Individual differences in GHB consumption in a new voluntary GHB self-administration model in outbred rats.

BACKGROUND AND PURPOSE: The use of the recreational drug gamma-hydroxybutyric acid (GHB) has increased over the past decade, concomitantly leading to a higher incidence of GHB use disorder. Evidence-based treatment interventions are hardly available and cognitive effects of long-term GHB use remain elusive. In order to study the development of GUD and the causal effects of chronic GHB consumption, a GHB self-administration model is required. EXPERIMENTAL APPROACH: Long Evans rats had access to GHB in their home cage according to a two-bottle choice procedure for 3 months. Intoxication and withdrawal symptoms were assessed using an automated sensor-based setup for longitudinal behavioral monitoring. Rats were trained in an operant environment according to a fixed ratio (FR) 1, 2, and 4 schedule of reinforcement. Addiction-like behaviors were assessed through progressive ratio-, non-reinforced-, and quinine-adulterated operant tests. In addition, the novel object recognition test and elevated plus maze test were performed before and after GHB self-administration to assess memory performance and anxiety-like behavior, respectively. KEY RESULTS: All rats consumed pharmacologically relevant levels of GHB in their home cage, and their intake remained stable over a period of 3 months. No clear withdrawal symptoms were observed following abstinence. Responding under operant conditions was characterized by strong inter-individual differences, where only a subset of rats showed high motivation for GHB, habitual GHB-seeking, and/or continued responding for GHB despite an aversive taste. Male rats showed a reduction in long-term memory performance 3 months after home-cage GHB self-administration. Anxiety-like behavior was not affected by GHB self-administration. CONCLUSION AND IMPLICATIONS: The GHB self-administration model was able to reflect individual susceptibility for addiction-like behavior. The reduction in long-term memory performance upon GHB self-administration calls for further research into the cognitive effects of chronic GHB use in humans.

Cognitive Performance during the Development of Diabetes in the Zucker Diabetic Fatty Rat.

Increased insulin levels may support the development of neural circuits involved in cognition, while chronic mild inflammation may also result in cognitive impairment. This study aimed to gain more insight into whether cognition is already impacted during adolescence in a genetic rat model for obesity and type 2 diabetes. Visual discrimination learning throughout adolescence and the level of motivation during early adulthood were investigated in Zucker Diabetic Fatty (ZDF) obese and ZDF lean rats using operant touchscreens. Blood glucose, insulin, and lipids were longitudinally analyzed. Histological analyses were performed in the liver, white adipose tissues, and the prefrontal cortex. Prior to the experiments with the genetic ZDF research model, all experimental assays were performed in two groups of outbred Long Evans rats to investigate the effect of different feeding circumstances. Adolescent ZDF obese rats outperformed ZDF lean rats on visual discrimination performance. During the longitudinal cognitive testing period, insulin levels sharply increased over weeks in ZDF obese rats and were significantly enhanced from 6 weeks of age onwards. Early signs of liver steatosis and enlarged adipocytes in white adipose tissue were observed in early adult ZDF obese rats. Histological analyses in early adulthood showed no group differences in the number of prefrontal cortex neurons and microglia, nor PSD95 and SIRT1 mRNA expression levels. Together, our data show that adolescent ZDF obese rats even display enhanced cognition despite their early diabetic profile.

Ultrasonic Vocalizations in Adult C57BL/6J Mice: The Role of Sex Differences and Repeated Testing.

Ultrasonic vocalizations (USVs) are a major tool for assessing social communication in laboratory mice during their entire lifespan. At adulthood, male mice preferentially emit USVs toward a female conspecific, while females mostly produce ultrasonic calls when facing an adult intruder of the same sex. Recent studies have developed several sophisticated tools to analyze adult mouse USVs, especially in males, because of the increasing relevance of adult communication for behavioral phenotyping of mouse models of autism spectrum disorder (ASD). Little attention has been instead devoted to adult female USVs and impact of sex differences on the quantitative and qualitative characteristics of mouse USVs. Most of the studies have also focused on a single testing session, often without concomitant assessment of other social behaviors (e.g., sniffing), so little is still known about the link between USVs and other aspects of social interaction and their stability/variations across multiple encounters. Here, we evaluated the USVs emitted by adult male and female mice during 3 repeated encounters with an unfamiliar female, with equal or different pre-testing isolation periods between sexes. We demonstrated clear sex differences in several USVs' characteristics and other social behaviors, and these were mostly stable across the encounters and independent of pre-testing isolation. The estrous cycle of the tested females exerted quantitative effects on their vocal and non-vocal behaviors, although it did not affect the qualitative composition of ultrasonic calls. Our findings obtained in B6 mice, i.e., the strain most widely used for engineering of transgenic mouse lines, contribute to provide new guidelines for assessing ultrasonic communication in male and female adult mice.

Measuring sociability of mice using a novel three-chamber apparatus and algorithm of the LABORAS™ system.

BACKGROUND: The social approach and social novelty tests utilizing the three-chamber apparatus are widely accepted to measure social behavior of rodents. The LABORAS™ system offers a possibility to assess sociability of mice in a reliable and objective manner. NEW METHOD: We assessed the capability of the LABORAS™ sociability cage and algorithm (2.6.6) to detect social behaviors in mice. Furthermore, we investigated whether the system is able to detect various levels of sociability due to genetic background or after pharmacological treatments. RESULTS: By comparing manual scoring with various detection zone settings of the automated registration, the most fitting algorithm with a detection zone radius of 90 mm was identified. When different strains were investigated, C57Bl/6 J and NMRI mice proved to be social, while CD1 mice were found asocial. The system was able to detect the sociability increasing effect of R-baclofen (0.5 mg/kg i.p.) and oxytocin (12 ng i.c.v.) in asocial CD1 mice. The negative control PCP impaired social behavior of C57Bl/6 J mice (1 mg/kg i.p.) and increased social avoidance in CD1 mice (0.3 mg/kg i.p.). COMPARISON WITH EXISTING METHOD(S): This setup, in contrast to video frame analysis softwares, determines signal changes caused by movements of rodents allowing accurate detection and analysis of trajectories. Parallel automated measurements also allow replacing time and labor intensive, highly subjective human observational work. CONCLUSIONS: The set-up provides a fast and reliable method to examine social behavior of mice in the three-chamber apparatus. The system is capable of detecting pro or antisocial activity of pharmacological agents.