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Attention deficit hyperactive disorder (ADHD) is the most common psychiatric disorder in children affecting around 11% of children 4–17 years of age (CDC 2019). Children with ADHD are widely treated with stimulant medications such as methylphenidate (Ritalin®). However, there has been little research on the developmental effects of methylphenidate on risk-taking and sociability. We investigated in zebrafish the potential developmental neurobehavioral toxicity of methylphenidate on these behavioral functions. We chose zebrafish because they provide a model with extensive genetic tools for future mechanistic studies. We studied whether sub-chronic methylphenidate exposure during juvenile development causes neurobehavioral impairments in zebrafish. Methylphenidate diminished responses to environmental stimuli after both acute and sub-chronic dosing. In adult zebrafish, acute methylphenidate impaired avoidance of an approaching visual stimulus modeling a predator and decreased locomotor response to the social visual stimulus of conspecifics. Adult zebrafish dosed acutely with methylphenidate demonstrated behaviors of less retreat from threatening visual stimuli and less approach to conspecifics compared with controls. In a sub-chronic dosing paradigm during development, methylphenidate caused less robust exploration of a novel tank. In the predator avoidance paradigm, sub-chronic dosing that began at an older age (28 dpf) decreased activity levels more than sub-chronic dosing that began at earlier ages (14 dpf and 21 dpf). In the social shoaling task, sub-chronic methylphenidate attenuated reaction to the social stimulus. Acute and developmental methylphenidate exposure decreased response to environmental cues. Additional research is needed to determine critical mechanisms for these effects and to see how these results may be translatable to neurobehavioral toxicity of prescribing Ritalin® to children and adolescents. [ABSTRACT FROM AUTHOR]

As marijuana legalization is increasing, research regarding possible long-term risks for users and their offspring is needed. Little data exists on effects of paternal tetrahydrocannabinol (THC) exposure prior to reproduction. This study determined if chronic THC exposure alters sperm DNA methylation (DNAm) and if such effects are intergenerationally transmitted. Adult male rats underwent oral gavage with THC or vehicle control. Differentially methylated (DM) loci in motile sperm were identified using reduced representation bisulfite sequencing (RRBS). Another cohort was injected with vehicle or THC, and sperm DNAm was analyzed. Finally, THC-exposed and control adult male rats were mated with THC-naïve females. DNAm levels of target genes in brain tissues of the offspring were determined by pyrosequencing. RRBS identified 2,940 DM CpGs mapping to 627 genes. Significant hypermethylation was confirmed (p < 0.05) following oral THC administration for cytochrome P450 oxidoreductase (Por), involved in toxin processing and disorders of sexual development. Por hypermethylation was not observed after THC injection or in the subsequent generation. These results support that THC alters DNAm in sperm and that route of exposure can have differential effects. Although we did not observe evidence of intergenerational transmission of the DNAm change, larger studies are required to definitively exclude this possibility. [ABSTRACT FROM AUTHOR]

Rationale: A variety of neural systems are involved in drug addiction, and some of these systems are shared across different addictive drugs. We have found several different types of drug treatments that successfully reduce nicotine self-administration. Objectives: The current set of studies is the first in a series to determine if drug treatments that have been found to significantly reduce nicotine self-administration would reduce opiate self-administration. Methods: Amitifadine, a triple reuptake inhibitor of dopamine, norepinephrine, and serotonin, was assessed in female Sprague-Dawley rats to determine whether it significantly reduces remifentanil self-administration with either acute or chronic treatment. Results: Acutely, amitifadine doses of 5, 10, and 20 mg/kg each significantly reduced remifentanil self-administration. In a chronic study, repeated treatment with 10 mg/kg of amitifadine continued to reduce remifentanil self-administration, even after the cessation of treatment. However, amitifadine was not found to attenuate the rise in remifentanil self-administration with continued access. This study and our earlier one showed that the 10 mg/kg amitifadine dose did not significantly affect food motivated responding. Amitifadine did not attenuate remifentanil-induced antinociception as measured on the hot plate test but extended and maintained antinociceptive effects. Conclusions: These studies show the promise of amitifadine as a treatment for countering opiate self-administration for adjunctive use with opioids for analgesia. Further studies are needed to determine the possible efficacy of amitifadine for combating opiate addiction or preventing it in humans during adjunctive use with opioids for chronic pain. [ABSTRACT FROM AUTHOR]

