Continuous renal replacement therapy and survival in acute liver failure: A systematic review and meta-analysis.

OBJECTIVE: Acute liver failure (ALF) is a rare syndrome leading to significant morbidity and mortality. An important cause of mortality is cerebral edema due to hyperammonemia. Different therapies for hyperammonemia have been assessed including continuous renal replacement therapy (CRRT). We conducted a systematic review and meta-analysis to determine the efficacy of CRRT in ALF patients. MATERIALS AND METHODS: We searched MEDLINE, EMBASE, Cochrane Library, and Web of Science. Inclusion criteria included adult patients admitted to an ICU with ALF. Intervention was the use of CRRT for one or more indications with the comparator being standard care without the use of CRRT. Outcomes of interest were overall survival, transplant-free survival (TFS), mortality and changes in serum ammonia levels. RESULTS: In total, 305 patients underwent CRRT while 1137 patients did not receive CRRT. CRRT was associated with improved overall survival [risk ratio (RR) 0.83, 95% confidence interval (CI) 0.70-0.99, p-value 0.04, I2 = 50%] and improved TFS (RR 0.65, 95% CI 0.49-0.85, p-value 0.002, I2 = 25%). There was a trend towards higher mortality with no CRRT (RR 1.24, 95% CI 0.84-1.81, p-value 0.28, I2 = 37%). Ammonia clearance data was unable to be pooled and was not analyzable. CONCLUSION: Use of CRRT in ALF patients is associated with improved overall and transplant-free survival compared to no CRRT.

Physical exercise and catecholamine reuptake inhibitors affect orienting behavior and social interaction in a rat model of attention-deficit/hyperactivity disorder.

The effects of methylphenidate (MPH), atomoxetine (ATMX), and/or physical exercise (EX) on orienting behavior and social interaction were examined in spontaneously hypertensive rats (SHRs), a commonly used animal model of attention-deficit/hyperactivity disorder (ADHD). During the orienting procedure, rats received repeated presentations of a nonreinforced visual stimulus. As observed previously, orienting behavior (rearing up on the hind legs) habituated across trials in normo-active control rats (Wistars) but not in SHRs, suggesting that SHRs have difficulty ignoring irrelevant behavioral stimuli. Treatment with MPH (0.125 mg/kg), ATMX (0.125 mg/kg), or EX (3 weeks of access to a running wheel), alone or in combination, reduced rearing behavior in SHRs to the level observed in the Wistar control group. Similarly, drug treatment and/or EX reduced the number of social interactions exhibited by SHRs, while having no effects on locomotor activity. It is important to note that EX was just as effective as MPH or ATMX in reducing orienting behavior and social interaction. In contrast to the SHRs, neither MPH nor ATMX affected orienting or social behavior in Wistar rats. Together, these findings support the growing literature that EX may be useful as an adjunctive or replacement therapy in ADHD. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Modulation of heroin intake by ovarian hormones in gonadectomized and intact female rats.

RATIONALE: Heroin intake decreases during the proestrus phase of the estrous cycle in female rats. Circulating concentrations of both estradiol and progesterone peak during proestrus, and it is not known which of these hormones, or their combination, are responsible for these effects. OBJECTIVES: The purpose of this study was to determine the effects of estradiol, progesterone, and their combination on heroin self-administration in female rats. METHODS: In Experiment 1, the estrous cycle of intact female rats was tracked daily. If a rat was in proestrus, either the estrogen receptor antagonist, raloxifene, the progesterone receptor antagonist, mifepristone, or their combination was administered 30 min prior to a heroin self-administration session. In Experiment 2, separate groups of ovariectomized female rats were treated chronically with exogenous estradiol, progesterone, estradiol + progesterone, or vehicle, and heroin intake was examined over a 100-fold dose range. RESULTS: In Experiment 1, raloxifene, but not mifepristone, significantly blocked proestrus-associated decreases in heroin intake. In Experiment 2, estrogentreated rats self-administered less heroin than any other group and significantly less heroin than rats treated with progesterone. CONCLUSIONS: These data suggest that (1) estradiol but not progesterone is responsible for proestrus-associated decreases in heroin intake and (2) estradiol decreases heroin intake relative to progesterone. These data differ from those reported previously with stimulants and suggest that estrogen-based pharmacotherapies may be of value to women with opioid use disorder.

