Prepulse Inhibition of the Startle Reflex as a Predictor of Vulnerability to Develop Locomotor Sensitization to Cocaine

Prepulse inhibition (PPI) of the startle reflex is a measure of sensory-motor synchronization. A deficit in PPI has been observed in psychiatric patients, especially those with schizophrenia and vulnerable subjects, since the neural bases of this disorder are also involved in the regulation of PPI. Recently, we have reported that baseline PPI levels in mice can predict their sensitivity to the conditioned reinforcing effects of cocaine in the conditioned place preference (CPP) paradigm. Mice with a low PPI presented a lower sensitivity to the conditioned rewarding effects of cocaine; however, once they acquired conditioned preference with a higher dose of the drug, a more persistent associative effect of cocaine with respect to environmental cues was evident in these animals when compared with High-PPI mice. Therefore, we proposed that the PPI paradigm can determine subjects with a higher vulnerability to the effects of cocaine. Developing locomotor sensitization after pre-exposure to cocaine is considered an indicator of transitioning from recreational use to a compulsive consumption of the drug. Thus, the aim of the present study was to evaluate whether subjects with a low PPI display a higher locomotor sensitization induced by cocaine. First, male and female OF1 mice were classified as High- or Low-PPI according to their baseline PPI levels. Subsequently, the motor effects induced by an acute dose of cocaine (Experiments 1 and 2) and the development of locomotor sensitization induced by pre-exposure to this drug (Experiments 3 and 4) were recorded using two apparatuses (Ethovision and actimeter). Low-PPI mice presented low sensitivity to the motor effects of an acute dose of cocaine, but a high increase of activity after repeated administration of the drug, thus suggesting a great developed behavioral sensitization. Differences after pretreatment with cocaine vs. saline were more pronounced among Low-PPI subjects than among High-PPI animals. These results endorse our hypothesis that the PPI paradigm can detect subjects who are more likely to display behaviors induced by cocaine and which can increase the risk of developing a cocaine use disorder. Herein, we further discuss whether a PPI deficit can be considered an endophenotype for cocaine use disorder

Sex differences in behavioral traits related with high sensitivity to the reinforcing effects of cocaine

Cocaine is the most prevalent illegal stimulant drug in Europe among the adult population. Its abuse is characterized by a faster substance abuse disorder (SUD) development than other drugs, with high vulnerability to relapse. However, there does not exist an effective treatment for cocaine dependence. Sex differences have been reported in psychological disorders including SUD. For this reason, it is essential to identify risk factors that predict susceptibility or resilience to cocaine addiction for the development of effective prevention strategies considering sex differences. In the present study, the main objective was to determine more sensitive phenotypes to the conditioned reinforcing effects of cocaine in both sexes. Anxiety-like behavior and the locomotor response to novelty were evaluated in the elevated plus maze, and despair in the tail suspension test, as well as vulnerability traits linked with a high sensitivity to the reinforcing effects of a subthreshold dose of cocaine (1 mg/kg) in the conditioned place preference (CPP) paradigm in male and female mice. Our results indicated that only female mice with high anxiety, low locomotor response to novelty or low despair levels acquired CPP induced by cocaine, while male mice with low anxiety, high locomotor response to novelty or high despair levels presented a higher susceptibility to the rewarding effects of cocaine than others. These sex differences in the results reveal an opposite pattern in males and females on the relationship between anxiety- and depressive-like behaviors and cocaine vulnerability, demonstrating the need to include female mice in preclinical studies

Ethanol intake in male mice exposed to social defeat: Environmental enrichment potentiates resilience