Histamine H1 receptor systems have been shown in animal studies to have important roles in the reversal of sensorimotor gating deficits, as measured by prepulse inhibition (PPI). H1-antagonist treatment attenuates the PPI impairments caused by either blockade of NMDA glutamate receptors or facilitation of dopamine transmission. The current experiment brought the investigation of H1 effects on sensorimotor gating to human studies. The effects of the histamine H1 antagonist meclizine on the startle response and PPI were investigated in healthy male subjects with high baseline startle responses and low PPI levels. Meclizine was administered to participants (n=24) using a within-subjects design with each participant receiving 0, 12.5, and 25 mg of meclizine in a counterbalanced order. Startle response, PPI, heart rate response, galvanic skin response, and changes in self-report ratings of alertness levels and affective states (arousal and valence) were assessed. When compared with the control (placebo) condition, the two doses of meclizine analyzed (12.5 and 25 mg) produced significant increases in PPI without affecting the magnitude of the startle response or other physiological variables. Meclizine also caused a significant increase in overall self-reported arousal levels, which was not correlated with the observed increase in PPI. These results are in agreement with previous reports in the animal literature and suggest that H1 antagonists may have beneficial effects in the treatment of subjects with compromised sensorimotor gating and enhanced motor responses to sensory stimuli. [ABSTRACT FROM AUTHOR]

Epidemiological evidence suggests that people who begin experimenting with drugs of abuse during early adolescence are more likely to develop substance use disorders (SUDs), but this correlation does not guarantee causation. Animal models, in which age of onset can be tightly controlled, offer a platform for testing causality. Many animal models address drug effects that might promote or discourage drug intake and drug-induced neuroplasticity. We have reviewed the preclinical literature to investigate whether adolescent rodents are differentially sensitive to rewarding, reinforcing, aversive, locomotor, and withdrawal-induced effects of drugs of abuse. The rodent model literature consistently suggests that the balance of rewarding and aversive effects of drugs of abuse is tipped toward reward in adolescence. However, increased reward does not consistently lead to increased voluntary intake: age effects on voluntary intake are drug and method specific. On the other hand, adolescents are consistently less sensitive to withdrawal effects, which could protect against compulsive drug seeking. Studies examining neuronal function have revealed several age-related effects but have yet to link these effects to vulnerability to SUDs. Taken together, the findings suggest factors which may promote recreational drug use in adolescents, but evidence relating to pathological drug-seeking behavior is lacking. A call is made for future studies to address this gap using behavioral models of pathological drug seeking and for neurobiologic studies to more directly link age effects to SUD vulnerability. [ABSTRACT FROM AUTHOR]

This review provides insight for the judicious selection of nicotine dose ranges and routes of administration for in vivo studies. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. In many cases, such discrepancies could be attributed to the complex variables comprising species-specific in vivo responses to acute or chronic nicotine exposure. This review capitalizes on the authors’ collective decades of in vivo nicotine experimentation to clarify the issues and to identify the variables to be considered in choosing a dosaging regimen. Nicotine dose ranges tolerated by humans and their animal models provide guidelines for experiments intended to extrapolate to human tobacco exposure through cigarette smoking or nicotine replacement therapies. Just as important are the nicotine dosaging regimens used to provide a mechanistic framework for acquisition of drug-taking behavior, dependence, tolerance, or withdrawal in animal models. Seven species are addressed: humans, nonhuman primates, rats, mice, Drosophila, Caenorhabditis elegans, and zebrafish. After an overview on nicotine metabolism, each section focuses on an individual species, addressing issues related to genetic background, age, acute vs chronic exposure, route of administration, and behavioral responses. The selected examples of successful dosaging ranges are provided, while emphasizing the necessity of empirically determined dose–response relationships based on the precise parameters and conditions inherent to a specific hypothesis. This review provides a new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine. [ABSTRACT FROM AUTHOR]

