What Information Do Neuropsychologists Use to Guide their Clinical Decisions? A Survey on Knowledge and Application of Evidence-Based Practice in a French-Speaking Population.

OBJECTIVE: Evidence-based practice (EBP) is an approach that encourages clinicians to base their practice on evidence to improve the quality of patient care and reduce uncertainty in their clinical decisions. However, the state of knowledge and practice of neuropsychologists in French-speaking countries is still unknown. This study aimed to find out what these neuropsychologists know about EBP and whether they use it. METHOD: A questionnaire with 39 questions for French-speaking neuropsychologists was distributed. The questions focused on neuropsychologists' knowledge and use of EBP and information that guide their clinical decisions. RESULTS: A total of 392 respondents started the survey. The data show that only 35% correctly defined EBP and there was confusion between this practice and the strict use of research data. In practice, their decisions are influenced by multiple factors, including the patient's difficulties and advice from peers. Regarding the research, a significant proportion of the sample stated that they did not search the scientific literature frequently. Barriers to accessing scientific information and ineffective article-reading behavior were highlighted. CONCLUSION: A lack of knowledge of EBP among French-speaking neuropsychologists was observed. Furthermore, the factors influencing their decision-making do not clearly fit the definitions of EBP. Information-seeking behaviors show several weaknesses and barriers to the integration of scientific evidence into practice. These results are like those of other studies conducted among psychologists or in other health professions. We will discuss possible courses of action that could be implemented to improve the knowledge and use of EBP.

Exposure to magnetic fields and childhood leukemia: a systematic review and meta-analysis of case-control and cohort studies.

The association between childhood leukemia and extremely low frequency magnetic fields (ELF-MF) generated by power lines and various electric appliances has been studied extensively during the past 40 years. However, the conditions under which ELF-MF represent a risk factor for leukemia are still unclear. Therefore, we have performed a systematic review and meta-analysis to clarify the relation between ELF-MF from several sources and childhood leukemia. We have systematically searched Medline, Scopus, Cochrane Database of Systematic Review and DARE to identify each article that has examined the relationship between ELF-MF and childhood leukemia. We have performed a global meta-analysis that takes into account the different measures used to assess magnetic field exposure: magnetic flux density measurements (<0.2 µT vs. >0.2 µT), distances between the child's home and power lines (>200 m vs. <200 m) and wire codings (low current configuration vs. high current configuration). Moreover, meta-analyses either based on magnetic flux densities, on proximity to power lines or on wire codings have been performed. The association between electric appliances and childhood leukemia has also been examined. Of the 863 references identified, 38 studies have been included in our systematic review. Our global meta-analysis indicated an association between childhood leukemia and ELF-MF (21 studies, pooled OR=1.26; 95% CI 1.06-1.49), an association mainly explained by the studies conducted before 2000 (earlier studies: pooled OR=1.51; 95% CI 1.26-1.80 vs. later studies: pooled OR=1.04; 95% CI 0.84-1.29). Our meta-analyses based only on magnetic field measurements indicated that the magnetic flux density threshold associated with childhood leukemia is higher than 0.4 µT (12 studies, >0.4 µT: pooled OR=1.37; 95% CI 1.05-1.80; acute lymphoblastic leukemia alone: seven studies, >0.4 µT: pooled OR=1.88; 95% CI 1.31-2.70). Lower magnetic fields were not associated with leukemia (12 studies, 0.1-0.2 µT: pooled OR=1.04; 95% CI 0.88-1.24; 0.2-0.4 µT: pooled OR=1.07; 95% CI 0.87-1.30). Our meta-analyses based only on distances (five studies) showed that the pooled ORs for living within 50 m and 200 m of power lines were 1.11 (95% CI 0.81-1.52) and 0.98 (95% CI 0.85-1.12), respectively. The pooled OR for living within 50 m of power lines and acute lymphoblastic leukemia analyzed separately was 1.44 (95% CI 0.72-2.88). Our meta-analyses based only on wire codings (five studies) indicated that the pooled OR for the very high current configuration (VHCC) was 1.23 (95% CI 0.72-2.10). Finally, the risk of childhood leukemia was increased after exposure to electric blankets (four studies, pooled OR=2.75; 95% CI 1.71-4.42) and, to a lesser extent, electric clocks (four studies, pooled OR=1.27; 95% CI 1.01-1.60). Our results suggest that ELF-MF higher than 0.4 µT can increase the risk of developing leukemia in children, probably acute lymphoblastic leukemia. Prolonged exposure to electric appliances that generate magnetic fields higher than 0.4 µT like electric blankets is associated with a greater risk of childhood leukemia.

