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See detailNeuro-functional correlates of the protective effects of exercise against cocaine sensitization and dopamine D2 receptors density: a [18F]Fallypride microPET study.
Becker, Guillaume ULiege; Lespine, Louis-Ferdinand ULiege; Serrano Navacerrada, Maria Elisa ULiege et al

in Molecular Imaging and Biology (in press)

Preclinical studies suggest that free access to a running wheel can attenuate behavioural effects of addictive drugs such as psychomotor sensitization to cocaine in rodents. This phenomenon has an ... [more ▼]

Preclinical studies suggest that free access to a running wheel can attenuate behavioural effects of addictive drugs such as psychomotor sensitization to cocaine in rodents. This phenomenon has an integral role in the process of drug addiction in craving and relapse (Steketee and Kalivas, 2011). Free wheel-running was recently shown to be efficacious at preventing the initiation or the long-term expression of psychomotor sensitization to cocaine in mice or rats (Diaz et al., 2013; Geuzaine and Tirelli, 2014). In the present study, we investigated the neuro-functional correlates of the protection against psychomotor sensitization to cocaine afforded by free wheel-running on dopaminergic neurotransmission, using microPET imaging with [18F]Fallypride, a Dopamine 2 receptor (D2R) antagonist. Sixty-four 28-day-old female C57BL/6J mice were randomly assigned to one of the two housing conditions, defined by the presence or the absence of a running wheel in the cage over a 6-week pre-testing period. Since mice from the two types of housing received either saline (controls) or cocaine (8 mg/kg, i.p.) during testing (9 once-daily sessions to establish sensitization plus 1 single session to test its expression), a basic 2x2 randomized blocks design was generated (2-way ANOVA and planned comparisons; n=10). Experimentation lasted 85 days, with a 42-day period of pre-testing and a 3-week interval preceding the test for long-term expression of sensitization (LTES). All mice underwent a microPET (Focus 120, Siemens) the day after the LTES. The microPET protocol consisted of a 60 min. dynamic acquisition after the injection of 10 MBq of [18F]Fallypride in the tail vein. Wheel-running strongly and significantly attenuated LTES (interaction) to cocaine (Cohen’s d=1.63; t(21)=3.75, p<.001) and cocaine-treated mice exhibited a clear-cut and significant increase (main effect) of the [18F]Fallypride BP (d=0.88, t(31)=2.45, p =.02). Wheel-running induced an overall moderate-sized decrease (main effect) of the [18F]Fallypride BP, but without achieving statistical significance (d=0.64, t(31)=1.79, p =.08). These findings suggest that LTES is associated with an increase of the [18F]Fallypride BP in the mouse striatum, probably reflecting an increase in postsynaptic D2R density in this region. Also, the protecting effect of free running on psychomotor sensitization goes together with a decrease in D2R density in the striatum of exercised mice. We intend to complement the present study with an identical experiment to reach a total number of 80 mice (n=20). This will confer to our study a sufficient power (80%) for the main effect of wheel-running exercise on [18F]Fallypride BP to be detected at an alpha-level of 5%. Finally, autoradiography studies, performed on the same mice with [18F]Fallypride, will strengthen our in vivo results. [less ▲]

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See detailWheel-running exercise before and during gestation against acute and sensitized cocaine psychomotor-activation in offspring.
Lespine, Louis-Ferdinand ULiege; Plenevaux, Alain ULiege; Tirelli, Ezio ULiege

in Behavioural Brain Research (2019), 363

While animal research has consistently reported preventive effects of exercise against drug abuse vulnerability, little is known about the influence of the developmental stage during which exercise is ... [more ▼]

