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Methylenedioxypyrovalerone (MDPV) mimics cocaine in its physiological and behavioral effects but induces distinct changes in NAc glucose.

Wakabayashi KT, Ren SE, Kiyatkin EA - Front Neurosci (2015)

Bottom Line: Using enzyme-based glucose sensors coupled with amperometery in freely moving rats, we found that MDPV tonically decreases NAc glucose levels, a response that is opposite to what we previously observed with cocaine.By analyzing Skin-Muscle temperature differentials, a valid measure of skin vascular tone, we found that MDPV induces vasoconstriction; a similar effect at the level of cerebral vessels could be responsible for the MDPV-induced decrease in NAc glucose.While cocaine also induced comparable, if not slightly stronger peripheral vasoconstriction, this effect was overpowered by local neural activity-induced vasodilation, resulting in rapid surge in NAc glucose.

View Article: PubMed Central - PubMed

Affiliation: In-Vivo Electrophysiology Unit, Behavioral Neuroscience Branch, National Institute on Drug Abuse - Intramural Research Program, Department of Health and Human Services, National Institutes of Health Baltimore, MD, USA.

ABSTRACT
Methylenedioxypyrovalerone (MDPV) is generally considered to be a more potent cocaine-like psychostimulant, as it shares a similar pharmacological profile with cocaine and induces similar physiological and locomotor responses. Recently, we showed that intravenous cocaine induces rapid rise in nucleus accumbens (NAc) glucose and established its relation to neural activation triggered by the peripheral drug actions. This study was conducted to find out whether MDPV, at a behaviorally equivalent dose, shares a similar pattern of NAc glucose dynamics. Using enzyme-based glucose sensors coupled with amperometery in freely moving rats, we found that MDPV tonically decreases NAc glucose levels, a response that is opposite to what we previously observed with cocaine. By analyzing Skin-Muscle temperature differentials, a valid measure of skin vascular tone, we found that MDPV induces vasoconstriction; a similar effect at the level of cerebral vessels could be responsible for the MDPV-induced decrease in NAc glucose. While cocaine also induced comparable, if not slightly stronger peripheral vasoconstriction, this effect was overpowered by local neural activity-induced vasodilation, resulting in rapid surge in NAc glucose. These results imply that cocaine-users may be more susceptible to addiction than MDPV-users due to the presence of an interoceptive signal (i.e., sensory cue), which may result in earlier and more direct reward detection. Additionally, while health complications arising from acute cocaine use are typically cardiovascular related, MDPV may be more dangerous to the brain due to uncompensated cerebral vasoconstriction.

No MeSH data available.


Related in: MedlinePlus

Relative changes in NAc [glucose] and locomotion induced by MDPV and cocaine injections (1–4) assessed at low temporal resolution (1-min bins). (A–D), The mean (±SEM) change in NAc [glucose] (μM) induced by MDPV (red circles) and cocaine (gray circles) for 60 min post-injection. (E–H), changes in locomotor activity (mean ± SEM; counts/min). Vertical hatched lines (at 0 min) marked the onset of 20-s injections of MDPV and cocaine. Horizontal dotted lines show basal levels (=0 μM). Concentration changes for the 60 min analysis window were significant for each MDPV [One-Way RM ANOVA, F(7, 420) = 2.63, 1.78, 1.48, and 3.54, all p < 0.05, respectively] and cocaine injection [F(6, 360) = 7.07, 3.63, 2.30, and 5.61]. Individual values significantly different from baseline (p < 0.05 Fisher test) are shown as filled symbols. MDPV induced significant locomotor activation after each injection [F(11, 671) = 2.06, 3.05, 3.80, 2.59 for injections 1–4, respectively; p < 0.05, for clarity post-hoc test results not shown]. Right panels (I,J) show mean ± SEM values of glucose and locomotor responses induced by MDPV and cocaine as assessed by the area under the curve for 45 min post-injection. Two-Way RM ANOVA analysis revealed a main effect of drug [F(1, 39) = 11.09, p < 0.05] and Injection [F(3, 39) = 3.28, p < 0.05] on NAc glucose. Interaction was not significant. Asterisks show significant between-drug differences. The effect of injection number on glucose response alone was not significant for both MDPV and cocaine (One-Way RM ANOVA). Overall locomotor responses during this time period showed no significant differences between drugs or injection numbers. Original cocaine data were previously reported in detail (Wakabayashi and Kiyatkin, 2015a) and shown here for comparison.
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Figure 2: Relative changes in NAc [glucose] and locomotion induced by MDPV and cocaine injections (1–4) assessed at low temporal resolution (1-min bins). (A–D), The mean (±SEM) change in NAc [glucose] (μM) induced by MDPV (red circles) and cocaine (gray circles) for 60 min post-injection. (E–H), changes in locomotor activity (mean ± SEM; counts/min). Vertical hatched lines (at 0 min) marked the onset of 20-s injections of MDPV and cocaine. Horizontal dotted lines show basal levels (=0 μM). Concentration changes for the 60 min analysis window were significant for each MDPV [One-Way RM ANOVA, F(7, 420) = 2.63, 1.78, 1.48, and 3.54, all p < 0.05, respectively] and cocaine injection [F(6, 360) = 7.07, 3.63, 2.30, and 5.61]. Individual values significantly different from baseline (p < 0.05 Fisher test) are shown as filled symbols. MDPV induced significant locomotor activation after each injection [F(11, 671) = 2.06, 3.05, 3.80, 2.59 for injections 1–4, respectively; p < 0.05, for clarity post-hoc test results not shown]. Right panels (I,J) show mean ± SEM values of glucose and locomotor responses induced by MDPV and cocaine as assessed by the area under the curve for 45 min post-injection. Two-Way RM ANOVA analysis revealed a main effect of drug [F(1, 39) = 11.09, p < 0.05] and Injection [F(3, 39) = 3.28, p < 0.05] on NAc glucose. Interaction was not significant. Asterisks show significant between-drug differences. The effect of injection number on glucose response alone was not significant for both MDPV and cocaine (One-Way RM ANOVA). Overall locomotor responses during this time period showed no significant differences between drugs or injection numbers. Original cocaine data were previously reported in detail (Wakabayashi and Kiyatkin, 2015a) and shown here for comparison.