Exercise against cocaine sensitization in mice: a [18F]fallypride micro-PET study.

Wheel-running exercise in laboratory rodents (animal model useful to study the neurobiology of aerobic exercise) decreases behavioural markers of vulnerability to addictive properties of various drugs of abuse including cocaine. However, neurobiological mechanisms underpinning this protective effect are far from fully characterized. Here, 28-day-old female C57BL/6J mice were housed with (n = 48) or without (n = 48) a running wheel for 6 weeks before being tested for acute locomotor responsiveness and initiation of locomotor sensitization to intraperitoneal injections of 8 mg/kg cocaine. The long-term expression of sensitization took place 3 weeks after the last session. On the day after, all mice underwent a micro-PET imaging session with [18F]fallypride radiotracer (dopamine 2/3 receptors antagonist). Exercised mice were less sensitive to acute and sensitized cocaine hyperlocomotor effects, such attenuation being particularly well marked for long-term expression of sensitization (η 2 P = 0.262). Chronic administration of cocaine was associated with a clear-cut increase of [18F]fallypride binding potential in mouse striatum (η 2 P = 0.170) while wheel-running exercise was associated with a moderate decrease in dopamine 2/3 receptors density in striatum (η 2 P = 0.075), a mechanism that might contribute to protective properties of exercise against drugs of abuse vulnerability.

Multi- and Transgenerational Outcomes of an Exposure to a Mixture of Endocrine-Disrupting Chemicals (EDCs) on Puberty and Maternal Behavior in the Female Rat.

BACKGROUND: The effects of endocrine-disrupting chemicals (EDCs) on fertility and reproductive development represent a rising concern in modern societies. Although the neuroendocrine control of sexual maturation is a major target of EDCs, little is known about the potential role of the hypothalamus in puberty and ovulation disruption transmitted across generations. OBJECTIVES: We hypothesized that developmental exposure to an environmentally relevant dose of EDC mixture could induce multi- and/or transgenerational alterations of sexual maturation and maternal care in female rats through epigenetic reprograming of the hypothalamus. We investigated the transmission of a disrupted reproductive phenotype via the maternal germline or via nongenomic mechanisms involving maternal care. METHODS: Adult female Wistar rats were exposed prior to and during gestation and until the end of lactation to a mixture of the following 13 EDCs: di-n-butyl phthalate (DnBP), di(2-ethylhexyl) phthalate (DEHP), bisphenol A (BPA), vinclozolin, prochloraz, procymidone, linuron, epoxynaxole, dichlorodiphenyldichloroethylene, octyl methoxynimmate, 4-methylbenzylidene camphor (4-MBC), butylparaben, and acetaminophen. Perinatally exposed offspring (F1) were mated with unexposed males to generate germ cell (F2) and transgenerationally exposed (F3 and F4) females. Sexual maturation, maternal behavior, and hypothalamic targets of exposure were studied across generations. RESULTS: Germ cell (F2) and transgenerationally (F3) EDC-exposed females, but not F1, displayed delayed pubertal onset and altered folliculogenesis. We reported a transgenerational alteration of key hypothalamic genes controlling puberty and ovulation (Kiss1, Esr1, and Oxt), and we identified the hypothalamic polycomb group of epigenetic repressors as actors of this mechanism. Furthermore, we found a multigenerational reduction of maternal behavior (F1-F3) induced by a loss in hypothalamic dopaminergic signaling. Using a cross-fostering paradigm, we identified that the reduction in maternal phenotype was normalized in EDC-exposed pups raised by unexposed dams, but no reversal of the pubertal phenotype was achieved. DISCUSSION: Rats developmentally exposed to an EDC mixture exhibited multi- and transgenerational disruption of sexual maturation and maternal care via hypothalamic epigenetic reprogramming. These results raise concerns about the impact of EDC mixtures on future generations. https://doi.org/10.1289/EHP8795.

