Clinical prediction models for diagnosis of COVID-19 among adult patients: a validation and agreement study.

BACKGROUND: Since the beginning of the pandemic, hospitals have been constantly overcrowded, with several observed waves of infected cases and hospitalisations. To avoid as much as possible this situation, efficient tools to facilitate the diagnosis of COVID-19 are needed. OBJECTIVE: To evaluate and compare prediction models to diagnose COVID-19 identified in a systematic review published recently using performance indicators such as discrimination and calibration measures. METHODS: A total of 1618 adult patients present at two Emergency Department triage centers and for whom qRT-PCR tests had been performed were included in this study. Six previously published models were reconstructed and assessed using diagnostic tests as sensitivity (Se) and negative predictive value (NPV), discrimination (Area Under the Roc Curve (AUROC)) and calibration measures. Agreement was also measured between them using Kappa's coefficient and IntraClass Correlation Coefficient (ICC). A sensitivity analysis has been conducted by waves of patients. RESULTS: Among the 6 selected models, those based only on symptoms and/or risk exposure were found to be less efficient than those based on biological parameters and/or radiological examination with smallest AUROC values (< 0.80). However, all models showed good calibration and values above > 0.75 for Se and NPV but poor agreement (Kappa and ICC < 0.5) between them. The results of the first wave were similar to those of the second wave. CONCLUSION: Although quite acceptable and similar results were found between all models, the importance of radiological examination was also emphasized, making it difficult to find an appropriate triage system to classify patients at risk for COVID-19.

Effects of nutritional counseling on physical performance and muscle strength in older adults: a systematic review protocol.

OBJECTIVE: The objective of this review is to synthesize the effects of nutritional counseling compared with no intervention (maintaining lifestyle habits) or nutritional counseling in combination with other interventions (eg, nutritional supplementation, physical activity) on physical performance and muscle strength in older adults. INTRODUCTION: Nutritional counseling, which is considered the first line of nutrition therapy, could play an important role in geriatric care programs by helping older adults understand the importance of nutrition and by promoting healthy, sustainable eating habits. However, the effects of nutritional counseling on physical function and muscle strength among older adults are not clear. INCLUSION CRITERIA: This review will consider randomized controlled trials and non-randomized controlled trials. Participants aged 65 years or older, who have received nutritional counseling alone or in combination with another intervention (eg, nutritional supplementation, physical exercise) will be considered for inclusion. Comparators will include another intervention or no intervention, but physical performance (ie, gait, endurance, balance) or muscle strength must be measured. METHODS: This systematic review will be conducted in accordance with the JBI methodology for systematic reviews of effectiveness. The databases to be searched will include MEDLINE (Ovid), Embase, CENTRAL (Ovid), CINAHL (EBSCOhost), and Scopus. Sources of unpublished studies and gray literature will include Google Scholar and protocol registers. Two independent reviewers will select relevant studies, critically appraise the studies, and extract data. Studies will be pooled in a statistical meta-analysis or presented in narrative format. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach will be used to grade the certainty of the evidence. REVIEW REGISTRATION: PROSPERO CRD42022374527.

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.

A systematic review of prediction models to diagnose COVID-19 in adults admitted to healthcare centers.

BACKGROUND: The COVID-19 pandemic is putting significant pressure on the hospital system. To help clinicians in the rapid triage of patients at high risk of COVID-19 while waiting for RT-PCR results, different diagnostic prediction models have been developed. Our objective is to identify, compare, and evaluate performances of prediction models for the diagnosis of COVID-19 in adult patients in a health care setting. METHODS: A search for relevant references has been conducted on the MEDLINE and Scopus databases. Rigorous eligibility criteria have been established (e.g., adult participants, suspicion of COVID-19, medical setting) and applied by two independent investigators to identify suitable studies at 2 different stages: (1) titles and abstracts screening and (2) full-texts screening. Risk of bias (RoB) has been assessed using the Prediction model study Risk of Bias Assessment Tool (PROBAST). Data synthesis has been presented according to a narrative report of findings. RESULTS: Out of the 2334 references identified by the literature search, 13 articles have been included in our systematic review. The studies, carried out all over the world, were performed in 2020. The included articles proposed a model developed using different methods, namely, logistic regression, score, machine learning, XGBoost. All the included models performed well to discriminate adults at high risks of presenting COVID-19 (all area under the ROC curve (AUROC) > 0.500). The best AUROC was observed for the model of Kurstjens et al (AUROC = 0.940 (0.910-0.960), which was also the model that achieved the highest sensitivity (98%). RoB was evaluated as low in general. CONCLUSION: Thirteen models have been developed since the start of the pandemic in order to diagnose COVID-19 in suspected patients from health care centers. All these models are effective, to varying degrees, in identifying whether patients were at high risk of having COVID-19.

