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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] induced by MDPV and cocaine injections (1–4) assessed at high temporal resolution (8-s bins). (A–D), mean (±SEM) changes in NAc [glucose] (μM) induced by MDPV (red circles) and cocaine (gray circles) for 720 s after the injection onset. Vertical shaded area (starting at 0 s) marked the onset of 20-s MDPV injection. Horizontal dotted lines show basal levels (=0 μM). Concentration changes for the 720 s analysis were significant for 2–4 injections of MDPV [F(7, 630) = 4.05, 3.73, 4.31, all p < 0.05] and 1–3 injections of cocaine [F(6, 534) = 3.24, 1.83, 4.19, all p < 0.05]. Individual concentration values significantly different from baseline (Fisher test) are shown as filled symbols. (E,F), mean ± SEM values of glucose responses induced by MDPV and cocaine as assessed by the area under the curve for 60 s post-injection (E) and between 60 s and 720 s post-injection (F). Two-Way RM ANOVA analysis revealed a main effect of drug [F(1, 39) = 13.9, p < 0.05] on NAc Glucose during 60 s post-injection. Neither Injection nor Interaction was significant. A similar analysis for the 60–720 s interval revealed a main effect of drug and injection [F(1, 39) = 28.63, F(3, 39) = 5.39, both p < 0.05). Interaction approached significance [F(3, 39) = 2.73 p = 0.057]. Asterisks show significant between-drug differences. The effect of injection number alone was not significant for MDPV- or cocaine-induced [glucose] at this time interval (One-Way RM ANOVA). Inset in (E) shows the correlation between the mean [glucose] response for the first 180 s after cocaine and MDPV injections (r = 0.98). Original cocaine data were previously reported in detail (Wakabayashi and Kiyatkin, 2015a) and shown here for comparison.
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Figure 3: Relative changes in NAc [glucose] induced by MDPV and cocaine injections (1–4) assessed at high temporal resolution (8-s bins). (A–D), mean (±SEM) changes in NAc [glucose] (μM) induced by MDPV (red circles) and cocaine (gray circles) for 720 s after the injection onset. Vertical shaded area (starting at 0 s) marked the onset of 20-s MDPV injection. Horizontal dotted lines show basal levels (=0 μM). Concentration changes for the 720 s analysis were significant for 2–4 injections of MDPV [F(7, 630) = 4.05, 3.73, 4.31, all p < 0.05] and 1–3 injections of cocaine [F(6, 534) = 3.24, 1.83, 4.19, all p < 0.05]. Individual concentration values significantly different from baseline (Fisher test) are shown as filled symbols. (E,F), mean ± SEM values of glucose responses induced by MDPV and cocaine as assessed by the area under the curve for 60 s post-injection (E) and between 60 s and 720 s post-injection (F). Two-Way RM ANOVA analysis revealed a main effect of drug [F(1, 39) = 13.9, p < 0.05] on NAc Glucose during 60 s post-injection. Neither Injection nor Interaction was significant. A similar analysis for the 60–720 s interval revealed a main effect of drug and injection [F(1, 39) = 28.63, F(3, 39) = 5.39, both p < 0.05). Interaction approached significance [F(3, 39) = 2.73 p = 0.057]. Asterisks show significant between-drug differences. The effect of injection number alone was not significant for MDPV- or cocaine-induced [glucose] at this time interval (One-Way RM ANOVA). Inset in (E) shows the correlation between the mean [glucose] response for the first 180 s after cocaine and MDPV injections (r = 0.98). Original cocaine data were previously reported in detail (Wakabayashi and Kiyatkin, 2015a) and shown here for comparison.

Mentions: Since the maximal between-drug differences in glucose dynamics were found within several minutes following injections, next our data were analyzed at a high time resolution (8-s bin) (Figure 3). In contrast to cocaine, which induced ultra-fast glucose rise within the first 60 s after each drug injection, MDPV within this time interval showed only weak, non-significant glucose increases (Figures 3A–E). These initial MDPV-induced increases were equally weak with each injection but the initial rises induced by cocaine decreased across repeated injections. However, MDPV induced a more prominent tonic decrease in NAc glucose within 60–720 s post-injection; this change remained relatively stable in amplitude, duration, and AUC (Figures 3A–D,F). Within this time window, cocaine induced greatest increases in NAc glucose during the first injection and this change rapidly became weaker such that the fourth response resembled that of MDPV. In this case, changes in glucose levels induced by both drugs tightly correlated (r = 0.97; see inset in Figure 3E).