Best-worst scaling identified adequate statistical methods and literature search as the most important items of AMSTAR2 (A measurement tool to assess systematic reviews).

OBJECTIVE: To assess the relative importance of A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR2) items. STUDY DESIGN AND SETTING: A best-worst scaling object case was conducted among a sample of experts in the field of systematic reviews (SRs) and meta-analyses (MAs). Respondents were asked in a series of 15 choice tasks to choose the most and the least important item from a set of four items from the master list, which included the 16 AMSTAR2 items. Hierarchical Bayes analysis was used to generate the relative importance score for each item. RESULTS: The most important items highlighted by our 242 experts to conduct overview of reviews and critically assess SRs/MAs were the appropriateness of statistical analyses and adequacy of the literature search, followed by items regarding the assessment of risk of bias, the research protocol, and the assessment of heterogeneity (relative importance score >6.5). Items related to funding sources and the assessment of study selection and data extraction in duplicate were rated as least important. CONCLUSION: Although all AMSTAR2 items can be considered as important, our results highlighted the importance of keeping the two items (the appropriateness of statistical analyses and the adequacy of the literature search) among the critical items proposed by AMSTAR2 to critically appraise SRs/MAs.

Methodological quality of meta-analyses indexed in PsycINFO: leads for enhancements: a meta-epidemiological study.

OBJECTIVES: Meta-analyses (MAs) are often used because they are lauded to provide robust evidence that synthesises information from multiple studies. However, the validity of MA conclusions relies on the procedural rigour applied by the authors. Therefore, this meta-research study aims to characterise the methodological quality and meta-analytic practices of MAs indexed in PsycINFO. DESIGN: A meta-epidemiological study. PARTICIPANTS: We evaluated a random sample of 206 MAs indexed in the PsycINFO database in 2016. PRIMARY AND SECONDARY OUTCOMES: Two authors independently extracted the methodological characteristics of all MAs and checked their quality according to the 16 items of the A MeaSurement Tool to Assess systematic Reviews (AMSTAR2) tool for MA critical appraisal. Moreover, we investigated the effect of mentioning Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) on the methodological quality of MAs. RESULTS: According to AMSTAR2 criteria, 95% of the 206 MAs were rated as critically low quality. Statistical methods were appropriate and publication bias was well evaluated in 87% and 70% of the MAs, respectively. However, much improvement is needed in data collection and analysis: only 11% of MAs published a research protocol, 44% had a comprehensive literature search strategy, 37% assessed and 29% interpreted the risk of bias in the individual included studies, and 11% presented a list of excluded studies. Interestingly, the explicit mentioning of PRISMA suggested a positive influence on the methodological quality of MAs. CONCLUSION: The methodological quality of MAs in our sample was critically low according to the AMSTAR2 criteria. Some efforts to tremendously improve the methodological quality of MAs could increase their robustness and reliability.

Long-term exposure to daily ethanol injections in DBA/2J and Swiss mice: Lessons for the interpretation of ethanol sensitization.