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.

The psychostimulant and rewarding effects of cocaine in histidine decarboxylase knockout mice do not support the hypothesis of an inhibitory function of histamine on reward.

RATIONALE AND OBJECTIVES: Lesion studies have shown that the tuberomammillary nucleus (TM) exerts inhibitory effects on the brain reward system. To determine whether histamine from the TM is involved in that reward inhibitory function, we assessed the stimulant and rewarding effects of cocaine in knockout mice lacking histidine decarboxylase (HDC KO mice), the histamine-synthesizing enzyme. If histamine actually plays an inhibitory role in reward, then it would be expected that mice lacking histamine would be more sensitive to the behavioral effects of cocaine. MATERIALS AND METHODS: The first experiment characterized spontaneous locomotion and cocaine-induced hyperactivity (0, 8, and 16 mg/kg, i.p.) in wild-type and HDC KO mice. The rewarding effects of cocaine were investigated in a second experiment with the place-conditioning technique. RESULTS: The first experiment demonstrated that histidine decarboxylase mice showed reduced exploratory behaviors but normal habituation to the test chambers. After habituation to the test chambers, HDC KO mice were slightly, but significantly, less stimulated by cocaine than control mice. This finding was replicated in the second experiment, when cocaine-induced activity was monitored with the place-conditioning apparatus. Furthermore, a significant place preference was present in both genotypes for 8 and 16 mg/kg cocaine, but not for 2 and 4 mg/kg. CONCLUSIONS: Our data confirm previous results demonstrating that HDC KO mice show reduced exploratory behaviors. However, contrary to the hypothesis that histamine plays an inhibitory role in reward, histamine-deficient mice were not more responsive to the psychostimulant effects of cocaine.

Effects of the H3-receptor inverse agonist thioperamide on the psychomotor effects induced by acutely and repeatedly given cocaine in C57BL/6J mice.

Previous studies have shown that histamine H(3) blockers potentiate the psychomotor and rewarding effects of cocaine. The present study examined the influence of thioperamide, an inverse H(3) receptor agonist, on the development of psychomotor sensitization and stereotyped activity induced by acute or intermittent cocaine in C57BL/6J mice. In the first experiment, mice were injected i.p. with saline, 10 or 20 mg/kg thioperamide and saline or 8 mg/kg cocaine, 10 min apart, before being tested for their locomotor activity (providing data on the acute effects of thioperamide on cocaine-induced activity). Subsequently, mice were treated in the same manner every other day over six additional sessions. Sensitization was assessed by the responsiveness to a cocaine challenge (8 mg/kg, i.p.) given 2 and 14 days following the intermittent treatment. In experiments 2 and 3, we tested the effects of thioperamide (10 or 20 mg/kg, i.p.) on gnawing and sniffing induced or affected by relatively high doses of cocaine (24 or 32 mg/kg, s.c.), the drugs being given 10 min apart. In the first experiment, both doses of thioperamide amplified cocaine-induced psychomotor hyperactivity almost on all experimental sessions. However, the histamine inverse agonist did not affect the induction of a psychomotor sensitization. All cocaine-treated mice showed similar levels of sensitized activity 2 and 14 days after the intermittent treatments, whether they received thioperamide or not. The second and the third experiments showed that thioperamide did not affect gnawing and sniffing induced by cocaine. Taken together, these results indicate that H(3) receptors clearly contribute to the neurobiological mechanisms of the locomotor component of cocaine-induced psychomotor activation, but less likely to those underlying the development of cocaine behavioral sensitization or the expression of cocaine-induced oro-facial stereotypies.

Response to novelty and cocaine stimulant effects: lack of stability across environments in female Swiss mice.