While animal research has consistently reported preventive effects of exercise against drug abuse vulnerability, little is known about the influence of the developmental stage during which exercise is displayed on addictive drugs responsiveness. This study aimed to determine whether prenatal exercise could attenuate acute cocaine reactivity and psychomotor sensitization in youth offspring. We used a split-plot factorial design where C57BL/6 J females were randomly assigned into sedentary or exercised (wheel-running) conditions before and during gestation, the wheels being removed on gestational day 18. Offspring were weaned, gendered and individually housed on 24–28 days old. At 38–42 days old, they were tested for their acute psychomotor responsiveness to 8 mg/kg cocaine and their initiation of sensitization over 8 additional once-daily administrations, the long-term expression of sensitization occurring 30 days later. Adolescent females born from exercised mothers were much less responsive to the acute psychomotor-stimulating effect of cocaine than those born from sedentary mothers (d=0.75, p=0.02), whereas there was no evidence for such a difference in males (d=0.34, p=0.17). However, we did not find sizeable attenuating effects of prenatal exercise on the initiation and the long-term expression of the psychomotor-activating effect of cocaine, in either sex (Cohen’s ds varying from −0.13 to 0.39). These results suggest that prenatal exercise may induce initial protection against cocaine responsiveness in youth females, a finding that warrants further research. [less ▲]

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See detailEvidence for a long-term protection of wheel-running exercise against cocaine psychomotor sensitization in adolescent but not in adult mice
Lespine, Louis-Ferdinand ULiege; Tirelli, Ezio ULiege

in Behavioural Brain Research (2018), 349

Rodents housed with a running wheel can exhibit attenuated cocaine seeking and cocaine-induced psychomotor activation. However, the longevity of such a protection and the influence of the developmental ... [more ▼]

Rodents housed with a running wheel can exhibit attenuated cocaine seeking and cocaine-induced psychomotor activation. However, the longevity of such a protection and the influence of the developmental stage during which exercise is displayed received little attention. Here, females and males C57BL/6J mice, aged 28 (adolescents) or 77 (adults) days were housed with (n = 56) or without (n = 28) a running wheel. After 3 weeks in these conditions, half of the exercised mice were deprived of their wheel (n = 28) whereas the other half and the sedentary mice were kept in their respective environments. After 3 additional weeks, mice were tested for initiation of psychomotor sensitization to 9 once-daily intraperitoneal injections of 8 mg/kg cocaine (following 2 drug-free sessions). The expression of sensitization was assessed on a single session 30 days after the last cocaine injection. Continuously exercised mice (wheel throughout experimentation) were less responsive to the initiation and the expression of cocaine effects, regardless of the gender and the developmental period during which exercise was introduced. A 3-week regimen of wheel-running exercise during adolescence (from 28 to 50 days of age) attenuated in later life the initiation and the expression of sensitization in females and its expression in males. In contrast, females and males previously exercised as adults (from 77 to 99 days of age) and their corresponding sedentary counterparts exhibited indiscernible levels of initiation and expression of sensitization. These results suggest that early-life period such as adolescence may be particularly sensitive to the long-term protection of exercise against cocaine vulnerability. [less ▲]

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See detailIncreased hippocampal volume in exercising mice: comparison of control conditions with in vivo voxel based morphometry
Becker, Guillaume ULiege; Lespine, Louis-Ferdinand ULiege; Bahri, Mohamed Ali ULiege et al

Poster (2018, March)

Introduction Both human and animal studies have shown that physical exercise (primarily aerobic exercise) may have facilitating effects on brain plasticity and cognition. In rodents, improvements of ... [more ▼]

Introduction Both human and animal studies have shown that physical exercise (primarily aerobic exercise) may have facilitating effects on brain plasticity and cognition. In rodents, improvements of various forms of learning and memory induced by wheel-running have been associated with numerous neuroplastic changes such as increased hippocampal neurogenesis. A few studies, using magnetic resonance imaging (MRI), consistently reported hippocampal volumetric increase relative to non-exercising mice. However, the control group is commonly limited either to a locked wheel or no wheel. Methods In the present study, we intended to test whether 6 weeks of voluntary wheel-running exercise during adulthood induced a detectable volumetric change in mice brain in comparison to non-exercised control mice housed either with a locked wheel or without such wheel. 54 C57Bl6 males were randomly assigned to one of the three groups and individually housed for 6 weeks before imaging session. MRI (Agilent 9.4T) acquisition consisted in 3D T2 volume sequence (voxel size: 0.21 mm isotropic) using a dedicated surface coil receiver. We used Dartel soware for the preprocessing of the data, and the Voxel Based Morphometry was done with SPM mouse toolbox (F test, threshold p < .001 uncor). A small volume correction was applied to limit the analysis to the hippocampus. Results/Discussion VBM analysis shows significant clusters with increased grey matter volume in the hippocampus (cluster sizes 1531 and 3460, p < .001) when we compare the wheel vs locked wheel groups. Regarding the wheel vs no wheel comparison, significant clusters were observed in the hippocampus (cluster sizes 955 and 238, p < .001). Interestingly, no dierences were found when we compare the two control groups (locked wheel vs no wheel). Conclusions In this study, we replicate previous studies depicting an increased hippocampal volume under physical exercise in mice using VBM. Moreover, we certified here that attempting to study the impact of physical exercise on brain volume, control groups with a locked wheel or no wheel are equivalent. [less ▲]