Most mice ethanol sensitization studies focused on neurobiology at the expense of its behavioral characterization. Furthermore, relatively short ethanol exposures (10 to 20 injections) were used in these studies. The first aim of the present study is to better characterize the development and expression of ethanol sensitization after an extended exposure of 45 daily injections. In some previous studies, mice were classified as "respondent" and "resistant" to ethanol sensitization. The second aim of the present study is to test the long-term reliability of such categorizations and the consequences of their use on the interpretation of the ethanol sensitization results. Swiss and DBA/2J female mice received 45 consecutive daily ethanol administrations (respectively 2.5 and 2.0 g/kg) and their locomotor activity was daily recorded to test the development of ethanol sensitization. At the end of the procedure, a challenge test assessed the inter-group ethanol sensitization.The results of the present study show that ethanol sensitization continues to develop beyond 20 days to reach maximal levels after about 25 injections in DBA/2J mice and 40 injections in Swiss mice, although the core phase of the development of ethanol sensitization occurred in both strains during the first 20 days. Remarkably, ethanol sensitization after such a long daily ethanol treatment resulted in both an upward shift of the magnitude of ethanol stimulant effects and a prolongation of these effects in time (up to 30 minutes). Mice classified as "resistant to ethanol sensitization" according to previous studies developed very significant levels of ethanol sensitization when tested after 45 ethanol injections and are best described as showing a delayed development of ethanol sensitization. Furthermore, mice classified as respondent or resistant to ethanol sensitization also differ in their acute response to ethanol, such that it is difficult to ascertain whether these classifications are specifically related to the sensitization process.

Anxiety-like features and spatial memory problems as a consequence of hippocampal SV2A expression.

The Synaptic Vesicle Protein 2A (SV2A) is a transmembrane protein whose presence is reduced both in animal models and in patients with chronic epilepsy. Besides its implication in the epileptic process, the behavioural consequences of the changes in its expression remain unclear. The purpose of our research is to better understand the possible role(s) of this protein through the phenotype of cKO (Grik4 Cre+/-, SV2A lox/lox) mice, male and female, which present a specific decrease of SV2A expression levels in the hippocampal glutamatergic neurons but without any epileptic seizures. In this study, we compare the cKO mice with cHZ (Grik4 Cre+/-, SV2A lox/+) and WT (Grik4 Cre+/+, SV2A lox/lox) mice through a battery of tests, used to evaluate different features: the anxiety-related features (Elevated Plus Maze), the locomotor activity (Activity Chambers), the contextual fear-related memory (Contextual Fear Conditioning), and the spatial memory (Barnes Maze). Our results showed statistically significant differences in the habituation to a new environment, an increase in the anxiety levels and spatial memory deficit in the cHZ and cKO groups, compared to the WT group. No statistically significant differences due to the genotype appeared in the spontaneous locomotor activity or the fear-linked memory. However, sexual differences were observed in this last feature. These results highlight not only an important role of the SV2A protein in the cognitive and anxiety problems typically encountered in epileptic patients, but also a possible role in the symptomatology of other neurodegenerative diseases, such as the Alzheimer's disease.

Meta-analyses indexed in PsycINFO had a better completeness of reporting when they mention PRISMA.

OBJECTIVES: To investigate the effect of the explicit mention of PRISMA, a statement designed to help authors report meta-analyses (MAs), on the reporting completeness of MAs. STUDY DESIGN AND SETTING: Two investigators evaluated a random sample of 206 MAs indexed in PsycINFO in 2016; 100 explicitly mentioned PRISMA and 106 did not. Two authors independently evaluated the 27 PRISMA items and extracted factors that could potentially be associated with reporting completeness. The data were analyzed descriptively. RESULTS: Among our 206 MAs, perfect adherence to PRISMA was found in less than 4%, of which 87% explicitly followed PRISMA. The following items were encountered significantly more frequently in MAs that explicitly mentioned PRISMA than in those that did not: summary, protocol, information sources, search strategy, study characteristics, results of individual studies, funding, study selection, risk of bias in individual studies, and bias across studies. The journal's impact factor, endorsement of PRISMA by the journal, number of authors, country of author, open access, and design of the included studies were significantly and positively associated with the explicit mention of PRISMA. CONCLUSIONS: Even if far from optimal, the explicit mention of PRISMA has a positive influence on the reporting completeness of MAs from PsycINFO.