RATIONALE: In humans, novelty/sensation seeking is seen as a personality trait with a positive relationship with addiction vulnerability. In animal studies, one of the standard procedures to model novelty seeking is the "response to novelty," i.e., the levels of locomotor activity in a new environment. In rodents, a positive correlation was demonstrated between the response to novelty and several effects of drugs, especially the locomotor stimulant effects of cocaine. OBJECTIVES: The present study was designed to test in mice whether the response to novelty is stable across environments and whether its relationship with the stimulant effects of cocaine is altered by environmental changes. Experiment 1 assessed the responses to novelty of the same mice in two different novel environments. Experiment 2 tested the correlation between response to novelty and acute stimulant effects of cocaine recorded in two distinct environments. RESULTS: The results show a weak correlation only during the first 5 min of the session between the responses to novelty measured in two distinct environments. Experiment 2 demonstrates that novelty responses and stimulant effects of cocaine are positively correlated only when both behavioral responses are measured in the same environment. In contrast, the relationship between response to novelty and acute stimulant effects of cocaine is completely lost when the behavioral responses are recorded in two different environments. CONCLUSIONS: The present results question the usual interpretation of the correlation between the response to novelty and the stimulant effects of cocaine as reflecting a relationship between two underlying individual stable characteristics.

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.

Influence of the dose and the number of drug-context pairings on the magnitude and the long-lasting retention of cocaine-induced conditioned place preference in C57BL/6J mice.

RATIONALE: The place conditioning procedure is increasingly used to study relapse in drug seeking in mice. However, the retention course of drug-induced place preference has not been systematically characterized. METHODS: The effects of cocaine doses and number of conditioning trials on both the magnitude and the persistence of cocaine-induced conditioned place preference (CPP) were investigated in C57BL/6J mice. Twelve groups of animals were injected with saline, 4, 8 or 12 mg/kg cocaine (i.p.) and submitted to an unbiased counterbalanced place conditioning protocol including one, two or four drug-pairing sessions. Subsequently, the animals were tested at various time intervals after the last conditioning session. RESULTS: One cocaine-pairing session was insufficient to induce a CPP. Two and four pairing sessions resulted in significant place preferences of similar magnitude for all tested doses of cocaine, the place preference induced by the greatest number of pairing sessions being the strongest. In the two-pairing groups, place preference lasted less than 14 days for any tested dose of cocaine. In contrast, all four-pairing groups still showed significant place preference 28 days after the last conditioning session. However, the magnitude of cocaine place preference slowly declined at a rate that was dependent upon cocaine dose. On the 35-day post-conditioning interval, only the 12-mg/kg cocaine group still displayed a significant place preference, whereas place preference was undetectable at 42 and 56 days post-conditioning for all groups. CONCLUSIONS: The number of cocaine-pairing sessions, but not cocaine dose, affected the magnitude of cocaine place preference in mice when tested 1 day after the last conditioning session. In contrast, both cocaine doses and the number of pairing sessions affected the persistence of cocaine place preference. Overall, these results demonstrate that cocaine-induced place preference is a long lasting phenomenon that is strongly affected by the number of drug-pairing trials.

Evidence that the relations between novelty-induced activity, locomotor stimulation and place preference induced by cocaine qualitatively depend upon the dose: a multiple regression analysis in inbred C57BL/6J mice.

It has been speculated that an individual's response to novelty is a reliable predictor of its vulnerability to develop addiction. However, the relationships between response to novelty and the development of drug-induced conditioned place preference are still unclear. The present study investigates the relationships between locomotor responses to novelty, cocaine-induced locomotor stimulation and conditioned place preference in C57BL/6J mice with multiple regression analyses. Four groups of mice receiving saline, 4, 8 or 12 mg/kg cocaine (i.p.) were submitted to an 8-day unbiased counterbalanced place conditioning protocol. Levels of locomotion on the pre-conditioning session were used as a score of locomotor response to a novel environment. The locomotor activity on the first cocaine-pairing session of the conditioning procedure served as a measure of the locomotion-activating response to a single injection of cocaine. Cocaine-induced dose-dependent locomotor stimulant effects and a significant place preference at all tested doses. A positive correlation was found between the locomotor responses to novelty and the locomotor stimulant effects of cocaine, but was significant only for the highest dose of cocaine (12 mg/kg). In contrast, there was a negative correlation between the locomotor response to novelty and the conditioned place preference induced by 4 mg/kg cocaine. Finally, the locomotor stimulant effects of cocaine do not correlate with cocaine-induced conditioned place preference at any tested dose of cocaine. The relationships between locomotor response to novelty and both cocaine-induced stimulant and rewarding effects can be differentially affected by the dose in inbred C57BL/6J mice.