Continuous renal replacement therapy and transplant-free survival in acute liver failure: protocol for a systematic review and meta-analysis.

BACKGROUND: Acute liver failure is a rare syndrome with significant morbidity and mortality, particularly in absence of transplantation as a rescue therapy. An important mechanism contributing to mortality is hyperammonemia which drives cerebral edema and raised intracranial pressure. Multiple therapies for managing hyperammonemia have been trialed. Continuous renal replacement therapy is effective in treating hyperammonemia in other disease states (notably inborn errors of metabolism). Its efficacy in acute liver failure has been suggested but further investigation is required to prove this. The objective of this systematic review will be to determine the efficacy of continuous renal replacement therapy in patients with acute liver failure and its effect on mortality and transplant-free survival. METHODS: MEDLINE, EMBASE, Web of Science, and Cochrane Database will be searched. Identified studies will include all patients with acute liver failure in a critical care unit treated with continuous renal replacement therapy. Primary outcome will be effectiveness of ammonia clearance and mortality. Patients treated with any other modality of ammonia lowering therapy (such as plasma exchange or Molecular Adsorbent Recirculating System) will be excluded. Narrative synthesis of the identified studies will occur and if clinical homogeneity is identified, data will be pooled for meta-analysis using a DerSimonian-Laird random effects model. DISCUSSION: We present a protocol for a systematic review seeking to establish a link between transplant-free survival in acute liver failure and the use of continuous renal replacement therapy. Given the anticipated paucity of literature on this subject, both narrative and quantitative syntheses are planned. SYSTEMATIC REVIEW REGISTRATION: (PROSPERO) CRD42019122520, registered April 16, 2019.

The effects of social contact on cocaine intake in female rats.

BACKGROUND: Studies conducted in male rats report that social contact can either facilitate or inhibit drug intake depending on the behavior of social partners. The purpose of the present study was to: (1) examine the effects of social contact on cocaine intake in female rats, (2) examine the behavioral mechanisms by which social contact influences cocaine intake, and (3) examine whether the estrous cycle moderates the effects of social contact on cocaine intake. METHODS: Female rats were assigned to either isolated or pair-housed conditions in which a social partner either had access to cocaine (cocaine partner) or did not have access to cocaine (abstinent partner). Pair-housed rats were tested in custom-built operant conditioning chambers that allowed both rats to be tested simultaneously in the same chamber. RESULTS: Rats housed with a cocaine partner self-administered more cocaine than isolated rats and rats housed with an abstinent partner. A behavioral economic analysis indicated that these differences were driven by a greater intensity of cocaine demand (i.e., greater intake at lower unit prices) in rats housed with a cocaine partner. Multivariate modeling revealed that the estrous cycle did not moderate the effects of social contact on cocaine intake. CONCLUSIONS: These findings indicate that: (1) social contact influences cocaine self-administration in females in a manner similar to that reported in males, (2) these effects are due to differences in the effects of social contact on the intensity of cocaine demand, and (3) these effects are consistent across all phases of the estrous cycle.

Exercise as a Prevention for Substance Use Disorder: A Review of Sex Differences and Neurobiological Mechanisms.

