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Central and peripheral contributions to dynamic changes in nucleus accumbens glucose induced by intravenous cocaine.

Wakabayashi KT, Kiyatkin EA - Front Neurosci (2015)

Bottom Line: The pattern of neural, physiological and behavioral effects induced by cocaine is consistent with metabolic neural activation, yet direct attempts to evaluate central metabolic effects of this drug have produced controversial results.While the rapid, phasic component of the glucose response remained stable following subsequent cocaine injections, the tonic component progressively decreased.However, this analog did not induce increases in either locomotion or tonic glucose, suggesting direct central mediation of these cocaine effects.

View Article: PubMed Central - PubMed

Affiliation: Behavioral Neuroscience Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, DHHS Baltimore, MD, USA.

ABSTRACT
The pattern of neural, physiological and behavioral effects induced by cocaine is consistent with metabolic neural activation, yet direct attempts to evaluate central metabolic effects of this drug have produced controversial results. Here, we used enzyme-based glucose sensors coupled with high-speed amperometry in freely moving rats to examine how intravenous cocaine at a behaviorally active dose affects extracellular glucose levels in the nucleus accumbens (NAc), a critical structure within the motivation-reinforcement circuit. In drug-naive rats, cocaine induced a bimodal increase in glucose, with the first, ultra-fast phasic rise appearing during the injection (latency 6-8 s; ~50 μM or ~5% of baseline) followed by a larger, more prolonged tonic elevation (~100 μM or 10% of baseline, peak ~15 min). While the rapid, phasic component of the glucose response remained stable following subsequent cocaine injections, the tonic component progressively decreased. Cocaine-methiodide, cocaine's peripherally acting analog, induced an equally rapid and strong initial glucose rise, indicating cocaine's action on peripheral neural substrates as its cause. However, this analog did not induce increases in either locomotion or tonic glucose, suggesting direct central mediation of these cocaine effects. Under systemic pharmacological blockade of dopamine transmission, both phasic and tonic components of the cocaine-induced glucose response were only slightly reduced, suggesting a significant role of non-dopamine mechanisms in cocaine-induced accumbal glucose influx. Hence, intravenous cocaine induces rapid, strong inflow of glucose into NAc extracellular space by involving both peripheral and central, non-dopamine drug actions, thus preventing a possible deficit resulting from enhanced glucose use by brain cells.

No MeSH data available.


Related in: MedlinePlus

Relative changes in NAc [glucose] induced by cocaine injections assessed at low temporal resolution (1-min bins). Top graphs (A,D,G,J) show mean ± SEM changes in relative currents (nA) detected by Glucose and Null sensors. Middle graphs (B,E,H,K) show mean ± SEM changes in [glucose] (μM) as a difference between active and  sensors. Bottom graphs (C,F,I,L) show changes in locomotor activity (mean ± SEM; counts/min). Vertical hatched lines (at 0 min) marked the onset of 20-s cocaine injection. Horizontal dotted lines show basal levels (= 0 nA and μM). The difference in current dynamics between active and  sensors was significant (p < 0.05) for the entire 60-min duration after each cocaine injection [Two-Way repeated measures (RM) ANOVA; Current × Time interaction F(6, 660) = 5.94, 3.03, 1.94, and 4.72, all p < 0.05 for injections 1–4, respectively]. Concentration change was also significant for each cocaine injection [F(60, 360) = 7.07, 3.63, 2.30, and 5.61, all P < 0.05 respectively]. Individual concentration values significantly different from baseline (Fisher test) are shown as filled symbols. Cocaine induced significant locomotor activation after each injection [F(12, 732) = 4.14, 5.45, 4.61, 5.20 for injections 1–4, respectively; p < 0.05]. Right panels (M,N) show differences in mean ± SEM values of glucose and locomotor responses induced by cocaine injections as assessed by area under the curve. The effect of injection number was significant for [glucose] [One-Way RM ANOVA: F(3, 18) = 4.94, p < 0.05] but not significant for locomotion. Asterisks and star show significant between-injection differences.
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Figure 1: Relative changes in NAc [glucose] induced by cocaine injections assessed at low temporal resolution (1-min bins). Top graphs (A,D,G,J) show mean ± SEM changes in relative currents (nA) detected by Glucose and Null sensors. Middle graphs (B,E,H,K) show mean ± SEM changes in [glucose] (μM) as a difference between active and sensors. Bottom graphs (C,F,I,L) show changes in locomotor activity (mean ± SEM; counts/min). Vertical hatched lines (at 0 min) marked the onset of 20-s cocaine injection. Horizontal dotted lines show basal levels (= 0 nA and μM). The difference in current dynamics between active and sensors was significant (p < 0.05) for the entire 60-min duration after each cocaine injection [Two-Way repeated measures (RM) ANOVA; Current × Time interaction F(6, 660) = 5.94, 3.03, 1.94, and 4.72, all p < 0.05 for injections 1–4, respectively]. Concentration change was also significant for each cocaine injection [F(60, 360) = 7.07, 3.63, 2.30, and 5.61, all P < 0.05 respectively]. Individual concentration values significantly different from baseline (Fisher test) are shown as filled symbols. Cocaine induced significant locomotor activation after each injection [F(12, 732) = 4.14, 5.45, 4.61, 5.20 for injections 1–4, respectively; p < 0.05]. Right panels (M,N) show differences in mean ± SEM values of glucose and locomotor responses induced by cocaine injections as assessed by area under the curve. The effect of injection number was significant for [glucose] [One-Way RM ANOVA: F(3, 18) = 4.94, p < 0.05] but not significant for locomotion. Asterisks and star show significant between-injection differences.