Large preclinical evidence shows that exposure to social defeat (SD) increases vulnerability to drug abuse, increasing the consumption of ethanol. However, not all subjects are equally affected by the changes induced by stress. Previous reports have evidenced that the resilient phenotype to depressive-like behaviors after SD is associated with the resistant phenotype to cocaine-increased rewarding effects and the smaller neuro- inflammatory response. The aim of the present study was to further clarify whether the resilient profile to depressive-like behavior also predicts a protection against the increase in ethanol intake induced by SD. The neuroinflammatory profile was studied after the end of the oral ethanol self-administration (SA) procedure, measuring levels of the pro-inflammatory cytokine IL-6 and the chemokine CX3CL1 or fractalkine in the striatum and prefrontal cortex. Previous studies have shown that environmental enrichment (EE) is an effective mecha- nism to dimish the detrimental effects of social stress. In a second study, we aimed to evaluate if EE housing before exposure to SD could potentiate resilience. Our results showed that mice with a phenotype susceptible to SD-induced depressive-like behaviors showed increased ethanol consumption and increased neuroinflammatory signaling. In contrast, despite the lack of effect on depressive-like behaviors, defeated mice previously housed under EE conditions did not show an increase in ethanol SA or an increase in immune response. To sum up, the resilient phenotype to SD develops at different levels, such as depressive-like behaviors, ethanol consumption and the neuroinflammatory response. Our results also point to the protective role of EE in potentiating resilience to SD effects

Effect of the CB1 cannabinoid agonist WIN 55212-2 on the acquisition and reinstatement of MDMA-induced conditioned place preference in mice

<p>Abstract</p> <p>Background</p> <p>Numerous reports indicate that MDMA users consume other psychoactive drugs, among which cannabis is one of the most common. The aim of the present study was to evaluate, using the conditioned place preference, the effect of the cannabinoid agonist WIN 55,212-2 on the rewarding effects of MDMA in mice.</p> <p>Methods</p> <p>In the first experiment adolescent mice were initially conditioned with 1.25, 2.5 or 5 mg/kg of MDMA or 0.1 or 0.5 mg/kg of WIN and subsequently with both drugs. Reinstatement of the extinguished preference by priming doses was performed in the groups that showed CPP. In the second experiment, animals were conditioned with 2.5 or 5 mg/kg of MDMA and, after extinction, reinstatement of the preference was induced by 0.5 or 0.1 mg/kg of WIN.</p> <p>Results</p> <p>A low dose of WIN 55212-2 (0.1 mg/kg) increased the rewarding effects of low doses of MDMA (1.25 mg/kg), although a decrease in the preference induced by MDMA (5 and 2.5 mg/kg) was observed when the dose of WIN 55212-2 was raised (0.5 mg/kg). The CB1 antagonist SR 141716 also increased the rewarding effects of the lowest MDMA dose and did not block the effects of WIN. Animals treated with the highest WIN dose plus a non-neurotoxic dose of MDMA exhibited decreases of striatal DA and serotonin in the cortex. On the other hand, WIN 55212-2-induced CPP was reinstated by priming injections of MDMA, although WIN did not reinstate the MDMA-induced CPP.</p> <p>Conclusions</p> <p>These results confirm that the cannabinoid system plays a role in the rewarding effects of MDMA and highlights the risks that sporadic drug use can pose in terms of relapse to dependence. Finally, the potential neuroprotective action of cannabinoids is not supported by our data; on the contrary, they are evidence of the potential neurotoxic effect of said drugs when administered with MDMA.</p

Efecto de la cocaína sobre la inhibición por prepulso de la respuesta de sobresalto

La inhibición por prepulso (IPP) de la respuesta de sobresalto es una medida de sincronización sensitivomotora basada en la respuesta del reflejo de sobresalto. Un déficit en la IPP se ha observado en pacientes psiquiátricos, especialmente con esquizofrenia, así como en sujetos vulnerables a desarrollarla. Asimismo, los consumidores de cocaína presentan un alto índice de patologías psiquiátricas como la esquizofrenia

Ultraviolet exposure of competitors during a Tokyo Olympic Sailing Regatta Test Event

