Background: Methamphetamine is an addictive stimulant that can cause many adverse physical, psychological and psychosocial effects. Preliminary evidence shows cannabidiol, a non-intoxicating constituent of the cannabis plant, may have efficacy in treating opioid and nicotine dependence. However, no study has yet examined whether cannabidiol treatment might impact on methamphetamine addiction. Aims: The current study investigated whether cannabidiol administration reduces the motivation to self-administer methamphetamine and relapse to methamphetamine-seeking behavior following abstinence. Methods: Thirty-two male Sprague Dawley rats with implanted jugular vein catheters were initially trained to self-administer methamphetamine via lever press during two-hour sessions on a fixed ratio 1 schedule of reinforcement. Rats in experiment 1 (n=16) then advanced to a progressive ratio reinforcement schedule to examine the effects of cannabidiol (0, 20, 40, and 80 mg/kg intraperitoneal) on motivation to self-administer methamphetamine. Rats in experiment 2 (n=16) were tested for cannabidiol effects on methamphetamine-primed reinstatement following extinction. Results: Cannabidiol (80 mg/kg, but not 40 mg/kg, or 20 mg/kg) reduced the motivation to self-administer methamphetamine and attenuated methamphetamine-primed relapse to methamphetamine-seeking behavior after extinction. Conclusion: This is the first demonstration that cannabidiol can reduce the motivation to seek and consume methamphetamine, and suggests that cannabidiol might be worth trialing as a novel pharmacotherapy for methamphetamine dependence.

This study aimed to assess cognition in patients with severe sepsis or septic shock and whether cognitive impairment was associated with clinical and laboratory parameters. We conducted a cohort study of patients with severe sepsis and septic shock evaluated within 24 h and one year after ICU discharge. Demographic, clinical and laboratory data were analyzed, and the following neuropsychological tests were applied: Consortium to Establish Registry for Alzheimer’s Disease, Mini-Mental State Examination, and Trail Making Test forms A and B. We included 33 patients, mean age of 49, 19% were female. Patients underperformed on most measures 24 h after ICU discharge, with improvement on follow-up. IQCODE, APACHE II scores, NSE and IFN-γ levels at ICU discharge were associated with poor cognitive performance, while higher educational level was associated with good cognitive performance. The time to first antibiotic dose, accumulated dose of haloperidol during UCI stay and mean glycemia were also associated with poor cognitive outcome. In general, patients with severe sepsis or septic shock have cognitive impairment that can improve over time. This improvement was associated with factors identified during their ICU stay, such as cognitive reserve, educational level, mean glycemia during ICU stay and NSE level.

Sepsis can lead to long-term cognitive changes, including memory and learning deficits, which are known as septic encephalopathy (SE). SE also includes behavioral changes. The underlying mechanism of SE is unknown, and several mechanisms have been proposed. This study investigated late anxiety-like behavior, serum cytokine levels and brain cytokine production in C57BL/6 mice subjected to polymicrobial sepsis induced by sublethal cecum ligature and puncture (CLP). Anxiety-like behavior and locomotor activity were assessed in mice 10 days after sham operation or CLP procedure using the elevated plus maze, contextual fear conditioning, and open field test. Brain and serum concentrations of the cytokines TNF-α, IFN-γ, IL-1β, IL-6, and IL-10 were determined by ELISA. We found that mice subjected to polymicrobial sepsis presented anxiety-like behavior, which was accompanied by increased serum TNF-α and brain TNF-α, IFN-γ, IL-1β, and IL-6 levels, 10 days after the surgical procedure. These findings suggest an involvement of central nervous system inflammatory mediators in the anxiety-like symptoms found in SE.

The neuropeptide oxytocin has emerged as a promising pharmacotherapy for methamphetamine (METH) addiction, and clinical trials of intranasal oxytocin are underway. However, there is debate as to how peripherally administered oxytocin alters brain signalling to modulate addiction processes. Interestingly, there is evidence for functional interactions between peripheral oxytocin administration and the vagus nerve. Therefore, this study investigated whether the effects of peripherally administered oxytocin require vagal signalling to reduce METH self-administration and reinstatement of METH-seeking behaviours. Male and female Sprague-Dawley rats underwent surgery for jugular catheterisation and either subdiaphragmatic vagotomy (SDV) or a sham operation. Rats were trained to self-administer METH, and the effect of peripherally administered oxytocin on METH intake was assessed. Rats then underwent extinction, and effects of oxytocin were assessed on cue-and METH-induced reinstatement of METH-seeking. Oxytocin treatment robustly attenuated METH intake in both sexes, and SDV entirely prevented the suppressant effect of oxytocin (0.3 mg/kg) on METH intake, and partially prevented the effects of 1 mg/kg oxytocin in both sexes. After extinction, SDV decreased the suppressing effects of oxytocin on cue-and METH-primed reinstatement in males, but not females. SDV was functionally confirmed by measuring food intake following administration of the vagal dependent peptide, cholecyostokin-8. Our data suggest that vagus nerve signalling is required for the inhibitory effects of peripherally administered oxytocin on METH self-administration and reinstatement, and that this vagal dependency is partially mediated by sex and drug withdrawal. This study has implications for the use of oxytocin as a therapy for METH use disorder for both sexes.