Mentions: When analyzed at the 1-min time-scale, the initial cocaine injection in a drug-naive rat induced a significantly different current response in the glucose and sensors [Current × Time interaction; F(6, 660) = 5.94; p < 0.05] for the entire 60-min analysis duration (Figure 1A), revealing a rapid, significant [glucose] increase from the first minute post-injection [Figure 1B; F(60, 360) = 7.07, p < 0.05]. This increase peaked at 15–20 min (~110 μM or ~11% of baseline) followed by a slow return to baseline at ~45 min post-injection. Importantly, the largest rate of [glucose] increase occurred during the first min post-injection. Cocaine also induced modest locomotor activation (Figure 1C) for ~20–30 min post-injection [F(12, 732) = 4.14, p < 0.05]. While the rise in [glucose] resulted primarily from current changes detected by glucose sensors, cocaine also induced a tonic increase in currents detected by currents; this latter change was much smaller than that recorded by glucose sensors.


Central and peripheral contributions to dynamic changes in nucleus accumbens glucose induced by intravenous cocaine.

Wakabayashi KT, Kiyatkin EA - Front Neurosci (2015)

Relative changes in NAc [glucose] induced by cocaine injections assessed at low temporal resolution (1-min bins). Top graphs (A,D,G,J) show mean ± SEM changes in relative currents (nA) detected by Glucose and Null sensors. Middle graphs (B,E,H,K) show mean ± SEM changes in [glucose] (μM) as a difference between active and  sensors. Bottom graphs (C,F,I,L) show changes in locomotor activity (mean ± SEM; counts/min). Vertical hatched lines (at 0 min) marked the onset of 20-s cocaine injection. Horizontal dotted lines show basal levels (= 0 nA and μM). The difference in current dynamics between active and  sensors was significant (p < 0.05) for the entire 60-min duration after each cocaine injection [Two-Way repeated measures (RM) ANOVA; Current × Time interaction F(6, 660) = 5.94, 3.03, 1.94, and 4.72, all p < 0.05 for injections 1–4, respectively]. Concentration change was also significant for each cocaine injection [F(60, 360) = 7.07, 3.63, 2.30, and 5.61, all P < 0.05 respectively]. Individual concentration values significantly different from baseline (Fisher test) are shown as filled symbols. Cocaine induced significant locomotor activation after each injection [F(12, 732) = 4.14, 5.45, 4.61, 5.20 for injections 1–4, respectively; p < 0.05]. Right panels (M,N) show differences in mean ± SEM values of glucose and locomotor responses induced by cocaine injections as assessed by area under the curve. The effect of injection number was significant for [glucose] [One-Way RM ANOVA: F(3, 18) = 4.94, p < 0.05] but not significant for locomotion. Asterisks and star show significant between-injection differences.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 1: Relative changes in NAc [glucose] induced by cocaine injections assessed at low temporal resolution (1-min bins). Top graphs (A,D,G,J) show mean ± SEM changes in relative currents (nA) detected by Glucose and Null sensors. Middle graphs (B,E,H,K) show mean ± SEM changes in [glucose] (μM) as a difference between active and sensors. Bottom graphs (C,F,I,L) show changes in locomotor activity (mean ± SEM; counts/min). Vertical hatched lines (at 0 min) marked the onset of 20-s cocaine injection. Horizontal dotted lines show basal levels (= 0 nA and μM). The difference in current dynamics between active and sensors was significant (p < 0.05) for the entire 60-min duration after each cocaine injection [Two-Way repeated measures (RM) ANOVA; Current × Time interaction F(6, 660) = 5.94, 3.03, 1.94, and 4.72, all p < 0.05 for injections 1–4, respectively]. Concentration change was also significant for each cocaine injection [F(60, 360) = 7.07, 3.63, 2.30, and 5.61, all P < 0.05 respectively]. Individual concentration values significantly different from baseline (Fisher test) are shown as filled symbols. Cocaine induced significant locomotor activation after each injection [F(12, 732) = 4.14, 5.45, 4.61, 5.20 for injections 1–4, respectively; p < 0.05]. Right panels (M,N) show differences in mean ± SEM values of glucose and locomotor responses induced by cocaine injections as assessed by area under the curve. The effect of injection number was significant for [glucose] [One-Way RM ANOVA: F(3, 18) = 4.94, p < 0.05] but not significant for locomotion. Asterisks and star show significant between-injection differences.