Mentions: Next, we analyzed the NAc glucose and locomotor responses induced by each of the four repeated MDPV injections (Figure 2). While the initial injection of MDPV induced a modest down-up change in NAc glucose (Figure 2A), subsequent injections resulted in modest decreases in glucose for ~10 min post-injection (Figures 2B–D). However, total response assessed by AUC for 45 min post-injection was minimal with no significant differences between MDPV injections (Figure 2I). This stability of MDPV-induced glucose responses contrasted to progressive decreases in NAc glucose responses occurring during repeated cocaine injections (Figures 2A–D). However, locomotor responses remained relatively stable across repeated injections of both MDPV and cocaine, with no significant differences in amplitude, duration, and the AUC (Figures 2E–H,J).


Methylenedioxypyrovalerone (MDPV) mimics cocaine in its physiological and behavioral effects but induces distinct changes in NAc glucose.

Wakabayashi KT, Ren SE, Kiyatkin EA - Front Neurosci (2015)

Relative changes in NAc [glucose] and locomotion induced by MDPV and cocaine injections (1–4) assessed at low temporal resolution (1-min bins). (A–D), The mean (±SEM) change in NAc [glucose] (μM) induced by MDPV (red circles) and cocaine (gray circles) for 60 min post-injection. (E–H), changes in locomotor activity (mean ± SEM; counts/min). Vertical hatched lines (at 0 min) marked the onset of 20-s injections of MDPV and cocaine. Horizontal dotted lines show basal levels (=0 μM). Concentration changes for the 60 min analysis window were significant for each MDPV [One-Way RM ANOVA, F(7, 420) = 2.63, 1.78, 1.48, and 3.54, all p < 0.05, respectively] and cocaine injection [F(6, 360) = 7.07, 3.63, 2.30, and 5.61]. Individual values significantly different from baseline (p < 0.05 Fisher test) are shown as filled symbols. MDPV induced significant locomotor activation after each injection [F(11, 671) = 2.06, 3.05, 3.80, 2.59 for injections 1–4, respectively; p < 0.05, for clarity post-hoc test results not shown]. Right panels (I,J) show mean ± SEM values of glucose and locomotor responses induced by MDPV and cocaine as assessed by the area under the curve for 45 min post-injection. Two-Way RM ANOVA analysis revealed a main effect of drug [F(1, 39) = 11.09, p < 0.05] and Injection [F(3, 39) = 3.28, p < 0.05] on NAc glucose. Interaction was not significant. Asterisks show significant between-drug differences. The effect of injection number on glucose response alone was not significant for both MDPV and cocaine (One-Way RM ANOVA). Overall locomotor responses during this time period showed no significant differences between drugs or injection numbers. Original cocaine data were previously reported in detail (Wakabayashi and Kiyatkin, 2015a) and shown here for comparison.
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Figure 2: Relative changes in NAc [glucose] and locomotion induced by MDPV and cocaine injections (1–4) assessed at low temporal resolution (1-min bins). (A–D), The mean (±SEM) change in NAc [glucose] (μM) induced by MDPV (red circles) and cocaine (gray circles) for 60 min post-injection. (E–H), changes in locomotor activity (mean ± SEM; counts/min). Vertical hatched lines (at 0 min) marked the onset of 20-s injections of MDPV and cocaine. Horizontal dotted lines show basal levels (=0 μM). Concentration changes for the 60 min analysis window were significant for each MDPV [One-Way RM ANOVA, F(7, 420) = 2.63, 1.78, 1.48, and 3.54, all p < 0.05, respectively] and cocaine injection [F(6, 360) = 7.07, 3.63, 2.30, and 5.61]. Individual values significantly different from baseline (p < 0.05 Fisher test) are shown as filled symbols. MDPV induced significant locomotor activation after each injection [F(11, 671) = 2.06, 3.05, 3.80, 2.59 for injections 1–4, respectively; p < 0.05, for clarity post-hoc test results not shown]. Right panels (I,J) show mean ± SEM values of glucose and locomotor responses induced by MDPV and cocaine as assessed by the area under the curve for 45 min post-injection. Two-Way RM ANOVA analysis revealed a main effect of drug [F(1, 39) = 11.09, p < 0.05] and Injection [F(3, 39) = 3.28, p < 0.05] on NAc glucose. Interaction was not significant. Asterisks show significant between-drug differences. The effect of injection number on glucose response alone was not significant for both MDPV and cocaine (One-Way RM ANOVA). Overall locomotor responses during this time period showed no significant differences between drugs or injection numbers. Original cocaine data were previously reported in detail (Wakabayashi and Kiyatkin, 2015a) and shown here for comparison.