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] induced by MDPV and cocaine injections (1–4) assessed at high temporal resolution (8-s bins). (A–D), mean (±SEM) changes in NAc [glucose] (μM) induced by MDPV (red circles) and cocaine (gray circles) for 720 s after the injection onset. Vertical shaded area (starting at 0 s) marked the onset of 20-s MDPV injection. Horizontal dotted lines show basal levels (=0 μM). Concentration changes for the 720 s analysis were significant for 2–4 injections of MDPV [F(7, 630) = 4.05, 3.73, 4.31, all p < 0.05] and 1–3 injections of cocaine [F(6, 534) = 3.24, 1.83, 4.19, all p < 0.05]. Individual concentration values significantly different from baseline (Fisher test) are shown as filled symbols. (E,F), mean ± SEM values of glucose responses induced by MDPV and cocaine as assessed by the area under the curve for 60 s post-injection (E) and between 60 s and 720 s post-injection (F). Two-Way RM ANOVA analysis revealed a main effect of drug [F(1, 39) = 13.9, p < 0.05] on NAc Glucose during 60 s post-injection. Neither Injection nor Interaction was significant. A similar analysis for the 60–720 s interval revealed a main effect of drug and injection [F(1, 39) = 28.63, F(3, 39) = 5.39, both p < 0.05). Interaction approached significance [F(3, 39) = 2.73 p = 0.057]. Asterisks show significant between-drug differences. The effect of injection number alone was not significant for MDPV- or cocaine-induced [glucose] at this time interval (One-Way RM ANOVA). Inset in (E) shows the correlation between the mean [glucose] response for the first 180 s after cocaine and MDPV injections (r = 0.98). Original cocaine data were previously reported in detail (Wakabayashi and Kiyatkin, 2015a) and shown here for comparison.
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Figure 3: Relative changes in NAc [glucose] induced by MDPV and cocaine injections (1–4) assessed at high temporal resolution (8-s bins). (A–D), mean (±SEM) changes in NAc [glucose] (μM) induced by MDPV (red circles) and cocaine (gray circles) for 720 s after the injection onset. Vertical shaded area (starting at 0 s) marked the onset of 20-s MDPV injection. Horizontal dotted lines show basal levels (=0 μM). Concentration changes for the 720 s analysis were significant for 2–4 injections of MDPV [F(7, 630) = 4.05, 3.73, 4.31, all p < 0.05] and 1–3 injections of cocaine [F(6, 534) = 3.24, 1.83, 4.19, all p < 0.05]. Individual concentration values significantly different from baseline (Fisher test) are shown as filled symbols. (E,F), mean ± SEM values of glucose responses induced by MDPV and cocaine as assessed by the area under the curve for 60 s post-injection (E) and between 60 s and 720 s post-injection (F). Two-Way RM ANOVA analysis revealed a main effect of drug [F(1, 39) = 13.9, p < 0.05] on NAc Glucose during 60 s post-injection. Neither Injection nor Interaction was significant. A similar analysis for the 60–720 s interval revealed a main effect of drug and injection [F(1, 39) = 28.63, F(3, 39) = 5.39, both p < 0.05). Interaction approached significance [F(3, 39) = 2.73 p = 0.057]. Asterisks show significant between-drug differences. The effect of injection number alone was not significant for MDPV- or cocaine-induced [glucose] at this time interval (One-Way RM ANOVA). Inset in (E) shows the correlation between the mean [glucose] response for the first 180 s after cocaine and MDPV injections (r = 0.98). Original cocaine data were previously reported in detail (Wakabayashi and Kiyatkin, 2015a) and shown here for comparison.
Mentions: Since the maximal between-drug differences in glucose dynamics were found within several minutes following injections, next our data were analyzed at a high time resolution (8-s bin) (Figure 3). In contrast to cocaine, which induced ultra-fast glucose rise within the first 60 s after each drug injection, MDPV within this time interval showed only weak, non-significant glucose increases (Figures 3A–E). These initial MDPV-induced increases were equally weak with each injection but the initial rises induced by cocaine decreased across repeated injections. However, MDPV induced a more prominent tonic decrease in NAc glucose within 60–720 s post-injection; this change remained relatively stable in amplitude, duration, and AUC (Figures 3A–D,F). Within this time window, cocaine induced greatest increases in NAc glucose during the first injection and this change rapidly became weaker such that the fourth response resembled that of MDPV. In this case, changes in glucose levels induced by both drugs tightly correlated (r = 0.97; see inset in Figure 3E).

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