PURPOSE OF REVIEW: This report provides an update on clinical and preclinical findings for the efficacy of exercise to prevent substance use disorder with a focus on recent evidence for sex differences and neurobiological mechanisms. RECENT FINDINGS: Exercise/physical activity is associated with decreased drug use in humans. Preclinical results further indicate that exercise decreases vulnerability to drug use and the development of features of substance use disorder, and suggest that females have an enhanced sensitivity to its reward-substitution effects. However, certain exercise conditions may sensitize the reward pathway and enhance vulnerability suggesting that parallel observations in humans (e.g., increased prescription opioid misuse and heroin use in high-school athletes) may be biologically-based. SUMMARY: Exercise is a promising prevention strategy for substance use disorder. Further work is needed to establish its efficacy as a sex-specific strategy using larger samples, and to understand the exercise conditions that induce beneficial versus risk-enhancing effects.

Exercise as a Sex-Specific Treatment for Substance Use Disorder.

PURPOSE OF REVIEW: Exercise is a promising treatment for substance use disorder that may reduce withdrawal symptoms and prevent relapse. In this review, we discuss recent evidence from clinical and preclinical studies for its efficacy, from a behavioral to a molecular level, in order to understand the exercise conditions that lead to beneficial effects. We also highlight the few recent findings of sex-specific differences. RECENT FINDINGS: Clinical and preclinical findings show that exercise decreases withdrawal symptoms, including craving, in both males and females. Evidence from clinical studies support the efficacy of exercise to prevent relapse to smoking, although further research is needed to examine sex differences, establish long-term efficacy, and to determine if effects extend to other substance use disorders. Preclinical findings also support the potential utility of exercise to prevent relapse with evidence suggesting that its efficacy is enhanced in males, and mediated by blocking drug-induced adaptations that occur during early abstinence. SUMMARY: Sex differences and timing of exercise availability during abstinence should be considered in future studies examining exercise as an intervention for relapse. A better understanding of the neurobiological mechanisms underlying the efficacy of exercise to reduce withdrawal symptoms and prevent relapse is needed to guide its development as a sex-specific treatment.

Acute bouts of wheel running decrease cocaine self-administration: Influence of exercise output.

Exercise is associated with lower rates of drug use in human populations and decreases drug self-administration in laboratory animals. Most of the existing literature examining the link between exercise and drug use has focused on chronic, long-term exercise, and very few studies have examined the link between exercise output (i.e., amount of exercise) and drug self-administration. The purpose of this study was to examine the effects of acute bouts of exercise on cocaine self-administration, and to determine whether these effects were dependent on exercise output and the time interval between exercise and drug self-administration. Female rats were trained to run in automated running wheels, implanted with intravenous catheters, and allowed to self-administer cocaine on a fixed ratio (FR1) schedule of reinforcement. Immediately prior to each test session, subjects engaged in acute bouts of exercise in which they ran for 0, 30, or 60min at 12m/min. Acute bouts of exercise before test sessions decreased cocaine self-administration in an output-dependent manner, with the greatest reduction in cocaine intake observed in the 60-min exercise condition. Exercise did not reduce cocaine self-administration when wheel running and test sessions were separated by 12h, and exercise did not reduce responding maintained by food or responding during a saline substitution test. These data indicate that acute bouts of exercise decrease cocaine self-administration in a time- and output-dependent manner. These results also add to a growing body of literature suggesting that physical activity may be an effective component of drug abuse treatment programs.

The Effects of Excitatory and Inhibitory Social Cues on Cocaine-Seeking Behavior.