Mentions: Next, we analyzed the NAc glucose and locomotor responses induced by each of the four repeated MDPV injections (Figure 2). While the initial injection of MDPV induced a modest down-up change in NAc glucose (Figure 2A), subsequent injections resulted in modest decreases in glucose for ~10 min post-injection (Figures 2B–D). However, total response assessed by AUC for 45 min post-injection was minimal with no significant differences between MDPV injections (Figure 2I). This stability of MDPV-induced glucose responses contrasted to progressive decreases in NAc glucose responses occurring during repeated cocaine injections (Figures 2A–D). However, locomotor responses remained relatively stable across repeated injections of both MDPV and cocaine, with no significant differences in amplitude, duration, and the AUC (Figures 2E–H,J).

Bottom Line: Using enzyme-based glucose sensors coupled with amperometery in freely moving rats, we found that MDPV tonically decreases NAc glucose levels, a response that is opposite to what we previously observed with cocaine.By analyzing Skin-Muscle temperature differentials, a valid measure of skin vascular tone, we found that MDPV induces vasoconstriction; a similar effect at the level of cerebral vessels could be responsible for the MDPV-induced decrease in NAc glucose.While cocaine also induced comparable, if not slightly stronger peripheral vasoconstriction, this effect was overpowered by local neural activity-induced vasodilation, resulting in rapid surge in NAc glucose.

View Article: PubMed Central - PubMed

Affiliation: In-Vivo Electrophysiology Unit, Behavioral Neuroscience Branch, National Institute on Drug Abuse - Intramural Research Program, Department of Health and Human Services, National Institutes of Health Baltimore, MD, USA.

ABSTRACT
Methylenedioxypyrovalerone (MDPV) is generally considered to be a more potent cocaine-like psychostimulant, as it shares a similar pharmacological profile with cocaine and induces similar physiological and locomotor responses. Recently, we showed that intravenous cocaine induces rapid rise in nucleus accumbens (NAc) glucose and established its relation to neural activation triggered by the peripheral drug actions. This study was conducted to find out whether MDPV, at a behaviorally equivalent dose, shares a similar pattern of NAc glucose dynamics. Using enzyme-based glucose sensors coupled with amperometery in freely moving rats, we found that MDPV tonically decreases NAc glucose levels, a response that is opposite to what we previously observed with cocaine. By analyzing Skin-Muscle temperature differentials, a valid measure of skin vascular tone, we found that MDPV induces vasoconstriction; a similar effect at the level of cerebral vessels could be responsible for the MDPV-induced decrease in NAc glucose. While cocaine also induced comparable, if not slightly stronger peripheral vasoconstriction, this effect was overpowered by local neural activity-induced vasodilation, resulting in rapid surge in NAc glucose. These results imply that cocaine-users may be more susceptible to addiction than MDPV-users due to the presence of an interoceptive signal (i.e., sensory cue), which may result in earlier and more direct reward detection. Additionally, while health complications arising from acute cocaine use are typically cardiovascular related, MDPV may be more dangerous to the brain due to uncompensated cerebral vasoconstriction.

No MeSH data available.


Related in: MedlinePlus