Limits...
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

Rapid changes in NAc [glucose] induced by saline injection (A,D) and exposure to a brief auditory stimulus (B,E) and a novel object (C,F). Top graphs show changes in Glucose and Null currents and bottom graphs show resulting changes in glucose concentration. Saline injections resulted in a significant difference in current dynamics (p < 0.05) for the entire analysis window [180 s; Interaction: F(90, 2430) = 1.94 p < 0.05] indicating a significant decrease in glucose after the injection [F(18, 1620) = 3.773 p < 0.05]. Concentration values significantly different from baseline (Fisher test) are shown as filled symbols. A brief audio stimulus and a novel object induced rapid and dynamic differences in Glucose and Null currents [Audio Stimulus, 129 s; Interaction F(65, 1690) = 1.95; Novel object, 180 s; Interaction F(90, 2070) = 4.34, both p < 0.05], revealing highly phasic glucose changes over the entire analysis window [Audio Stimulus, F(18, 1620) = 2.41; Novel object, F(18, 1620) = 14.85, both p < 0.05].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4325903&req=5

Figure 7: Rapid changes in NAc [glucose] induced by saline injection (A,D) and exposure to a brief auditory stimulus (B,E) and a novel object (C,F). Top graphs show changes in Glucose and Null currents and bottom graphs show resulting changes in glucose concentration. Saline injections resulted in a significant difference in current dynamics (p < 0.05) for the entire analysis window [180 s; Interaction: F(90, 2430) = 1.94 p < 0.05] indicating a significant decrease in glucose after the injection [F(18, 1620) = 3.773 p < 0.05]. Concentration values significantly different from baseline (Fisher test) are shown as filled symbols. A brief audio stimulus and a novel object induced rapid and dynamic differences in Glucose and Null currents [Audio Stimulus, 129 s; Interaction F(65, 1690) = 1.95; Novel object, 180 s; Interaction F(90, 2070) = 4.34, both p < 0.05], revealing highly phasic glucose changes over the entire analysis window [Audio Stimulus, F(18, 1620) = 2.41; Novel object, F(18, 1620) = 14.85, both p < 0.05].

Mentions: During each experiment, we also examined drug-free glucose responses induced by two sensory stimuli (a brief auditory stimulus and 1-min exposure to a novel object) and one or two injections of saline (Figure 7). The brief auditory stimulus induced a very rapid but short-lived difference in active and currents [Figure 7B; 129 s, current × time: F(65, 1690) = 1.95, p < 0.05] reflecting a rise of NAc [glucose] [Figure 7E: F(18, 1620) = 2.41, p < 0.05] that became significant within the first 2–4 s after the stimulus onset. After peaking at 5–7 s (15–20 μM), [glucose] decreased gradually below the pre-stimulus baseline. A similarly rapid but stronger and more prolonged difference in active and currents was found after the introduction of a novel object into the cage [Figure 7C; F(90, 2070) = 4.34, p < 0.05]. This difference indicated a dynamic elevation in [glucose] [Figure 7F; F(18, 1620) = 14.9 p < 0.05], which peaked at 10–20 s (~30 μM), remained elevated within the test, and showed an additional, weaker peak when the novel object was removed from the cage. In contrast to both sensory stimuli, stress- and cue-free iv injection of saline failed to induce significant changes in NAc glucose (Figures 7A,D).


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

Wakabayashi KT, Kiyatkin EA - Front Neurosci (2015)

Rapid changes in NAc [glucose] induced by saline injection (A,D) and exposure to a brief auditory stimulus (B,E) and a novel object (C,F). Top graphs show changes in Glucose and Null currents and bottom graphs show resulting changes in glucose concentration. Saline injections resulted in a significant difference in current dynamics (p < 0.05) for the entire analysis window [180 s; Interaction: F(90, 2430) = 1.94 p < 0.05] indicating a significant decrease in glucose after the injection [F(18, 1620) = 3.773 p < 0.05]. Concentration values significantly different from baseline (Fisher test) are shown as filled symbols. A brief audio stimulus and a novel object induced rapid and dynamic differences in Glucose and Null currents [Audio Stimulus, 129 s; Interaction F(65, 1690) = 1.95; Novel object, 180 s; Interaction F(90, 2070) = 4.34, both p < 0.05], revealing highly phasic glucose changes over the entire analysis window [Audio Stimulus, F(18, 1620) = 2.41; Novel object, F(18, 1620) = 14.85, both p < 0.05].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Rapid changes in NAc [glucose] induced by saline injection (A,D) and exposure to a brief auditory stimulus (B,E) and a novel object (C,F). Top graphs show changes in Glucose and Null currents and bottom graphs show resulting changes in glucose concentration. Saline injections resulted in a significant difference in current dynamics (p < 0.05) for the entire analysis window [180 s; Interaction: F(90, 2430) = 1.94 p < 0.05] indicating a significant decrease in glucose after the injection [F(18, 1620) = 3.773 p < 0.05]. Concentration values significantly different from baseline (Fisher test) are shown as filled symbols. A brief audio stimulus and a novel object induced rapid and dynamic differences in Glucose and Null currents [Audio Stimulus, 129 s; Interaction F(65, 1690) = 1.95; Novel object, 180 s; Interaction F(90, 2070) = 4.34, both p < 0.05], revealing highly phasic glucose changes over the entire analysis window [Audio Stimulus, F(18, 1620) = 2.41; Novel object, F(18, 1620) = 14.85, both p < 0.05].
Mentions: During each experiment, we also examined drug-free glucose responses induced by two sensory stimuli (a brief auditory stimulus and 1-min exposure to a novel object) and one or two injections of saline (Figure 7). The brief auditory stimulus induced a very rapid but short-lived difference in active and currents [Figure 7B; 129 s, current × time: F(65, 1690) = 1.95, p < 0.05] reflecting a rise of NAc [glucose] [Figure 7E: F(18, 1620) = 2.41, p < 0.05] that became significant within the first 2–4 s after the stimulus onset. After peaking at 5–7 s (15–20 μM), [glucose] decreased gradually below the pre-stimulus baseline. A similarly rapid but stronger and more prolonged difference in active and currents was found after the introduction of a novel object into the cage [Figure 7C; F(90, 2070) = 4.34, p < 0.05]. This difference indicated a dynamic elevation in [glucose] [Figure 7F; F(18, 1620) = 14.9 p < 0.05], which peaked at 10–20 s (~30 μM), remained elevated within the test, and showed an additional, weaker peak when the novel object was removed from the cage. In contrast to both sensory stimuli, stress- and cue-free iv injection of saline failed to induce significant changes in NAc glucose (Figures 7A,D).

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