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See detailFunctional correlates of the protective effects of free wheel-running against cocaine psychomotor sensitization on dopamine D2 receptors: a [18F]Fallypride microPET study.
Becker, Guillaume ULiege; Lespine, Louis-Ferdinand ULiege; Bahri, Mohamed Ali ULiege et al

Conference (2017, April 05)

Preclinical studies suggest that free access to a running wheel can attenuate the behavioural responsiveness to addictive drugs in rodents. Regarding the behavioural responsiveness to drugs, psychomotor ... [more ▼]

Preclinical studies suggest that free access to a running wheel can attenuate the behavioural responsiveness to addictive drugs in rodents. Regarding the behavioural responsiveness to drugs, psychomotor sensitization has an integral role in the process of drug addiction in craving and relapse (Steketee and Kalivas, 2011). Free wheel-running was recently shown to be efficacious at preventing the initiation or the long-term expression of psychomotor sensitization to cocaine in mice or rats (Diaz et al., 2013; Geuzaine and Tirelli, 2014). In the present study, we investigated the neuro-functional correlates of the protection against psychomotor sensitization to cocaine afforded by free wheel-running on dopaminergic neurotransmission, using microPET imaging with [18F]Fallypride, a Dopamine 2 receptor (D2R) antagonist. We used a total of 32 female C57BL/6J mice. At 28 days of age, the mice were randomly assigned to on of the two experimental housing conditions, defined by the presence or the absence of a running wheel in the cage (pre-testing period: 6 weeks). Since mice from the two types of housing received either saline or cocaine (8 mg/kg, i.p.) during testing (9 days), a basic 2*2 factorial design was generated (two-way ANOVA). The whole experimentation lasted 85 days, included the 42-days pre-testing period and the 3 weeks (housing condition, no injection) between the testing and the long-term expression of sensitization (LTES). All mice underwent a microPET (Focus 120, Siemens) the day after the LTES. The microPET protocol consisted of a 60 min. dynamic acquisition after the injection of 10 MBq of [18F]Fallypride in the tail vein. We observe a strong attenuating effect of exercise on the expression of sensitization to cocaine (Effect Size = 2.66 at p < .001 one-tailed, N.B: Effect Size is the mean difference in standard deviation units). Regarding the microPET outcomes ([18F]Fallypride Binding Potential, BP), we have a significant increase of the [18F]Fallypride BP for the cocaine-treated mice, compared to the saline-injected mice (Effect Size = 0.78 at p = .02 one-tailed). We observe a decrease tendency of the [18F]Fallypride BP in the exercise condition compared to the sedentary condition (ES = 0.48 at p = .09 one-tailed). These findings indicate that LTES is associated with an increase of the [18F]Fallypride BP in the mouse striatum, probably reflecting an increase in postsynaptic D2R density in this region. Besides that, the protecting effect of free running on psychomotor sensitization goes together with a decrease in D2R density in the striatum of exercised mice. Those data will be augmented with identical sub-experiment. All data will be pooled together to reach a total number of 64 mice (n = 16 per group). [less ▲]

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See detailWheel-running exercise during adolescence does not substantially affect cocaine conditioned place preference in male C57BL/6J mice
Lespine, Louis-Ferdinand ULiege; Tirelli, Ezio ULiege

Poster (2017)

Epidemiological studies suggest that physical exercise could have preventive properties against drugs of abuse vulnerability. Animal research showed that rats or mice housed with a running wheel (a model ... [more ▼]