Investigating the reciprocal relationships between locomotor sensitization to ethanol and PTSD-like clusters in DBA/2J mice.

BACKGROUND: Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are two conditions that co-occur frequently. The mechanistic explanations of this co-morbidity are still unclear. The goal of this study was twofold. First to investigate whether PTSD reduces the threshold for the acquisition of ethanol sensitization in an animal model of PTSD. Then to investigate whether ethanol sensitization modulates the expression of PTSD. METHODS: 152 female inbred DBA/2 J mice were submitted to an inescapable footshock paradigm to induce a PTSD-like condition (PTSDLC) and to a paradigm of locomotor sensitization to ethanol. In a first experiment, mice were submitted to the PTSDLC and then repeatedly injected with either saline, 1 g/kg ethanol or 2 g/kg ethanol. Their sensitization to the locomotor stimulant effects of ethanol was then tested in an open field. In a second experiment, mice were first sensitized to the locomotor stimulant effects of ethanol and then tested for their behavioral response to PTSDLC. RESULTS: In the first experiment, PTSDLC failed to induce a significant locomotor sensitization at the subthreshold dose of 1 g/kg ethanol. However, with 2 g/kg ethanol, a stronger ethanol sensitization was observed in mice submitted to the footshock relative to the control group. In the second experiment, ethanol sensitization increased only some of the behavioral clusters of PTSDLC, namely the fear generalization in a new context. CONCLUSION: PTSDLC did not reduce the dose threshold for the acquisition of ethanol sensitization but strengthened the development of ethanol sensitization with effective doses. This suggests that PTSD might interact with one of the mechanisms underlying the development of alcohol sensitization. When the relationship between ethanol sensitization and PTSDLC is tested in the reverse direction, the present study only shows a significant effect of ethanol administration on the "sensitized fear" PTSD cluster.

No evidence that wheel-running exercise impacts cocaine conditioned place preference in male C57BL/6J mice.

Wheel-running in rodents can mitigate addiction-related effects of drugs of abuse like cocaine. However, conditioned place preference (CPP) experiments have reported conflicting results, a situation warranting further studies. 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. Male C57BL/6 J mice were individually housed either with (n = 32) or without (n = 32) a running wheel from the age of 35 days. Behavioral testing began 3 weeks after such housing, mice underwent a baseline session followed by 10 once-daily conditioning sessions receiving peritoneal injections of 10 mg/kg cocaine and saline on alternate days (n = 16), control mice receiving saline every day (n = 16). One and 21 days after the last conditioning session, they were tested for CPP. Both groups exhibited comparable well-marked cocaine-induced CPP in both post-conditioning tests resulting in a negligible interaction between housing and the pharmacological treatment (η²p < 0.01). These results, along with the discrepancy found in the literature, question the nature (and the robustness) of the effects that exercise induces on CPP to cocaine.

Pitolisant and intravenous cocaine self-administration in mice.

Pitolisant, a selective inverse agonist for the histamine H3 receptor, is a new treatment for adults suffering from narcolepsy. Numerous studies have shown that striatal H3 receptors can modulate the activity of the dopamine mesolimbic system, a neuronal pathway that plays a crucial role in drug addiction. Therefore, it is important to guarantee that pitolisant has no abuse potential and does not potentiate the behavioral effects of psychostimulants. The present study tested the effects of pitolisant on cocaine reinforcement in C57BL/6J mice using the intravenous self-administration technique. Mice were trained to self-administer cocaine intravenously. After the acquisition of cocaine self-administration, pitolisant was tested on cocaine self-administration under different schedules of reinforcement (fixed ratio and progressive ratio). In another group of mice, cocaine was replaced with pitolisant after the acquisition of cocaine self-administration. Finally, a group of mice was trained to self-administer pitolisant intravenously and directly compared to mice trained to self-administer cocaine under the same conditions. Our results indicate that pitolisant does not influence the reinforcing effects of cocaine under any of the experimental conditions used in this study. Moreover, pitolisant has no reinforcing properties alone when tested in the self-administration paradigm. Our results offer more evidence to support the hypothesis that pitolisant is not addictive. In addition, pitolisant does not alter the reinforcing effects of cocaine. Finally, the present study provides no evidence for a significant involvement of histamine H3 receptors in cocaine dependence.