Social partners influence the likelihood of using drugs, developing a substance use disorder and relapse to drug use after a period of abstinence. Preclinical studies report that social cues influence the acquisition of cocaine use, the escalation of cocaine use over time, and the compulsive patterns of cocaine use that emerge during an extended binge. The purpose of this study was to examine the effects of social cues on the reinstatement of cocaine-seeking behavior after a period of abstinence. Male rats were obtained at weaning, assigned to triads (three rats/cage), reared to adulthood and implanted with intravenous catheters. Rats from each triad were then assigned to one of three conditions: (1) test rats were trained to self-administer cocaine and were tested for reinstatement; (2) cocaine partners were trained to self-administer cocaine and were predictive of response-contingent cocaine delivery; and (3) abstinent partners were not given access to cocaine and were predictive of extinction. The test rats alternated social partners every 5 days for 20 days such that responding was reinforced with cocaine in the presence of the cocaine partner (S+) for 10 days and not reinforced with cocaine in the presence of the abstinent partner (S-) for 10 days. Responding of the test rats was then extinguished over 7 days under isolated conditions. Tests of reinstatement were then conducted in the presence of the cocaine partner and abstinent partner under extinction conditions. Neither social partner reinstated responding relative to that observed on the final day of extinction; however, responding was greater in the presence of the cocaine partner (S+) than the abstinent partner (S-) during the reinstatement test. These data fail to demonstrate that a social partner reinstates cocaine-seeking behavior after a period of abstinence, but they do indicate that social partners can serve as either excitatory or inhibitory discriminative stimuli to influence drug-seeking responses.

The effects of social contact on cocaine intake under extended-access conditions in male rats.

Social learning theories of drug use propose that drug use is influenced by the behavior of peers. We previously reported that cocaine self-administration under limited-access conditions can be either facilitated or inhibited by social contact, depending on the behavior of a peer. The purpose of this study was to determine whether social contact influences cocaine self-administration under conditions that are more representative of problematic patterns of drug use. Male rats were assigned to either isolated or pair-housed conditions in which a social partner either had access to cocaine or did not have access to cocaine. Pair-housed rats were tested in custom-built operant conditioning chambers that allowed both rats to be tested simultaneously in the same chamber. In Experiment 1, rats were tested for 14 consecutive days during daily 6-hr test sessions. In Experiment 2, different doses of cocaine were tested in 23-hr test sessions conducted every 3 days. All groups of rats escalated their cocaine intake in Experiment 1; however, pair-housed rats with a partner without access to cocaine had lower levels of intake throughout the 14 days of testing. In Experiment 2, pair-housed rats with a partner without access to cocaine had lower levels of cocaine intake than did rats with a partner with access to cocaine, and this effect was observed at all doses of cocaine tested. These data indicate that the behavior of a social partner (i.e., whether or not that partner is also self-administering cocaine) influences cocaine self-administration under conditions that model problematic patterns of drug use. (PsycINFO Database Record

The effects of sex, estrous cycle, and social contact on cocaine and heroin self-administration in rats.

RATIONALE: Preclinical studies indicate that gonadal hormones are important determinants of drug self-administration. To date, little is known about the influence of sex and estrous cycle on drug self-administration in ecologically relevant social contexts. OBJECTIVE: The objective of this study was to examine the role of sex and estrous cycle in a rat model during cocaine and heroin self-administration with male-female and female-female social dyads. METHODS: Male and female virgin rats were trained to self-administer cocaine and heroin in operant conditioning chambers that permitted two rats to self-administer concurrently, but prevented physical contact. Experiment 1 examined cocaine self-administration on a progressive ratio schedule in male-female dyads. Experiments 2 and 3 examined heroin self-administration on a fixed ratio schedule in male-female dyads at constant and varying doses, respectively. Experiment 4 examined heroin self-administration in female-female dyads on a fixed ratio schedule. RESULTS: Cocaine-maintained breakpoints increased by ∼17 % in females during estrus, but remained consistent in males. Heroin self-administration decreased by ∼70 % during proestrus in females whether they were isolated, housed with males, or housed with females. Heroin self-administration was lower in males than females under some conditions and was not consistently associated with the responding of females. CONCLUSIONS: Cocaine and heroin self-administration is influenced by the estrous cycle in females when in the presence of a male partner. As a novel finding, these data illustrate that heroin self-administration is reduced in females during proestrus regardless of the social context tested. Finally, these data suggest that drug self-administration in males is only minimally influenced by the hormonal status of a female partner.

Physical exercise affects attentional orienting behavior through noradrenergic mechanisms.