Epidemiological studies suggest that physical exercise could have preventive properties against drugs of abuse vulnerability. Animal research showed that rats or mice housed with a running wheel (a model of aerobic exercise) can exhibit attenuated drug self-administration or drug-induced psychomotor hyperactivity in comparison with their sedentary counterparts. However, the few experiments using conditioned place preference (CPP) are conflicting (positive, negative or null effects of exercise). Aspects or deficiencies of the methods used in some studies, in particular the low sample size (median n=8), the absence of a baseline pre-conditioning session or a control group in the design or (when present) in the data analyses, make the whole picture of results difficult to understand, a situation which warrants further studies, possibly of a better quality than the previous ones. Objectives. Our purpose was to test whether wheel-running exercise during adolescence could impact the formation and long-term retention of CPP to cocaine in mice. Method. Male C57BL/6J mice were individually housed either with (n=32) or without (n=32) a running wheel from 35 days of age. Behavioral testing begun 3 weeks after such housing, all animals being first tested under saline for their baseline preference (white or black compartments). Then, mice underwent 10 once-daily conditioning sessions receiving peritoneal injections of 10 mg/kg cocaine and saline on alternate days (n=16). The white compartment (always non-preferred) was systematically associated to cocaine effects. Control mice received saline every day (n=16). One and 21 days after the last conditioning session, mice were tested for place preference under saline. CPP scores were analyzed with a priori single (cocaine vs saline) and crossed contrasts (testing the housing-by-drug interaction). Each contrast (t-test) incorporated the mean-square error (MSE) provided by a preliminary two-way fixed-model 2x2 ANOVA incorporating the housing condition (2 levels) and the drug treatment (2 levels) as between-group factors and time of testing as a blocking factor (8 levels). Estimates of effect sizes were provided by Cohen’s d calculated from ts and degree of freedom. Results. The two groups exhibited significant well-marked cocaine-induced CPP in both 1-day (d = 1.38 and d = 1.11 at ps < .001 one-tailed in exercised and sedentary mice) and 21-day post-conditioning tests (d = 1.09 and d = 1.15 at ps < .001 one-tailed in exercised and sedentary mice). The (small) effects underlying interaction between housing and the drug treatment were not significant for 1-day (d = 0.19 at p = .48 two-tailed; 95% CI -0.35 to 0.73) or 21-day post-conditioning tests (d = 0.05 at p = .87 two-tailed; 95% CI -0.49 to 0.59). Conclusion. If physical exercise in rodents “truly” impacts CPP induced by drugs of abuse under comparable experimental parameters - as suggested by some studies (either positively or negatively) -, our results indicate that the size of such effects may be quite small, an information rarely reported in the literature. [less ▲]

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See detailLong-term effects of exercise during youth or adulthood on cocaine reactivity in mice: qualitative developmental differences
Lespine, Louis-Ferdinand ULiege; Tirelli, Ezio ULiege

Conference (2017)

Epidemiological studies suggest that physical exercise could have preventive properties on drugs vulnerability. Animal research showed that rats or mice housed with a running wheel (a model of physical ... [more ▼]

Epidemiological studies suggest that physical exercise could have preventive properties on drugs vulnerability. Animal research showed that rats or mice housed with a running wheel (a model of physical exercise) can exhibit attenuated drug seeking and drug-induced psychomotor hyperactivity in comparison with their sedentary counterparts. Objectives: the aim was to evaluate the longevity of the protective effects of exercise on cocaine vulnerability and the influence of the developmental stage during which exercise is applied (in 4 experiments). Method: females and males C57BL/6J mice, aged 28 (youth) or 77 days (adults) were housed with (n=56) or without (n=28) a running wheel. After 3 weeks, half of the exercised mice (n=28) were deprived of their wheel (3 housing conditions/experiment). Three weeks later, mice were tested for sensitization to the psychomotor-activating effects of 8 mg/kg cocaine over 9 once-daily sessions (controls: saline solution). Mice were also tested 30 days later for their long-term expression of sensitization. Results: continuous wheel-running housing reduced cocaine responsiveness in both females and males regardless of the age on which exercise was introduced. Exercise performed exclusively in youth, but not over adulthood, reduced durably cocaine responsiveness, particularly in females. Conclusion: the likelihood of the long-term protection of exercise against cocaine responsiveness may depend on the age of exercise application and the gender. [less ▲]

