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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 injections of cocaine-methiodide 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 Glucose and Null 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 drug injection. Horizontal dotted lines show basal levels (= 0 nA and μM). There were significant differences in Glucose and Null currents for the first three injections (A 1: interaction [59.5 min, F(60, 540) = 2.64]; D 2: Glucose/Null [10.5 min F(1, 9) = 5.72], interaction [3.5 min F(4, 36) = 2.91]; G 3: Glucose/Null [59.5 min F(1, 9) = 6.08], interaction [2.5 min F(3, 27) = 3.08], all p < 0.05), and no changes for injection 4. This resulted in significant changes in glucose concentration after the first [F(60, 300) = 3.83] and third injection [F(60, 300) = 1.49, both p < 0.05] for the entire analysis window. Individual concentration values significantly different from baseline (Fisher test) are shown as filled symbols. (M) shows significant differences in mean ± SEM glucose responses to cocaine and cocaine methiodide [mean of 4 injections; Main effect F(1, 50) = 5.89, Drug × Time interaction F(60, 3000) = 8.20, both p < 0.05]. (N,O) show mean ± SEM glucose and locomotor responses induced by cocaine-methiodide injections as assessed by area under the curve (both n.s.).
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Figure 4: Relative changes in NAc [glucose] induced by injections of cocaine-methiodide 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 Glucose and Null 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 drug injection. Horizontal dotted lines show basal levels (= 0 nA and μM). There were significant differences in Glucose and Null currents for the first three injections (A 1: interaction [59.5 min, F(60, 540) = 2.64]; D 2: Glucose/Null [10.5 min F(1, 9) = 5.72], interaction [3.5 min F(4, 36) = 2.91]; G 3: Glucose/Null [59.5 min F(1, 9) = 6.08], interaction [2.5 min F(3, 27) = 3.08], all p < 0.05), and no changes for injection 4. This resulted in significant changes in glucose concentration after the first [F(60, 300) = 3.83] and third injection [F(60, 300) = 1.49, both p < 0.05] for the entire analysis window. Individual concentration values significantly different from baseline (Fisher test) are shown as filled symbols. (M) shows significant differences in mean ± SEM glucose responses to cocaine and cocaine methiodide [mean of 4 injections; Main effect F(1, 50) = 5.89, Drug × Time interaction F(60, 3000) = 8.20, both p < 0.05]. (N,O) show mean ± SEM glucose and locomotor responses induced by cocaine-methiodide injections as assessed by area under the curve (both n.s.).

Mentions: The lack of a tonic effect can be seen even more clearly at the 1-min time scale (Figure 4), where cocaine-methiodide induced changes in the glucose current relative to the current for only the first three injections (Figures 4A,D,G,J), and only showed relatively clear changes in [glucose] during the first injection [Figure 4B; F(60, 300) = 3.83 p < 0.05]. Unlike regular cocaine, this increase in [glucose] in this case was transient (13–15 min) and was followed by a strong decrease below the pre-injection baseline. The lack of a tonic rise contributed to an overall much lower [glucose] response assessed as an area under the curve (Figure 4N). When the averages for all injections were compared for cocaine and cocaine-methiodide groups (Figure 4M), both drugs induced identical NAc [glucose] changes for the first post-injection minute, and thereafter these changes drastically differed from each other. Consistent with our previous findings (Brown and Kiyatkin, 2006; Wakabayashi and Kiyatkin, 2014), cocaine-methiodide induced only minimal increases in locomotion during and immediately after the injection (Figures 4C,F,I,L,O).


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 injections of cocaine-methiodide 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 Glucose and Null 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 drug injection. Horizontal dotted lines show basal levels (= 0 nA and μM). There were significant differences in Glucose and Null currents for the first three injections (A 1: interaction [59.5 min, F(60, 540) = 2.64]; D 2: Glucose/Null [10.5 min F(1, 9) = 5.72], interaction [3.5 min F(4, 36) = 2.91]; G 3: Glucose/Null [59.5 min F(1, 9) = 6.08], interaction [2.5 min F(3, 27) = 3.08], all p < 0.05), and no changes for injection 4. This resulted in significant changes in glucose concentration after the first [F(60, 300) = 3.83] and third injection [F(60, 300) = 1.49, both p < 0.05] for the entire analysis window. Individual concentration values significantly different from baseline (Fisher test) are shown as filled symbols. (M) shows significant differences in mean ± SEM glucose responses to cocaine and cocaine methiodide [mean of 4 injections; Main effect F(1, 50) = 5.89, Drug × Time interaction F(60, 3000) = 8.20, both p < 0.05]. (N,O) show mean ± SEM glucose and locomotor responses induced by cocaine-methiodide injections as assessed by area under the curve (both n.s.).
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Related In: Results  -  Collection

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Show All Figures
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Figure 4: Relative changes in NAc [glucose] induced by injections of cocaine-methiodide 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 Glucose and Null 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 drug injection. Horizontal dotted lines show basal levels (= 0 nA and μM). There were significant differences in Glucose and Null currents for the first three injections (A 1: interaction [59.5 min, F(60, 540) = 2.64]; D 2: Glucose/Null [10.5 min F(1, 9) = 5.72], interaction [3.5 min F(4, 36) = 2.91]; G 3: Glucose/Null [59.5 min F(1, 9) = 6.08], interaction [2.5 min F(3, 27) = 3.08], all p < 0.05), and no changes for injection 4. This resulted in significant changes in glucose concentration after the first [F(60, 300) = 3.83] and third injection [F(60, 300) = 1.49, both p < 0.05] for the entire analysis window. Individual concentration values significantly different from baseline (Fisher test) are shown as filled symbols. (M) shows significant differences in mean ± SEM glucose responses to cocaine and cocaine methiodide [mean of 4 injections; Main effect F(1, 50) = 5.89, Drug × Time interaction F(60, 3000) = 8.20, both p < 0.05]. (N,O) show mean ± SEM glucose and locomotor responses induced by cocaine-methiodide injections as assessed by area under the curve (both n.s.).
Mentions: The lack of a tonic effect can be seen even more clearly at the 1-min time scale (Figure 4), where cocaine-methiodide induced changes in the glucose current relative to the current for only the first three injections (Figures 4A,D,G,J), and only showed relatively clear changes in [glucose] during the first injection [Figure 4B; F(60, 300) = 3.83 p < 0.05]. Unlike regular cocaine, this increase in [glucose] in this case was transient (13–15 min) and was followed by a strong decrease below the pre-injection baseline. The lack of a tonic rise contributed to an overall much lower [glucose] response assessed as an area under the curve (Figure 4N). When the averages for all injections were compared for cocaine and cocaine-methiodide groups (Figure 4M), both drugs induced identical NAc [glucose] changes for the first post-injection minute, and thereafter these changes drastically differed from each other. Consistent with our previous findings (Brown and Kiyatkin, 2006; Wakabayashi and Kiyatkin, 2014), cocaine-methiodide induced only minimal increases in locomotion during and immediately after the injection (Figures 4C,F,I,L,O).

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