Spontaneously hypertensive rats (SHRs), a commonly used animal model of attention-deficit/hyperactivity disorder, exhibit little habituation of the orienting response to repeated presentations of a nonreinforced visual stimulus. However, SHRs that have access to a running wheel for 5, 10, or 21 days exhibit robust habituation that is indistinguishable from normo-active rats. Two days of exercise, in comparison, is not sufficient to affect habituation. Here we tested the hypothesis that the effect of exercise on orienting behavior in SHRs is mediated by changes in noradrenergic function. In Experiment 1, we found that 5, 10, or 21 days of access to a running wheel, but not 2 days, significantly reduced levels of the norepinephrine transporter in medial prefrontal cortex. In Experiment 2, we tested for a causal relationship between changes in noradrenergic function and orienting behavior by blocking noradrenergic receptors during exercise. Rats that received propranolol (beta adrenergic/noradrenergic receptor blocker) during 10 days of exercise failed to exhibit an exercise-induced reduction in orienting behavior. The results inform a growing literature regarding the effects of exercise on behavior and the potential use of exercise as a treatment for mental disorders.

Individual and combined effects of physical exercise and methylphenidate on orienting behavior and social interaction in spontaneously hypertensive rats.

This study determined the duration of exercise and amount of methylphenidate that is needed to affect attentional function and social behavior in spontaneously hypertensive rats (SHR), a commonly used animal model of Attention-Deficit/Hyperactivity Disorder (ADHD). Attention was assessed by measuring the orienting response to repeated presentations of a nonreinforced visual cue. Social behavior was examined by allowing rats to freely explore a large arena containing an unfamiliar conspecific rat. Consistent with their hyper-responsive phenotype, nonexercising SHRs exhibited a high level of orienting behavior and little habituation, as well as hyper-social behavior compared with normo-active rats. Exercise or methylphenidate decreased orienting behavior and social behavior in a dose-dependent fashion. In addition, we found an additive effect of combining doses of exercise and methylphenidate that alone were ineffective in altering behavior. These data indicate that physical exercise and methylphenidate can reduce hyper-responsiveness to irrelevant stimuli and reduce hyper-social behavior in SHR. Moreover, subthreshold doses of methylphenidate can be used in combination with moderate amounts of exercise to reduce distractibility, supporting the notion that exercise may be useful as an adjunctive or replacement therapy in ADHD.

Repeated Acquisition in the Morris Swim Task: Effects of MDMA, Methamphetamine and Methylphenidate.

Acute effects of methylenedioxymethamphetamine (MDMA), methamphetamine (MA) and methylphenidate (MPD) were studied using a within-subject, repeated acquisition/performance procedure adapted to the Morris Swim Task. To investigate place learning, the acquisition component consisted of a hidden platform that varied in location across experimental sessions. As a control for drug effects not specific to acquisition, a performance component was included in which the hidden platform was in the same pool location in every experimental session. All three drugs increased escape latencies and swim distances in dose-dependent fashion. However, impairment in the acquisition component was generally observed only at doses that also produced impairment in the performance component, suggesting that effects were not selective to place learning. None of the drugs produced enhancement of learning or performance at any dose. Taken together, the results suggest that acute exposure to these psychomotor stimulants produce global impairment of performance in the Morris task, rather than specific deficits in place learning.

Physical exercise and catecholamine reuptake inhibitors affect orienting behavior and social interaction in a rat model of attention-deficit/hyperactivity disorder.