Wheel-running exercise before and during gestation against acute and sensitized cocaine psychomotor-activation in offspring.

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.

Evidence for a long-term protection of wheel-running exercise against cocaine psychomotor sensitization in adolescent but not in adult mice.

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.

Action of Pitolisant on the stimulant and rewarding effects of cocaine in mice.

Previous studies have demonstrated that the histamine H3 receptor inverse agonist thioperamide potentiates the stimulant and rewarding effects of cocaine. However, these potentiating effects of thioperamide do not necessarily result from H3 receptor blockade since thioperamide is an imidazole-based compound capable of enhancing plasma cocaine concentrations by blocking cytochrome P450 activity. In contrast, Pitolisant is a non-imidazole H3 receptor inverse agonist that has already been tested in clinical trials but it remains to be determined whether this compound also potentiates the behavioral effects of cocaine. The present study tested the effects of Pitolisant on locomotion, on cocaine-induced hyperactivity and on the development of conditioned place preference induced by cocaine (2 and 8mg/kg, i.p.) in male C57BL/6J mice. Pitolisant was injected 30min before each cocaine-pairing session. Locomotion recorded on the first cocaine-pairing session was used to test the effects of Pitolisant on the locomotor effects of cocaine. Our results show that doses of Pitolisant higher than 10mg/kg depressed locomotion. When injected alone at doses that did not affect locomotion, Pitolisant (2.5-10mg/kg, i.p.) had no rewarding properties in the place conditioning technique. Additionally, Pitolisant did not significantly alter cocaine-induced hyperactivity and cocaine-induced conditioned place preference. Taken together, our study indicates that Pitolisant has no addictive properties alone. Moreover, this compound does not significantly affect the stimulant and rewarding effects of cocaine. These results add further evidence to support the hypothesis that a pharmacokinetic interaction is involved in the ability of thioperamide to potentiate cocaine's psychomotor effects.

Differential effects of context on psychomotor sensitization to ethanol and cocaine.

Repeated drug injections lead to sensitization of their stimulant effects in mice, a phenomenon sometimes referred to as drug psychomotor sensitization. Previous studies showed that sensitization to cocaine is context dependent as its expression is reduced in an environment that was not paired with cocaine administration. In contrast, the effects of the test context on ethanol sensitization remain unclear. In the present study, female OF1 mice were repeatedly injected with 1.5 g/kg ethanol to test for both the effects of context novelty/familiarity and association on ethanol sensitization. A first group of mice was extensively pre-exposed to the test context before ethanol sensitization and ethanol injections were paired with the test context (familiar and paired group). A second group was not pre-exposed to the test context, but ethanol injections were paired with the test context (nonfamiliar and paired group). Finally, a third group of mice was not pre-exposed to the test context and ethanol was repeatedly injected in the home cage (unpaired group). Control groups were similarly exposed to the test context, but were injected with saline. In a second experiment, cocaine was used as a positive control. The same behavioral procedure was used, except that mice were injected with 10 mg/kg cocaine instead of ethanol. The results show a differential involvement of the test context in the sensitization to ethanol and cocaine. Cocaine sensitization is strongly context dependent and is not expressed in the unpaired group. In contrast, the expression of ethanol sensitization is independent of the context in which it was administered, but is strongly affected by the relative novelty/familiarity of the environment. Extensive pre-exposure to the test context prevented the expression of ethanol sensitization. One possible explanation is that expression of ethanol sensitization requires an arousing environment.

Amphetamine reward in food restricted mice lacking the melanin-concentrating hormone receptor-1.

