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

Relative changes in NAc [glucose] induced by cocaine-methiodide 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 Glucose and Null sensors. Two vertical hatched lines (at 0 and 20) marked the onset and offset of the 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 180-s duration after each cocaine injection (A 1: Glucose/Null [F(1, 9) = 6.69], interaction [F(91, 819) = 3.60]; C 2: Glucose/Null [F(1, 9) = 26.6], interaction [F(91, 819) = 2.23]; E 3: Glucose/Null [F(1, 9) = 1.85], interaction [F(91, 819) = 4.03]; G 4: interaction [F(91, 819) = 2.33], all p < 0.05]. Concentration change was also significant for each cocaine injection for the entire analysis window [F(5, 445) = 4.28, 2.74, 5.01, and 2.95, all p < 0.05]. Individual values significantly different from baseline (Fisher test) are shown as filled symbols. Right panel (I) shows mean ± SEM v glucose responses assessed by area under the curve (n.s.). Right panel (J) compares the mean glucose response between the cocaine and cocaine-methiodide group; no significant differences found.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Relative changes in NAc [glucose] induced by cocaine-methiodide 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 Glucose and Null sensors. Two vertical hatched lines (at 0 and 20) marked the onset and offset of the 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 180-s duration after each cocaine injection (A 1: Glucose/Null [F(1, 9) = 6.69], interaction [F(91, 819) = 3.60]; C 2: Glucose/Null [F(1, 9) = 26.6], interaction [F(91, 819) = 2.23]; E 3: Glucose/Null [F(1, 9) = 1.85], interaction [F(91, 819) = 4.03]; G 4: interaction [F(91, 819) = 2.33], all p < 0.05]. Concentration change was also significant for each cocaine injection for the entire analysis window [F(5, 445) = 4.28, 2.74, 5.01, and 2.95, all p < 0.05]. Individual values significantly different from baseline (Fisher test) are shown as filled symbols. Right panel (I) shows mean ± SEM v glucose responses assessed by area under the curve (n.s.). Right panel (J) compares the mean glucose response between the cocaine and cocaine-methiodide group; no significant differences found.

Mentions: When injected at an equimolar dose (Figure 3) cocaine-methiodide induced highly rapid increases in the glucose current while having a minimal influence on the current when all four injections were analyzed at second-scale resolution (Figures 3A,C,E,G). The differences between these currents revealed significant increases in [glucose] during and immediately after each drug injection (Figures 3B,D,F,H). However, these changes differed from those seen with regular cocaine. While the rapid effects of cocaine-methiodide were very similar to cocaine in their time-course, magnitude and tendency to show a slight tolerance for ~30 s after the injection onset (Figure 3I), cocaine-methiodide always induced an unimodal, phasic increases with no evidence of a second, tonic rise seen most clearly during the first cocaine injection. When compared as an average for all injections in cocaine and cocaine-methiode groups (Figure 3J), the time-course of changes was surprisingly similar with no statistical differences between groups.


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-methiodide 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 Glucose and Null sensors. Two vertical hatched lines (at 0 and 20) marked the onset and offset of the 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 180-s duration after each cocaine injection (A 1: Glucose/Null [F(1, 9) = 6.69], interaction [F(91, 819) = 3.60]; C 2: Glucose/Null [F(1, 9) = 26.6], interaction [F(91, 819) = 2.23]; E 3: Glucose/Null [F(1, 9) = 1.85], interaction [F(91, 819) = 4.03]; G 4: interaction [F(91, 819) = 2.33], all p < 0.05]. Concentration change was also significant for each cocaine injection for the entire analysis window [F(5, 445) = 4.28, 2.74, 5.01, and 2.95, all p < 0.05]. Individual values significantly different from baseline (Fisher test) are shown as filled symbols. Right panel (I) shows mean ± SEM v glucose responses assessed by area under the curve (n.s.). Right panel (J) compares the mean glucose response between the cocaine and cocaine-methiodide group; no significant differences found.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Relative changes in NAc [glucose] induced by cocaine-methiodide 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 Glucose and Null sensors. Two vertical hatched lines (at 0 and 20) marked the onset and offset of the 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 180-s duration after each cocaine injection (A 1: Glucose/Null [F(1, 9) = 6.69], interaction [F(91, 819) = 3.60]; C 2: Glucose/Null [F(1, 9) = 26.6], interaction [F(91, 819) = 2.23]; E 3: Glucose/Null [F(1, 9) = 1.85], interaction [F(91, 819) = 4.03]; G 4: interaction [F(91, 819) = 2.33], all p < 0.05]. Concentration change was also significant for each cocaine injection for the entire analysis window [F(5, 445) = 4.28, 2.74, 5.01, and 2.95, all p < 0.05]. Individual values significantly different from baseline (Fisher test) are shown as filled symbols. Right panel (I) shows mean ± SEM v glucose responses assessed by area under the curve (n.s.). Right panel (J) compares the mean glucose response between the cocaine and cocaine-methiodide group; no significant differences found.
Mentions: When injected at an equimolar dose (Figure 3) cocaine-methiodide induced highly rapid increases in the glucose current while having a minimal influence on the current when all four injections were analyzed at second-scale resolution (Figures 3A,C,E,G). The differences between these currents revealed significant increases in [glucose] during and immediately after each drug injection (Figures 3B,D,F,H). However, these changes differed from those seen with regular cocaine. While the rapid effects of cocaine-methiodide were very similar to cocaine in their time-course, magnitude and tendency to show a slight tolerance for ~30 s after the injection onset (Figure 3I), cocaine-methiodide always induced an unimodal, phasic increases with no evidence of a second, tonic rise seen most clearly during the first cocaine injection. When compared as an average for all injections in cocaine and cocaine-methiode groups (Figure 3J), the time-course of changes was surprisingly similar with no statistical differences between groups.

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