The effects of methylphenidate (MPH), atomoxetine (ATMX), and/or physical exercise (EX) on orienting behavior and social interaction were examined in spontaneously hypertensive rats (SHRs), a commonly used animal model of attention-deficit/hyperactivity disorder (ADHD). During the orienting procedure, rats received repeated presentations of a nonreinforced visual stimulus. As observed previously, orienting behavior (rearing up on the hind legs) habituated across trials in normo-active control rats (Wistars) but not in SHRs, suggesting that SHRs have difficulty ignoring irrelevant behavioral stimuli. Treatment with MPH (0.125 mg/kg), ATMX (0.125 mg/kg), or EX (3 weeks of access to a running wheel), alone or in combination, reduced rearing behavior in SHRs to the level observed in the Wistar control group. Similarly, drug treatment and/or EX reduced the number of social interactions exhibited by SHRs, while having no effects on locomotor activity. It is important to note that EX was just as effective as MPH or ATMX in reducing orienting behavior and social interaction. In contrast to the SHRs, neither MPH nor ATMX affected orienting or social behavior in Wistar rats. Together, these findings support the growing literature that EX may be useful as an adjunctive or replacement therapy in ADHD.

Task demands dissociate the effects of muscarinic M1 receptor blockade and protein kinase C inhibition on attentional performance in rats.

The cholinergic system is known to be necessary for normal attentional processing. However, the receptors and mechanisms mediating the effects of acetylcholine on attention remain unclear. Previous work in our laboratory suggested that cholinergic muscarinic receptors are critical for maintaining performance in an attention-demanding task in rats. We examined the role of the muscarinic M(1) receptor and protein kinase C (PKC), which is activated by the M(1) receptor, in attention task performance. Rats were trained in an attention-demanding task requiring discrimination of brief (500, 100, 25 ms) visual signals from trials with no signal presentation. The effects of muscarinic M(1) receptor blockade were assessed by administering dicyclomine (0-5.0 mg/kg). The effects of PKC inhibition were assessed by administering chelerythrine chloride (0-2.0 mg/kg). Dicyclomine decreased the accuracy of detecting longer signals in this attention task, including when attentional demands were increased by flashing a houselight throughout the session. Chelerythrine chloride decreased the accuracy of signal detection in the standard version of the task but not when the houselight was flashed throughout the session. The present findings indicate that muscarinic M(1) receptors are critical for maintaining performance when attentional demands are increased, and that PKC activity may contribute to some aspects of attentional performance.

Maternal Exercise and Cognitive Functions of the Offspring.

Substantial research has established that exercise can improve mental health and cognitive function in both human and non-human animals. Exercise has been shown to improve learning and memory in both adult and juvenile animals, with larger and more durable effects associated with exercising during development. Exercise during the gestational period has also been shown to improve cognition in the offspring. Several recent studies indicate that the offspring of mothers that exercised during pregnancy exhibit improved learning and memory and decreased anxiety-like behaviors. These behavioral changes are accompanied by increased neurogenesis, neurotrophic factor expression, and neuronal activity in the offspring. This review summarizes the current literature regarding the effects of maternal exercise in rodents and presents avenues for future research to reveal the biological mechanism(s) through which maternal exercise changes the brain and behavior of the offspring.

Effects of physical exercise on ADHD-like behavior in male and female adolescent spontaneously hypertensive rats.

The present study examined the effects of exercising (voluntary wheel running) during adolescence on attentional function in male and female spontaneously hypertensive rats (SHRs), a commonly used animal model of attention-deficit/hyperactivity disorder (ADHD). Once rats reached adulthood, they received one session in which a light was presented 12 times but not reinforced, followed by training sessions in which the light was paired with a food reward. Male and female SHRs that had access to running wheels exhibited levels of unconditioned orienting behavior that were similar to Wistar-Kyoto rats (normo-active control) while SHRs that did not have access to running wheels exhibited higher levels of unconditioned orienting behavior. When the light was later paired with food there were no differences between the groups of male rats, but exercising female SHRs exhibited a decrease in conditioned food cup behavior. Consistent with their established phenotype, SHR rats exhibited more locomotor activity during an open field exploration session than WKY rats, but there was no relationship between orienting behavior and locomotor activity. Together these data suggest that physical exercise during adolescence can benefit attentional capabilities.