Chronic food restriction (FR) and maintenance of low body weight have long been known to increase the rewarding and motor-activating effects of addictive drugs. However, the neurobiological mechanisms through which FR potentiates drug reward remain largely unknown. Melanin-concentrating hormone (MCH) signaling could be one of these mechanisms since this peptide is involved in energy homeostasis and modulates mesolimbic dopaminergic transmission. The purpose of the present study was to test this hypothesis by investigating the impact of FR on amphetamine reward in wild-type (WT) and knockout mice lacking the melanin-concentrating hormone receptor-1 (MCHR1-KO). The rewarding effects of amphetamine (0.75-2.25 mg/kg, i.p.) were measured with the conditioned place preference (CPP) technique. The food of the mice was restricted to maintain their body weight at 80-85% of their free-feeding (FF) weight throughout the entire CPP experiment. Locomotor activity of the animals was recorded during the conditioning sessions. Our results show that locomotion of all the food-restricted mice treated with saline or amphetamine increased over the sessions whatever the genotype. On the place preference test, the amplitude of CPP induced by 0.75 mg/kg amphetamine was higher in food restricted WT mice than in free-fed WT mice and food restricted MCHR1-KO mice. However, FR did not affect amphetamine reward in MCHR1-KO mice. The present results indicate that MCH signaling could be involved in the ability of FR to increase amphetamine-induced CPP.

Wheel-running mitigates psychomotor sensitization initiation but not post-sensitization conditioned activity and conditioned place preference induced by cocaine in mice.

Previous literature suggests that physical exercise allowed by an unlimited access to a running wheel for several weeks can mitigate chronic neurobehavioral responsiveness to several addictive drugs in rodents. Here, the potential preventive effects of unlimited wheel-running on the initiation of psychomotor sensitization and the acquisition and extinction of conditioned place preference (CPP) induced by 10 mg/kg cocaine in C56BL/6J mice were assessed in two independent experiments. To this end, half of the mice were singly housed with a running wheel at 28 days of age for 10 weeks prior to psychopharmacological tests, during which housing conditions did not change, and the other half of mice were housed without running wheel. In Experiment 1, prior to initiating sensitization, psychomotor activity on the two first drug-free once-daily sessions was not affected by wheel-running. This was also found for the acute psychomotor-activating effect of cocaine on the first sensitization session. Psychomotor sensitization readily developed over the 9 following once-daily sessions in mice housed without wheel, whereas it was inhibited in mice housed with a wheel. However, that difference did not transfer to post-sensitization conditioned activity. In contrast with the sensitization results, mice housed with a wheel still expressed a clear-cut CPP which did not extinguish differently from that of the other group, a result in disaccord with previous studies reporting either an attenuating or an increasing effect of wheel-running on cocaine-induced conditioned reward. The available results together indicate that interactions between wheel-running and cocaine effects are far from being satisfactorily characterized.

Assessment of behavioral flexibility after middle cerebral artery occlusion in mice.

Middle cerebral artery occlusion (MCAO) is the most common animal model of cerebral ischemia and induces various functional impairments. Long-lasting deficits resulting from MCAO however, remain insufficiently characterized, especially regarding cognition. Yet, behavioral flexibility, a prominent cognitive process is found impaired after stroke in humans. We thus used an operant-based task to assess behavioral flexibility in mice after MCAO. Three weeks after 30 min MCAO surgery, mice were subjected to a battery of sensorimotor tests (rotarod, vertical pole test, spontaneous locomotion and grip-strength test). Behavioral flexibility was then assessed in an operant task, in which mice, rewarded according to a FR5 schedule of reinforcement, had to alternate their operant responses between two levers from trial to trial. Regarding sensory and motor functioning, only the pole test yielded a significant difference between MCAO and sham mice. In the operant flexibility task, results showed a behavioral flexibility deficit in MCAO mice; neither the operant response acquisition nor the appeal for food rewards was altered. In conclusion, our operant-based task revealed a long-lasting behavioral flexibility deficit after MCAO in mice.