Cocaine-conditioned activity persists for a longer time than cocaine-sensitized activity in mice: implications for the theories using Pavlovian excitatory conditioning to explain the context-specificity of sensitization.

The present study was aimed at testing the prediction of the Pavlovian excitatory conditioning explanation of context-specific sensitization that the sensitized effect (SE) should persist as long as the post-sensitization conditioned activity (CR). C57BL/6J mice were tested for the expression of cocaine-induced conditioned and sensitized locomotion on several intervals after the establishment of a sensitization in an unchanging context. A group of mice received 10 once-daily injections of 10 mg/kg cocaine (s.c.) in a short time prior to being tested in activity-meters for 60 min sessions (cocaine-pretreated group), mice from a control group receiving saline in the same manner (saline-pretreated group). On the test sessions, taking place 1, 8 and 28 days after cocaine pretreatment, half of the animals of each pretreatment group (n=8) received a challenge test with saline and the other half with 10 mg/kg cocaine in the pretreatment context room (for CR and SE tests, respectively). The CR was significantly expressed on the three successive saline-challenge tests, albeit the activity levels were markedly decreased on the 28-day retention test. In contrast, the SE was significantly expressed only during the first half of the 1-day test session and the first 10 min of the 8-day test session, no SE effect being expressed on the 28-day retention test. The results, suggesting a functional uncoupling of the CR from the SE, disprove the theories of context-specificity of sensitization based completely or partially on Pavlovian excitatory conditioning mechanisms.

The H3 antagonist thioperamide reveals conditioned preference for a context associated with an inactive small dose of cocaine in C57BL/6J mice.

The histaminergic system has been speculated to be involved in the inhibitory control of drug reward, H1 and H2 antagonists having been found to potentiate conditioned place preference induced by morphine or cocaine. In contrast, the role of H3 receptors in cocaine-induced place preference is still unknown. The present study tested the effects of thioperamide (0, 10 and 20 mg/kg, i.p.), an H3 autoreceptor antagonist, on the development of a conditioned place preference induced by cocaine (0, 2 and 8 mg/kg, i.p.) in C57BL/6J mice. Thioperamide was injected 10 min before each cocaine-pairing session. The activity scores recorded on the first cocaine-pairing session were also used to test the effects of thioperamide on cocaine-induced locomotor activity. Thioperamide alone had no reinforcing effects and did not affect the conditioned place preference induced by 8 mg/kg cocaine. However, thioperamide dose-dependently revealed a conditioned place preference induced by 2 mg/kg cocaine, a dose that was inactive per se. Finally, thioperamide dose-dependently potentiated the stimulant effects of cocaine, in spite of its slight hypolocomotor effect when given alone. Our results strongly suggest that H3 antagonists potentiate the stimulant and reinforcing effects of cocaine in mice.

Acamprosate reduces context-dependent ethanol effects.