The involvement of TNF-α type 1 receptor (TNFR1) in memory deficits induced by sepsis was explored by using TNFR1 knockout (KO) mice. We reported that wild type (WT) mice presented memory deficits in the novel object recognition test 10 days after sepsis induced by cecum ligation and perforation (CLP). These deficits were not observed in TNFR1 KO mice. The involvement of serum and brain cytokines TNF-α, IL-1β, IL-6, IFN-γ and IL-10 was then investigated. TNFR1 KO mice had higher serum levels of TNF-α and IL-1β, and brain levels of TNF-α than WT mice. After CLP, the brain levels of TNF-α, IL-1β, IL-6 and IFN-γ increased in both WT and KO mice. Our next step was to determine the expression of inflammatory cytokines, BDNF and TrKb in the hippocampus. The absence of TNFR1 in mice subjected to polymicrobial sepsis resulted in higher BDNF expression in the hippocampus. In conclusion, after CLP, memory is preserved in the absence of TNFR1. This finding was associated with increased BDNF expression in the hippocampus.

Cocaine sensitization is a marker for some facets of addiction, is greater in female rats, and may be influenced by their sex hormones. We compared the modulatory effects of endogenous or exogenous estradiol and progesterone on cocaine-induced behavioral sensitization in 106 female rats. Ovariectomized female rats received progesterone (0.5 mg/mL), estradiol (0.05 mg/mL), progesterone plus estradiol, or the oil vehicle. Sham-operated control females received oil. Control and acute subgroups received injections of saline, while the repeated group received cocaine (15 mg/kg, ip) for 8 days. After 10 days, the acute and repeated groups received a challenge dose of cocaine, after which locomotion and stereotypy were monitored. The estrous cycle phase was evaluated and blood was collected to verify hormone levels. Repeated cocaine treatment induced overall behavioral sensitization in female rats, with increased locomotion and stereotypies. In detailed analysis, ovariectomized rats showed no locomotor sensitization; however, the sensitization of stereotypies was maintained. Only females with endogenous estradiol and progesterone demonstrated increased locomotor activity after cocaine challenge. Estradiol replacement enhanced stereotyped behaviors after repeated cocaine administration. Cocaine sensitization of stereotyped behaviors in female rats was reduced after progesterone replacement, either alone or concomitant with estradiol. The behavioral responses (locomotion and stereotypy) to cocaine were affected differently, depending on whether the female hormones were of an endogenous or exogenous origin. Therefore, hormonal cycling appears to be an important factor in the sensitization of females. Although estradiol increases the risk of cocaine sensitization, progesterone warrants further study as a pharmacological treatment in the prevention of psychostimulant abuse.

Objective: Sepsis survivors present a wide range of sequelae; few studies have evaluated psychiatric disorders after sepsis. The objective of this study was to define the prevalence of and risk factors for anxiety, depression and post-traumatic stress disorder (PTSD) symptoms in sepsis survivors. Method: Anxiety, depression and post-traumatic stress symptoms in severe sepsis and septic shock survivors 24 h and 1 year after intensive care unit (ICU) discharge were assessed using the Beck Anxiety/Depression Inventories and the PTSD Checklist-Civilian Version. Differences in psychiatric symptoms over time and the influence of variables on these symptoms were calculated with marginal models. Results: A total of 33 patients were enrolled in the study. The frequencies of anxiety, depression and PTSD 24 h after ICU discharge were 67%, 49%, and 46%, respectively and, among patients reevaluated 1 year after ICU discharge, the frequencies were 38%, 50%, and 31%, respectively. Factors associated with PTSD included serum S100B level, age, and Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) score. Factors associated with depression included patient age and cumulative dose of dobutamine. IQCODE score and cumulative dose of haloperidol in the ICU were associated with anxiety after ICU discharge. Conclusion: Patients who survive sepsis have high levels of psychiatric symptoms. Sepsis and associated treatment-related exposures may have a role in increasing the risk of subsequent depression, anxiety, and PTSD.

The animal model of repeated intermittent ethanol access induced behavioral changes in rats, and this ethanol exposure model induced an increase in DNA single-strand breaks and ROS production in all brain areas. Our results suggest that these brain damages may influence future behaviors.