Mentions: When analyzed at the 1-min time-scale, the initial cocaine injection in a drug-naive rat induced a significantly different current response in the glucose and sensors [Current × Time interaction; F(6, 660) = 5.94; p < 0.05] for the entire 60-min analysis duration (Figure 1A), revealing a rapid, significant [glucose] increase from the first minute post-injection [Figure 1B; F(60, 360) = 7.07, p < 0.05]. This increase peaked at 15–20 min (~110 μM or ~11% of baseline) followed by a slow return to baseline at ~45 min post-injection. Importantly, the largest rate of [glucose] increase occurred during the first min post-injection. Cocaine also induced modest locomotor activation (Figure 1C) for ~20–30 min post-injection [F(12, 732) = 4.14, p < 0.05]. While the rise in [glucose] resulted primarily from current changes detected by glucose sensors, cocaine also induced a tonic increase in currents detected by currents; this latter change was much smaller than that recorded by glucose sensors.

Bottom Line: The pattern of neural, physiological and behavioral effects induced by cocaine is consistent with metabolic neural activation, yet direct attempts to evaluate central metabolic effects of this drug have produced controversial results.While the rapid, phasic component of the glucose response remained stable following subsequent cocaine injections, the tonic component progressively decreased.However, this analog did not induce increases in either locomotion or tonic glucose, suggesting direct central mediation of these cocaine effects.

View Article: PubMed Central - PubMed

Affiliation: Behavioral Neuroscience Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, DHHS Baltimore, MD, USA.

ABSTRACT
The pattern of neural, physiological and behavioral effects induced by cocaine is consistent with metabolic neural activation, yet direct attempts to evaluate central metabolic effects of this drug have produced controversial results. Here, we used enzyme-based glucose sensors coupled with high-speed amperometry in freely moving rats to examine how intravenous cocaine at a behaviorally active dose affects extracellular glucose levels in the nucleus accumbens (NAc), a critical structure within the motivation-reinforcement circuit. In drug-naive rats, cocaine induced a bimodal increase in glucose, with the first, ultra-fast phasic rise appearing during the injection (latency 6-8 s; ~50 μM or ~5% of baseline) followed by a larger, more prolonged tonic elevation (~100 μM or 10% of baseline, peak ~15 min). While the rapid, phasic component of the glucose response remained stable following subsequent cocaine injections, the tonic component progressively decreased. Cocaine-methiodide, cocaine's peripherally acting analog, induced an equally rapid and strong initial glucose rise, indicating cocaine's action on peripheral neural substrates as its cause. However, this analog did not induce increases in either locomotion or tonic glucose, suggesting direct central mediation of these cocaine effects. Under systemic pharmacological blockade of dopamine transmission, both phasic and tonic components of the cocaine-induced glucose response were only slightly reduced, suggesting a significant role of non-dopamine mechanisms in cocaine-induced accumbal glucose influx. Hence, intravenous cocaine induces rapid, strong inflow of glucose into NAc extracellular space by involving both peripheral and central, non-dopamine drug actions, thus preventing a possible deficit resulting from enhanced glucose use by brain cells.

No MeSH data available.


Related in: MedlinePlus