RATIONALE: Previous studies have indicated that the conditioned effects of environmental stimuli contribute to ethanol tolerance and abuse. Acamprosate was recently suggested to reduce the effects of environmental stimuli previously associated with ethanol administrations. This action is believed to contribute to the clinical benefits of acamprosate treatment in alcoholics. OBJECTIVES: In the present experiment, a classical drug-conditioning paradigm was used to test whether acamprosate modulates the effects of ethanol-paired environmental stimuli on spontaneous motor activity. METHODS: Wistar rats were divided into three groups: cued, uncued and control. The cued group daily received ethanol injections (2.0 g/kg, IP) in a specific testing environment. The uncued group daily received ethanol injections (2.0 g/kg, IP) in their home cage but never experienced ethanol in the testing environment. The control group was injected with saline and never experienced ethanol. After 8 conditioning days, the rats were IP injected with various ethanol doses (saline, 1.0, 1.5 or 2.0 g/kg) and their spontaneous motor activity in the testing environment was recorded to investigate their respective tolerance to ethanol inhibitory effects. In the second part of the study, the same procedure was repeated with chronically acamprosate-treated rats. The chronic acamprosate treatment (400 mg/kg per day) started 2 weeks before the conditioning procedure by diluting acamprosate in the drinking bottles and was maintained throughout the whole experiment. RESULTS: The cued rats showed a significant environment-dependent tolerance to ethanol inhibitory effects relative to the uncued and control rats. This higher ethanol tolerance of the cued rats was mainly due to a faster recovery from ethanol's inhibitory effects on spontaneous activity. Furthermore, the cued rats showed a higher level of activity in the testing environment after the saline injection. However, it is not clear whether this hyperactivity is a conditioned compensatory response or an increased exploratory behavior. Acamprosate totally abolished the environment-dependent tolerance to ethanol, whereas it did not alter the hyperactivity of the cued rats in the testing environment. CONCLUSIONS: The results of the present study suggest that acamprosate reduces ethanol-conditioned effects. Such an action may be of importance to explain the anti-relapse effects of acamprosate.

Quasi-asymptotic development of conditioned hyperactivity induced by intermittent injections of cocaine in C57BL/6J mice.

The emergence of a conditioned cocaine-induced hyperlocomotion was examined in C57BL/6J mice using a procedure that has not been used previously. Two days after a session of preexposure to the test chambers under saline, a first group of mice (cocaine-cued) received five once-daily injections of 10-mg/kg s.c. cocaine every other day (on the odd days of the chronic treatment period) and a saline injection on the 5 days following each cocaine injection day (on the even days of the treatment period), in all cases before being placed in the test chamber. Another group of mice (saline-cued) received 10 injections of saline on both the even and the odd days in the same context, and a third group of mice (cocaine-uncued) received five injections of saline on the even days in the test context and five injections of cocaine on the odd days in an alternative context. On the odd days sessions, the cocaine-cued group showed significant repeated increases in locomotion without behavioural sensitisation being induced, whereas the saline-cued levels of locomotion remained on baseline levels. On the first even session, the three groups did not differ from each other and showed lower levels of locomotion than on the preexposure session. During the two following even sessions, the cocaine-cued group showed an increase in locomotion that levelled off on the two remaining sessions, whereas the saline-cued and the cocaine-uncued groups (which presented comparable values) exhibited significantly lower levels of locomotion. That pattern of successive placebo responses resembles the typical S-shaped development of a Pavlovian conditioned response, albeit the increase described here was quite rapid. The protocol used here may provide an additional method for the experimental analysis of stimulant-induced conditioned placebo activity.

Stimulant and motivational effects of alcohol: lessons from rodent and primate models.

In several animal species including humans, the acute administration of low doses of alcohol increases motor activity. Different theories have postulated that alcohol-induced hyperactivity is causally related to alcoholism. Moreover, a common biological mechanism in the mesolimbic dopamine system has been proposed to mediate the stimulant and motivational effects of alcohol. Numerous studies have examined whether alcohol-induced hyperactivity is related to alcoholism using a great variety of animal models and several animal species. However, there is no review that has summarized this extensive literature. In this article, we present the various experimental models that have been used to study the relationship between the stimulant and motivational effects of alcohol in rodents and primates. Furthermore, we discuss whether the theories hypothesizing a causal link between alcohol-induced hyperactivity and alcoholism are supported by published results. The reviewed findings indicate that animal species that are stimulated by alcohol also exhibit alcohol preference. Additionally, the role of dopamine in alcohol-induced hyperactivity is well established since blocking dopaminergic activity suppresses the stimulant effects of alcohol. However, dopamine transmission plays a much more complex function in the motivational properties of alcohol and the neuronal mechanisms involved in alcohol stimulation and reward are distinct. Overall, the current review provides mixed support for theories suggesting that the stimulant effects of alcohol are related to alcoholism and highlights the importance of animal models as a way to gain insight into alcoholism.

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.

Therapeutic potential of histaminergic compounds in the treatment of addiction and drug-related cognitive disorders.

