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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 full dopamine receptor antagonism 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). Bottom graphs (C,F,I,L) show mean ± SEM changes in locomotion. Vertical hatched line (0 min) marked the onset of injection. Horizontal dotted lines denote basal levels (= 0 nA and μM). The difference in current dynamics between active and  sensors was significant (p < 0.05) for the entire analysis window (59.5 min) after each cocaine injection [Current × Time interaction: F(60, 480) = 2.25, 2.83, 4.01, and 7.57, respectively, all p < 0.05] indicating a significant concentration change over the same time period for each cocaine injection [F(6, 360) = 5.64, 7.10, 10.06, and 18.95, all p < 0.05] Concentration values significantly different from baseline (Fisher test) are shown as filled symbols. Right panel (M) compares mean ± SEM glucose responses induced by cocaine injections in control conditions and during DA receptor blockade [Main effect: F(1, 54) = 9.32, Treatment × Time interaction F(60, 3240) = 4.73, both p < 0.05]. (N) shows mean ± SEM [glucose] responses induced by cocaine injections during DA receptor antagonism assessed by area under the curve [F(3, 18) = 10.53 p < 0.05]. Asterisk denotes significant differences between first and all other injections (Fisher test). (O) shows mean ± SEM locomotor responses (as area under curve); no significant between-injection changes were seen.
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Figure 6: Relative changes in NAc [glucose] induced by cocaine injections under full dopamine receptor antagonism 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). Bottom graphs (C,F,I,L) show mean ± SEM changes in locomotion. Vertical hatched line (0 min) marked the onset of injection. Horizontal dotted lines denote basal levels (= 0 nA and μM). The difference in current dynamics between active and sensors was significant (p < 0.05) for the entire analysis window (59.5 min) after each cocaine injection [Current × Time interaction: F(60, 480) = 2.25, 2.83, 4.01, and 7.57, respectively, all p < 0.05] indicating a significant concentration change over the same time period for each cocaine injection [F(6, 360) = 5.64, 7.10, 10.06, and 18.95, all p < 0.05] Concentration values significantly different from baseline (Fisher test) are shown as filled symbols. Right panel (M) compares mean ± SEM glucose responses induced by cocaine injections in control conditions and during DA receptor blockade [Main effect: F(1, 54) = 9.32, Treatment × Time interaction F(60, 3240) = 4.73, both p < 0.05]. (N) shows mean ± SEM [glucose] responses induced by cocaine injections during DA receptor antagonism assessed by area under the curve [F(3, 18) = 10.53 p < 0.05]. Asterisk denotes significant differences between first and all other injections (Fisher test). (O) shows mean ± SEM locomotor responses (as area under curve); no significant between-injection changes were seen.

Mentions: Surprisingly, DA receptor blockade that fully blocked the locomotor effects of cocaine (Figures 6C,F,I,L,O) did not block the second, tonic elevation of NAc glucose induced by cocaine (Figures 6A,B,D,E,G,H,J,K). The tonic rise in NAc [glucose] was greatest after the first cocaine injection (~100 μM), progressively decreased following subsequent injections, and was almost absent (~20 μM) after the last cocaine injection [Figure 6N; F(3, 18) = 10.53, p < 0.05]. These changes were associated with a progressive enhancement of rebound-like decreases in NAc glucose, which were atypical to cocaine in untreated conditions. A between-group comparison (Figure 6M) revealed that during DA antagonism the rise in glucose was significantly less, its levels fell more strongly below the pre-injection baseline [effect of treatment: F(1, 54) = 9.32 p < 0.05], and the response dynamics differed by a delayed onset and faster time to peak [Treatment × Time interaction F(60, 3240) = 4.73 p < 0.05].


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 full dopamine receptor antagonism 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). Bottom graphs (C,F,I,L) show mean ± SEM changes in locomotion. Vertical hatched line (0 min) marked the onset of injection. Horizontal dotted lines denote basal levels (= 0 nA and μM). The difference in current dynamics between active and  sensors was significant (p < 0.05) for the entire analysis window (59.5 min) after each cocaine injection [Current × Time interaction: F(60, 480) = 2.25, 2.83, 4.01, and 7.57, respectively, all p < 0.05] indicating a significant concentration change over the same time period for each cocaine injection [F(6, 360) = 5.64, 7.10, 10.06, and 18.95, all p < 0.05] Concentration values significantly different from baseline (Fisher test) are shown as filled symbols. Right panel (M) compares mean ± SEM glucose responses induced by cocaine injections in control conditions and during DA receptor blockade [Main effect: F(1, 54) = 9.32, Treatment × Time interaction F(60, 3240) = 4.73, both p < 0.05]. (N) shows mean ± SEM [glucose] responses induced by cocaine injections during DA receptor antagonism assessed by area under the curve [F(3, 18) = 10.53 p < 0.05]. Asterisk denotes significant differences between first and all other injections (Fisher test). (O) shows mean ± SEM locomotor responses (as area under curve); no significant between-injection changes were seen.
© Copyright Policy - open-access
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Figure 6: Relative changes in NAc [glucose] induced by cocaine injections under full dopamine receptor antagonism 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). Bottom graphs (C,F,I,L) show mean ± SEM changes in locomotion. Vertical hatched line (0 min) marked the onset of injection. Horizontal dotted lines denote basal levels (= 0 nA and μM). The difference in current dynamics between active and sensors was significant (p < 0.05) for the entire analysis window (59.5 min) after each cocaine injection [Current × Time interaction: F(60, 480) = 2.25, 2.83, 4.01, and 7.57, respectively, all p < 0.05] indicating a significant concentration change over the same time period for each cocaine injection [F(6, 360) = 5.64, 7.10, 10.06, and 18.95, all p < 0.05] Concentration values significantly different from baseline (Fisher test) are shown as filled symbols. Right panel (M) compares mean ± SEM glucose responses induced by cocaine injections in control conditions and during DA receptor blockade [Main effect: F(1, 54) = 9.32, Treatment × Time interaction F(60, 3240) = 4.73, both p < 0.05]. (N) shows mean ± SEM [glucose] responses induced by cocaine injections during DA receptor antagonism assessed by area under the curve [F(3, 18) = 10.53 p < 0.05]. Asterisk denotes significant differences between first and all other injections (Fisher test). (O) shows mean ± SEM locomotor responses (as area under curve); no significant between-injection changes were seen.
Mentions: Surprisingly, DA receptor blockade that fully blocked the locomotor effects of cocaine (Figures 6C,F,I,L,O) did not block the second, tonic elevation of NAc glucose induced by cocaine (Figures 6A,B,D,E,G,H,J,K). The tonic rise in NAc [glucose] was greatest after the first cocaine injection (~100 μM), progressively decreased following subsequent injections, and was almost absent (~20 μM) after the last cocaine injection [Figure 6N; F(3, 18) = 10.53, p < 0.05]. These changes were associated with a progressive enhancement of rebound-like decreases in NAc glucose, which were atypical to cocaine in untreated conditions. A between-group comparison (Figure 6M) revealed that during DA antagonism the rise in glucose was significantly less, its levels fell more strongly below the pre-injection baseline [effect of treatment: F(1, 54) = 9.32 p < 0.05], and the response dynamics differed by a delayed onset and faster time to peak [Treatment × Time interaction F(60, 3240) = 4.73 p < 0.05].

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