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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 under conditions of full dopamine receptor blockade 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 injection. Horizontal dotted lines show basal levels (= 0 nA and μM). The difference in current dynamics between Glucose and Null sensors was significant after each cocaine injection (A 1: Glucose/Null [25 s F(1, 8) = 5.89], interaction [21 s F(10, 80) = 2.24]; C 2, E 3, G 4: interaction [180 s, F(90, 720) = 1.41, 1.28, 1.30, respectively] all p < 0.05. [Glucose] change was also significant for each cocaine injection [F(6, 540) = 2.56, 3.53, 3.11, 3.62, respectively all p < 0.05] Concentration values significantly different from baseline (Fisher test) are shown as filled symbols. (I) shows significant differences in mean ± SEM glucose responses (area under curve) induced by four cocaine injections during DA receptor antagonism [F(3, 18) = 6.62 p < 0.05]. Asterisk denotes significant (p < 0.05) differences between the 4th injection and all others (Fisher test). (J) shows significant differences in [glucose] between cocaine and cocaine-methiodide groups for the entire analysis window [Main effect: F(1, 54) = 5.16, Treatment × Time interaction: F(90, 4860) both p < 0.05] assessed for all drug injections.
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Figure 5: Relative changes in NAc [glucose] induced by cocaine injections under conditions of full dopamine receptor blockade 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 injection. Horizontal dotted lines show basal levels (= 0 nA and μM). The difference in current dynamics between Glucose and Null sensors was significant after each cocaine injection (A 1: Glucose/Null [25 s F(1, 8) = 5.89], interaction [21 s F(10, 80) = 2.24]; C 2, E 3, G 4: interaction [180 s, F(90, 720) = 1.41, 1.28, 1.30, respectively] all p < 0.05. [Glucose] change was also significant for each cocaine injection [F(6, 540) = 2.56, 3.53, 3.11, 3.62, respectively all p < 0.05] Concentration values significantly different from baseline (Fisher test) are shown as filled symbols. (I) shows significant differences in mean ± SEM glucose responses (area under curve) induced by four cocaine injections during DA receptor antagonism [F(3, 18) = 6.62 p < 0.05]. Asterisk denotes significant (p < 0.05) differences between the 4th injection and all others (Fisher test). (J) shows significant differences in [glucose] between cocaine and cocaine-methiodide groups for the entire analysis window [Main effect: F(1, 54) = 5.16, Treatment × Time interaction: F(90, 4860) both p < 0.05] assessed for all drug injections.

Mentions: When analyzed at a second-scale resolution (Figure 5), DA receptor blockade did not eliminate the first, rapid component of the cocaine-induced NAc glucose response (Figures 5A–H). Similar to untreated conditions, this immediate effect also showed progressive tolerance following repeated cocaine injections [Figure 5I; F(3, 18) = 6.62 p < 0.05]. The overall glucose response to cocaine during DA receptor blockade was weaker than that with cocaine in untreated conditions and cocaine methiodide [effect of drug F(2, 17) = 5.30 p < 0.05]. While the time-course of the cocaine-induced glucose rise was initially identical in both groups, the peak magnitude during DA antagonism was lower, and was followed by a more pronounced negative rebound (Figures 5D,F,H,I,J).


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 under conditions of full dopamine receptor blockade 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 injection. Horizontal dotted lines show basal levels (= 0 nA and μM). The difference in current dynamics between Glucose and Null sensors was significant after each cocaine injection (A 1: Glucose/Null [25 s F(1, 8) = 5.89], interaction [21 s F(10, 80) = 2.24]; C 2, E 3, G 4: interaction [180 s, F(90, 720) = 1.41, 1.28, 1.30, respectively] all p < 0.05. [Glucose] change was also significant for each cocaine injection [F(6, 540) = 2.56, 3.53, 3.11, 3.62, respectively all p < 0.05] Concentration values significantly different from baseline (Fisher test) are shown as filled symbols. (I) shows significant differences in mean ± SEM glucose responses (area under curve) induced by four cocaine injections during DA receptor antagonism [F(3, 18) = 6.62 p < 0.05]. Asterisk denotes significant (p < 0.05) differences between the 4th injection and all others (Fisher test). (J) shows significant differences in [glucose] between cocaine and cocaine-methiodide groups for the entire analysis window [Main effect: F(1, 54) = 5.16, Treatment × Time interaction: F(90, 4860) both p < 0.05] assessed for all drug injections.
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Show All Figures
getmorefigures.php?uid=PMC4325903&req=5

Figure 5: Relative changes in NAc [glucose] induced by cocaine injections under conditions of full dopamine receptor blockade 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 injection. Horizontal dotted lines show basal levels (= 0 nA and μM). The difference in current dynamics between Glucose and Null sensors was significant after each cocaine injection (A 1: Glucose/Null [25 s F(1, 8) = 5.89], interaction [21 s F(10, 80) = 2.24]; C 2, E 3, G 4: interaction [180 s, F(90, 720) = 1.41, 1.28, 1.30, respectively] all p < 0.05. [Glucose] change was also significant for each cocaine injection [F(6, 540) = 2.56, 3.53, 3.11, 3.62, respectively all p < 0.05] Concentration values significantly different from baseline (Fisher test) are shown as filled symbols. (I) shows significant differences in mean ± SEM glucose responses (area under curve) induced by four cocaine injections during DA receptor antagonism [F(3, 18) = 6.62 p < 0.05]. Asterisk denotes significant (p < 0.05) differences between the 4th injection and all others (Fisher test). (J) shows significant differences in [glucose] between cocaine and cocaine-methiodide groups for the entire analysis window [Main effect: F(1, 54) = 5.16, Treatment × Time interaction: F(90, 4860) both p < 0.05] assessed for all drug injections.
Mentions: When analyzed at a second-scale resolution (Figure 5), DA receptor blockade did not eliminate the first, rapid component of the cocaine-induced NAc glucose response (Figures 5A–H). Similar to untreated conditions, this immediate effect also showed progressive tolerance following repeated cocaine injections [Figure 5I; F(3, 18) = 6.62 p < 0.05]. The overall glucose response to cocaine during DA receptor blockade was weaker than that with cocaine in untreated conditions and cocaine methiodide [effect of drug F(2, 17) = 5.30 p < 0.05]. While the time-course of the cocaine-induced glucose rise was initially identical in both groups, the peak magnitude during DA antagonism was lower, and was followed by a more pronounced negative rebound (Figures 5D,F,H,I,J).

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