Addiction is a behavioral disorder characterized by the compulsive seeking and taking of drugs despite serious negative consequences. In particular, the chronic use of drugs impairs memory and cognitive functions, which aggravates the loss of control over drug use and complicates treatment outcome. Therefore, cognitive enhancers targeting acetylcholine have been proposed to treat addiction. Interestingly, histamine H(3) receptor (H(3)R) antagonists/inverse agonists stimulate acetylcholine transmission in different brain areas, facilitate memory in animal models and can reverse learning deficits induced by drugs such as scopolamine, dizocilpine and alcohol. Moreover, several studies found that compounds capable of activating the histaminergic system generally decrease the reinforcing effects of drugs, namely alcohol and opioids, in preclinical models of addiction. Finally, several H(3)R antagonists/inverse agonists increase histamine in the brain and have proven to be safe in humans. However, no studies have yet investigated the therapeutic potential of cognitive enhancing H(3)R antagonists/inverse agonists in the treatment of addiction in humans. The present review first describes the impact of addictive drugs on learning processes and cognitive functions that play an important role for addicts to remain abstinent. Second, our work briefly summarizes the relevant literature describing the function of histamine in learning, memory and drug addiction. Finally, the potential therapeutic use of histaminergic agents in the treatment of addiction is discussed. Our review suggests that histaminergic compounds like H(3)R antagonists/inverse agonists may improve the treatment outcome of addiction by reversing drug-induced cognitive deficits and/or diminishing the reinforcing properties of addictive drugs, especially opioids and alcohol.

The histamine H3-receptor inverse agonist pitolisant improves fear memory in mice.

Numerous studies have demonstrated that brain histamine plays a crucial role in learning and memory and histamine H3 receptor inverse agonists (H3R inverse agonists) have been proposed to treat cognitive disorders. Pitolisant (BF2.649, 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine, hydrochloride) was the first H3R inverse agonist that has been tested in human trials and is well tolerated. The present study investigated whether Pitolisant (0.625-20mg/kg, i.p.) improves consolidation and reconsolidation processes in the fear conditioning task in female C57BL/6J mice. We also tested whether Pitolisant reverses memory deficits induced by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (MK-801). Our results indicate that post-training systemic injections of Pitolisant facilitated consolidation of contextual fear memory and reversed amnesia induced by an i.p. injection of 0.12 mg/kg dizocilpine. In addition, none of the doses of Pitolisant we have tested after reactivation (reexposure to the context in which training took place 48 h earlier) affected reconsolidation, whereas dizocilpine disrupted it. However, Pitolisant was able to reverse the deficit in reconsolidation induced by 0.12 mg/kg dizocilpine. The present results are the first demonstration that Pitolisant is effective in improving consolidation processes in the fear condition task and add further evidence to its potential for treating cognitive disorders.

The prototypical histamine H3 receptor inverse agonist thioperamide improves multiple aspects of memory processing in an inhibitory avoidance task.

Numerous studies have found that histamine plays a major role in memory and that the histamine H3 receptor (H3R) inverse agonist thioperamide improves cognitive performance in various animal models. However, little is known about the stages of memory that are specifically affected by thioperamide. The purpose of the present study was to investigate the effects of thioperamide on acquisition, consolidation and retrieval processes in a one-trial inhibitory avoidance task in female C57BL/6J mice. In addition, potential state-dependency effects were studied by injecting thioperamide before the training and the test sessions in order to induce similar physiological states during acquisition and retrieval. Our results indicate that post-training systemic administration of thioperamide facilitated consolidation. Moreover, the administration of thioperamide before the training session had no effect on latency to enter the black compartment during training but enhanced memory during the retention test. The administration of thioperamide before the retention test also increased performance, which indicates that this compound ameliorates memory retrieval. Finally, when animals received thioperamide before the training session and before the retention test, the cognitive enhancing effects of thioperamide were not significantly changed. Together, our results show that thioperamide improves cognitive performance in an inhibitory avoidance task through actions on different memory stages. Furthermore, inducing a similar physiological state with thioperamide during acquisition and retrieval do not significantly affect cognitive enhancement. Our results suggest that the blockade of H3R can be helpful for the treatment of neuropsychiatric conditions characterized by deficits affecting several stages of memory processing.