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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 high temporal resolution (2-s bins). Top graphs (A,C,E,G) show mean ± SEM changes in relative currents (nA) detected by Glucose and Null sensors. Bottom graphs (B,D,F,H) show mean ± SEM changes in [glucose] (μM) as a difference between active and  sensors. Two vertical hatched lines (at 0 and 20) marked the onset and offset injection. Horizontal dotted lines show basal levels (= 0 nA and μM). After cocaine injections, the Glucose and Null currents differed significantly (A 1: Glucose/Null [180 s, F(1, 11) = 6.97], interaction [180 s, F(90, 990) = 2.88]; C 2: Interaction [180 s, F(90, 990) = 1.44]; E 3: Glucose/Null [180 s, F(1, 11) = 8.31], interaction [153.5 s, F(77, 847) = 1.31]; G 4: Glucose/Null [47.5 s, F(1, 11) = 4.69], interaction [180s, F(90, 990) = 3.58], all p < 0.05), resulting in a significant [glucose] change for each cocaine injection during the entire analysis window [F(6, 546) = 3.47, 1.69, 1.37, and 4.31, all p < 0.05]. Concentration values significantly different from baseline (Fisher test) are shown as filled symbols. Right panel (I) shows mean ± SEM values of glucose responses induced by cocaine injections assessed by area under the curve for 30 s after the injection onset (n.s.).
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Figure 2: Relative changes in NAc [glucose] induced by cocaine injections assessed at high temporal resolution (2-s bins). Top graphs (A,C,E,G) show mean ± SEM changes in relative currents (nA) detected by Glucose and Null sensors. Bottom graphs (B,D,F,H) show mean ± SEM changes in [glucose] (μM) as a difference between active and sensors. Two vertical hatched lines (at 0 and 20) marked the onset and offset injection. Horizontal dotted lines show basal levels (= 0 nA and μM). After cocaine injections, the Glucose and Null currents differed significantly (A 1: Glucose/Null [180 s, F(1, 11) = 6.97], interaction [180 s, F(90, 990) = 2.88]; C 2: Interaction [180 s, F(90, 990) = 1.44]; E 3: Glucose/Null [180 s, F(1, 11) = 8.31], interaction [153.5 s, F(77, 847) = 1.31]; G 4: Glucose/Null [47.5 s, F(1, 11) = 4.69], interaction [180s, F(90, 990) = 3.58], all p < 0.05), resulting in a significant [glucose] change for each cocaine injection during the entire analysis window [F(6, 546) = 3.47, 1.69, 1.37, and 4.31, all p < 0.05]. Concentration values significantly different from baseline (Fisher test) are shown as filled symbols. Right panel (I) shows mean ± SEM values of glucose responses induced by cocaine injections assessed by area under the curve for 30 s after the injection onset (n.s.).

Mentions: When analyzed at the second scale (Figure 2; 2-s bins, 180-s analysis window), we found significant differences between glucose and currents after all cocaine injections (Figures 2A,C,E,G; see statistical details in figure legends), indicating a rapid increase in [glucose] during each drug injection (Figures 2B,D,F,H). This rise peaked near the end of the injection (20–50 μM or a 3–7% increase) and began to fall thereafter. Immediately after the first injection (Figure 2A), this post-injection decrease was minimal before the onset of the second, slower increase clearly seen in the longer 60-min analysis window (see Figure 1A). However, during each subsequent injection the onset of this second rise was weaker and delayed, revealing a gap distinguishing the rapid and slow components of the glucose response to cocaine (Figures 2D,F,H). The rapid initial rise was relatively stable after each cocaine injection, but showed a tendency to decrease in magnitude and duration (Figure 2I).


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 high temporal resolution (2-s bins). Top graphs (A,C,E,G) show mean ± SEM changes in relative currents (nA) detected by Glucose and Null sensors. Bottom graphs (B,D,F,H) show mean ± SEM changes in [glucose] (μM) as a difference between active and  sensors. Two vertical hatched lines (at 0 and 20) marked the onset and offset injection. Horizontal dotted lines show basal levels (= 0 nA and μM). After cocaine injections, the Glucose and Null currents differed significantly (A 1: Glucose/Null [180 s, F(1, 11) = 6.97], interaction [180 s, F(90, 990) = 2.88]; C 2: Interaction [180 s, F(90, 990) = 1.44]; E 3: Glucose/Null [180 s, F(1, 11) = 8.31], interaction [153.5 s, F(77, 847) = 1.31]; G 4: Glucose/Null [47.5 s, F(1, 11) = 4.69], interaction [180s, F(90, 990) = 3.58], all p < 0.05), resulting in a significant [glucose] change for each cocaine injection during the entire analysis window [F(6, 546) = 3.47, 1.69, 1.37, and 4.31, all p < 0.05]. Concentration values significantly different from baseline (Fisher test) are shown as filled symbols. Right panel (I) shows mean ± SEM values of glucose responses induced by cocaine injections assessed by area under the curve for 30 s after the injection onset (n.s.).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4325903&req=5

Figure 2: Relative changes in NAc [glucose] induced by cocaine injections assessed at high temporal resolution (2-s bins). Top graphs (A,C,E,G) show mean ± SEM changes in relative currents (nA) detected by Glucose and Null sensors. Bottom graphs (B,D,F,H) show mean ± SEM changes in [glucose] (μM) as a difference between active and sensors. Two vertical hatched lines (at 0 and 20) marked the onset and offset injection. Horizontal dotted lines show basal levels (= 0 nA and μM). After cocaine injections, the Glucose and Null currents differed significantly (A 1: Glucose/Null [180 s, F(1, 11) = 6.97], interaction [180 s, F(90, 990) = 2.88]; C 2: Interaction [180 s, F(90, 990) = 1.44]; E 3: Glucose/Null [180 s, F(1, 11) = 8.31], interaction [153.5 s, F(77, 847) = 1.31]; G 4: Glucose/Null [47.5 s, F(1, 11) = 4.69], interaction [180s, F(90, 990) = 3.58], all p < 0.05), resulting in a significant [glucose] change for each cocaine injection during the entire analysis window [F(6, 546) = 3.47, 1.69, 1.37, and 4.31, all p < 0.05]. Concentration values significantly different from baseline (Fisher test) are shown as filled symbols. Right panel (I) shows mean ± SEM values of glucose responses induced by cocaine injections assessed by area under the curve for 30 s after the injection onset (n.s.).
Mentions: When analyzed at the second scale (Figure 2; 2-s bins, 180-s analysis window), we found significant differences between glucose and currents after all cocaine injections (Figures 2A,C,E,G; see statistical details in figure legends), indicating a rapid increase in [glucose] during each drug injection (Figures 2B,D,F,H). This rise peaked near the end of the injection (20–50 μM or a 3–7% increase) and began to fall thereafter. Immediately after the first injection (Figure 2A), this post-injection decrease was minimal before the onset of the second, slower increase clearly seen in the longer 60-min analysis window (see Figure 1A). However, during each subsequent injection the onset of this second rise was weaker and delayed, revealing a gap distinguishing the rapid and slow components of the glucose response to cocaine (Figures 2D,F,H). The rapid initial rise was relatively stable after each cocaine injection, but showed a tendency to decrease in magnitude and duration (Figure 2I).

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