Background Overexposure to sunlight is the main cause of skin cancer. Photoprotection practices and sunburn play a crucial role in skin cancer prevention. Objectives This study aimed to quantify the risk of sun exposure and to evaluate photoprotection practices in Spanish sailors during Olympic competitions. Methods Solar daily ultraviolet (UV) radiation cycle, personal UV dosimetry, photoprotection practices and sunburn checking were followed during three consecutive days of competition among sailors from the Spanish Olympic Sailing Team during a Tokyo Olympic Regatta Test Event. Results A total of 13 sailors (7 women), with mean age of 27.6 +/- 4.7 years and sports experience of 17.7 +/- 5.4 years, were studied. The most common phototypes were type III (53.8%) and type II (38.5%). The rate of sunburn checked was high (46.2%). The mean daily personal UV exposure received was 761.0 +/- 263.6 J/m(2), 3.0 +/- 1.1 minimal erythemal dose and 7.6 +/- 2.6 standard erythemal dose, seven times greater than the maximum permissible UV light exposure values for an 8 h working day. The use of a T-shirt was the most common practice (94.2%), followed by the use of shade (50.2%), hat/cap (44.0%), sunglasses (26.1%) and sunscreen (11.8%). Conclusions Olympic sailor's studies presented high levels of UV radiation received, high rate of sunburn and insufficient adherence to sun-protective behaviours (especially, to use of sunscreen) to prevent sunburn, the main cause of skin cancer. Sport Federations should develop educational campaigns addressing sun-related exposure habits and photoprotection behaviours to reduce the risk of skin cancer among these athletes

Binge eating of a high fat diet during adolescence modulates the rewarding effects of ethanol

Binge-eating is considered a specific form of overeating characterized by intermittent and high caloric food intake in a short period of time. Epidemiologic studies support a positive relation between the ingestion of fat and ethanol (EtOH), specifically among adolescent subjects. The aim of this work was to clarify the role of the compulsive, limited and intermittent intake of a high-fat food during adolescence on the rewarding effects of EtOH. After binge eating for 2 h, three days a week from postnatal day 29, the reinforcing effects of EtOH were tested with EtOH self-administration (SA) and conditioned place preference (CPP). Animals in the high fat binge (HFB) group that underwent the EtOH SA procedure presented greater EtOH consumption and a higher motivation to obtain the drug. HFB mice also developed preference for the paired compartment in the CPP with a subthreshold dose of EtOH. After the SA procedure, HFB mice exhibited reduced levels of the mu opioid receptor (MOr) and increased cannabinoid 1 receptor gene expression in the nucleus accumbens (N Acc), and decreased of tyrosine hydroxylase gene expression in the ventral tegmental area (VTA). Taken together the results suggest that bingeing on fat may represent a vulnerability factor to an escalation of EtOH consumption

Oxytocin prevents the increase of cocaine-related responses produced by social defeat

The neuropeptide oxytocin (OXT) plays a critical role in the regulation of social and emotional behaviors. OXT plays a role in the stress response and in drug reward, but to date no studies have evaluated its implication in the long-lasting increase of the motivational effects of cocaine induced by repeated social defeat (SD). During the social defeat procedure, 1 mg/kg of OXT was administered 30 minutes before each episode of SD. Three weeks after the last defeat, the effects of cocaine on conditioned place preference (CPP), locomotor sensitization and the self-administration (SA) paradigm were evaluated. Our results confirm that raising the levels of OXT during social defeat stress can block the long-lasting effects of this type of stress. OXT counteracts the anxiety induced by SD. Moreover, OXT prevents SD-induced increases in the motivational effects of cocaine. Administration of OXT before each social defeat blocked the SD-induced increment in the conditioned rewarding effects of cocaine in the CPP, favors the extinction of cocaine-associated memories in both the CPP and SA, and decreases reinstatement of cocaine-seeking behavior in the SA. In conclusion, the long-lasting effects of SD are counteracted by administering OXT prior to stress.Prometeo/2018/13