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See detailStudy Protocol: Effect of prenatal wheel-running exercise (before and during gestation) on cocaine psychomotor sensitization expressed in the offspring in periadolescent females and males C57BL/6J mice
Lespine, Louis-Ferdinand ULiege; Plenevaux, Alain ULiege; Tirelli, Ezio ULiege

E-print/Working paper (2017)

The present study principally aims at determining to which extent prenatal exercise (before and during gestation) could affect the initiation (establishment) and the expression of psychomotor ... [more ▼]

The present study principally aims at determining to which extent prenatal exercise (before and during gestation) could affect the initiation (establishment) and the expression of psychomotor sensitization induced by a representative dose of cocaine in young female and male mice. More specifically, we will assess cocaine-induced acute psychomotor-activating effects, psychomotor sensitization developing over 9 daily sessions (daily peritoneal injections of cocaine or saline) and the long-term expression of the sensitized response (30 days after the last sensitizing injection) in C57BL/6J mice born from mothers housed with or without a running wheel before and during gestation. Based on literature and on our prior results, the mice born from exercised mothers are expected to show significantly reduced levels of cocaine responsiveness in comparison with the control mice (born from unexercised mothers). [less ▲]

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See detailThe protective effects of free wheel-running against cocaine psychomotor sensitization persist after exercise cessation in C57BL/6J mice
Lespine, Louis-Ferdinand ULiege; Tirelli, Ezio ULiege

in Neuroscience (2015), 310

Previous literature suggests that free access to a running wheel can attenuate the behavioral responsiveness to addictive drugs in rodents. In a few studies, wheel-running cessation accentuated drug ... [more ▼]

Previous literature suggests that free access to a running wheel can attenuate the behavioral responsiveness to addictive drugs in rodents. In a few studies, wheel-running cessation accentuated drug responsiveness. Here, we tested whether free wheel-running cessation is followed by (1) an accentuation or (2) an attenuation of cocaine psychomotor sensitization, knowing that no cessation of (continuous) wheel-running is associated with an attenuation of cocaine responsiveness. Male C57BL/6J mice, aged 35 days, were housed singly either with (exercising mice) or without (non-exercising mice) a running wheel. At the end of a period of 36 days, half of the exercising mice were deprived of their wheel whereas the other half of exercising mice kept their wheel until the end of experimentation (which lasted 85 days). The non-exercising mice were housed without wheel throughout experimentation. Testing took place 3 days after exercise cessation. After 2 once-daily drug-free test sessions, mice were tested for initiation of psychomotor sensitization over 13 once-daily injections of 8 mg/kg cocaine. Post-sensitization conditioned activation (saline challenge) and long-term expression of sensitization were assessed 2 or 30 days after the last sensitizing injection (same treatments as for initiation of sensitization), respectively. Exercising mice and mice undergoing wheel-running cessation exhibited comparable degrees of attenuation of all cocaine effects in comparison with the continuously non-exercising mice, which showed the greatest effects. Thus, the efficaciousness of wheel-running at attenuating cocaine sensitization not only resisted to exercise cessation but also was unambiguously persistent (an important effect rarely reported in previous literature). [less ▲]

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See detailExploration of volumetric cerebral changes, with de micro-MRi, due to psychomotor exercise in mice
Moës, Florian ULiege; Plenevaux, Alain ULiege; Becker, Guillaume ULiege et al

Poster (2015, January 27)

It's well know that exercise is good for health .In addition exercise has postive effects on cognition ,neurodegenerative disease and on mood. Some studies show that exercise has effect on brain so the ... [more ▼]

It's well know that exercise is good for health .In addition exercise has postive effects on cognition ,neurodegenerative disease and on mood. Some studies show that exercise has effect on brain so the aim of this study is to see if there are volumetric changes due to exercise or not. [less ▲]

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See detailLong-term protective effect of wheel-running on cocaine reactivity
Lespine, Louis-Ferdinand ULiege; Tirelli, Ezio ULiege

Poster (2013, September)

Chronic running activity performed during adolescence in C57BL/6J mice induce a protective long term effect on psycho-stimulating effect of cocaine

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