was an inverse relationship between stimulus duration and evoked dopamine amplitude following AMPH. Application of the stimulus train is indicated by the solid line underneath each representative response for short (left), intermediate (middle) and long (right) durations.

Mentions: Individual recordings of electrically evoked dopamine levels collected during the four treatments are shown in Figure 2 for the dorsal striatum and Figure 3 for the ventral striatum. Average results for [DA]max, the maximal concentration of the evoked signal, and obtained from these recordings are shown in Figure 4A (left, dorsal striatum; right, ventral striatum). Both individual responses and averaged results demonstrate drug-, dose-, stimulus-, and region-dependent effects, and four general observations can be made. First, psychostimulant effects were inversely related to stimulus duration in both striatal regions. Second, AMPH but not cocaine decreased [DA]max evoked by the long train, and this only occurred in the dorsal striatum. Third, AMPH was more proficient in increasing [DA]max evoked by the short train in the ventral striatum, whereas cocaine elicited greater effects in the dorsal striatum. And fourth, the high dose of AMPH was more proficient at increasing [DA]max during short trains in both striatal regions compared to the low dose. Statistical analysis of [DA]max revealed a significant effect of drug treatment in the dorsal (F3,75 = 13.45, p = <0.001) and ventral (F3,74 = 8.81, p<0.001) striatum, a significant effect of stimulus duration in the dorsal (F2,75 = 47.94, p<0.001) and ventral (F2,74 = 13.96, p<0.001) striatum, and a significant interaction in the dorsal (F6,75 = 8.45, p<0.001) and ventral (F6,74 = 3.08, p<0.01) striatum. In the dorsal striatum, 10 mg/kg AMPH and 40 mg/kg cocaine significantly (p<0.002) increased [DA]max evoked by the short train, but only cocaine was effective at the intermediate train (p<0.001). Both doses of AMPH (1 and 10 mg/kg) significantly (p<0.001) decreased [DA]max evoked by the long train, whereas cocaine was without effect. In the ventral striatum, both doses of AMPH and cocaine significantly (p<0.01) increased [DA]max evoked by short and intermediate trains, but were without effect with the long train.


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

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

Representative psychostimulant- and stimulation-dependent effects on evoked dopamine dynamics in the dorsal striatum.A. Saline. B. 1 mg/kg AMPH. C. 10 mg/kg AMPH. D. 40 mg/kg cocaine (COC). AMPH and cocaine altered the amplitude of evoked dopamine signals in the dorsal striatum, while saline had no effect. In contrast to cocaine, there was an inverse relationship between stimulus duration and evoked dopamine amplitude following AMPH. Application of the stimulus train is indicated by the solid line underneath each representative response for short (left), intermediate (middle) and long (right) durations.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0060763-g002: Representative psychostimulant- and stimulation-dependent effects on evoked dopamine dynamics in the dorsal striatum.A. Saline. B. 1 mg/kg AMPH. C. 10 mg/kg AMPH. D. 40 mg/kg cocaine (COC). AMPH and cocaine altered the amplitude of evoked dopamine signals in the dorsal striatum, while saline had no effect. In contrast to cocaine, there was an inverse relationship between stimulus duration and evoked dopamine amplitude following AMPH. Application of the stimulus train is indicated by the solid line underneath each representative response for short (left), intermediate (middle) and long (right) durations.
Mentions: Individual recordings of electrically evoked dopamine levels collected during the four treatments are shown in Figure 2 for the dorsal striatum and Figure 3 for the ventral striatum. Average results for [DA]max, the maximal concentration of the evoked signal, and obtained from these recordings are shown in Figure 4A (left, dorsal striatum; right, ventral striatum). Both individual responses and averaged results demonstrate drug-, dose-, stimulus-, and region-dependent effects, and four general observations can be made. First, psychostimulant effects were inversely related to stimulus duration in both striatal regions. Second, AMPH but not cocaine decreased [DA]max evoked by the long train, and this only occurred in the dorsal striatum. Third, AMPH was more proficient in increasing [DA]max evoked by the short train in the ventral striatum, whereas cocaine elicited greater effects in the dorsal striatum. And fourth, the high dose of AMPH was more proficient at increasing [DA]max during short trains in both striatal regions compared to the low dose. Statistical analysis of [DA]max revealed a significant effect of drug treatment in the dorsal (F3,75 = 13.45, p = <0.001) and ventral (F3,74 = 8.81, p<0.001) striatum, a significant effect of stimulus duration in the dorsal (F2,75 = 47.94, p<0.001) and ventral (F2,74 = 13.96, p<0.001) striatum, and a significant interaction in the dorsal (F6,75 = 8.45, p<0.001) and ventral (F6,74 = 3.08, p<0.01) striatum. In the dorsal striatum, 10 mg/kg AMPH and 40 mg/kg cocaine significantly (p<0.002) increased [DA]max evoked by the short train, but only cocaine was effective at the intermediate train (p<0.001). Both doses of AMPH (1 and 10 mg/kg) significantly (p<0.001) decreased [DA]max evoked by the long train, whereas cocaine was without effect. In the ventral striatum, both doses of AMPH and cocaine significantly (p<0.01) increased [DA]max evoked by short and intermediate trains, but were without effect with the long train.

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