Despite established links between nicotine dependence and depression, little research has examined the effects of nicotine on depression symptoms. This study evaluated the acute and chronic effects of transdermal nicotine in nonsmokers with baseline depression symptoms during a 4-week, double-blind, placebo-controlled trial. Nonsmokers with scores ≥10 on the Center for Epidemiological Studies Depression scale (CES-D) were recruited from the community. Mood and cognitive performance were measured at baseline (day 0) and at 1, 8, 21, and 28 days. Participants were randomly assigned to wear a placebo or nicotine patch for 4 weeks (3.5 mg/day during weeks 1 and 4; 7 mg/day during weeks 2 and 3). The final sample consisted of 11 nonsmokers with a mean baseline CES-D score of 27.36 (SD=10.53). Salivary nicotine levels indicated the majority of participants were compliant with treatment. Acute nicotine did not alter mood. After adjusting for baseline values, chronic nicotine resulted in a significant decline in CES-D scores at day 8 (3.5 mg/day), but returned to placebo levels by the last visit. This return to baseline levels was coincident with a decrease in nicotine administration from 7 to 3.5 mg/day. A similar trend for improved response inhibition as measured by the Conners Continuous Performance Task was also observed. Reported side effects were infrequent and minimal. These findings suggest a role for nicotinic receptor systems in the pathophysiology of depression and that nicotinic compounds should be evaluated for treating depression symptoms. [ABSTRACT FROM AUTHOR]

The article discusses research on the timing of nicotine effects on learning in zebrafish. It highlights the limits of some studies on nicotine. It states the significance of the zebrafish to neurobehavioral toxicology. It provides information on the methods and materials used in the study. It also discusses the results of the study.

The article discusses research on the effects of nicotine on cognitive function among cigarette smokers. It highlights the development of nicotinic treatments for cognitive dysfunction. It provides information on the methods and materials used in the study. It also discusses the results of the study.

Glucocorticoids are the consensus treatment for preventing respiratory distress syndrome in preterm infants but there is emerging evidence of subsequent neurobehavioral abnormalities, independent of somatic growth effects. Pregnant rats were given 0.2 mg/kg of dexamethasone, a dose commensurate with clinical use, on gestational days 17-19 and behavioral evaluations were made on the offspring in adolescence and adulthood. The dexamethasone groups had the same body weights as the controls but nevertheless displayed long-term, sex-selective alterations in locomotor and cognitive behaviors. In the figure-8 activity apparatus, dexamethasone treatment ablated the normal sex differences in locomotor activity by reducing values in females to the lower level typical of males; habituation of activity similarly was impaired in females, reducing the profile to match that of control males, while male rats in the dexamethasone group showed a partially feminized pattern of habituation. In the 8-arm radial maze, control rats displayed typical sex differences, with male rats performing more accurately than females. Dexamethasone treatment eliminated this normal dichotomy, delaying learning in males while improving performance in females to the level normally seen in control males. Finally, we assessed hippocampal [³H]hemicholinium-3 binding as a biomarker for cholinergic synaptic activity, and again found loss of sex differences in the dexamethasone group: values in males were increased to the higher levels typical of females. These results indicate that gestational treatment with dexamethasone obtunds the normal sex differences in neurochemistry and behavior that are typically seen in adolescence in adulthood, thus producing sex-selective alterations in activity, learning, and memory. [ABSTRACT FROM AUTHOR]

Extracellular superoxide dismutase (EC-SOD) plays an important role in controlling oxidative stress as well as intercellular signaling. In the current study, we tested the effect of EC-SOD overexpression over the lifespan of a set of mice and their wild-type controls to determine the time scale over which EC-SOD overexpression might attenuate aging-induced memory impairment. Mice with overexpression of EC-SOD and wild-type controls were initially trained on the radial-arm maze as young adults (3–5 months) and then retrained during middle age (12–14 months) and retested in old age at 27 and 30 months. There was little EC-SOD effect during the young adult middle age periods. EC-SOD overexpression prevented the decline in choice accuracy when the mice were 27–30 months of age. The EC-SOD overexpressing mice maintained their performance, while the wild-type mice declined to naïve levels of performance by 30 months of age. Enhancement of EC-SOD activity appears to improve memory performance specifically in aging mice. EC-SOD mimetic treatment during the course of aging may hold promise for aging-induced cognitive impairment. [ABSTRACT FROM AUTHOR]

Clozapine is an effective antipsychotic drug, but its effects on cognitive function are unclear. Previously, we found that clozapine caused a working memory deficit which was reversed by nicotine. Hippocampal systems are important in determining clozapine effect on memory. In the current study, the memory effects of clozapine and nicotine administration were determined in rats with lesions of the fimbria-fornix, a fiber bundle which carries cholinergic and other projections between the septum and the hippocampus. Female Sprague-Dawley rats were trained on a win-shift procedure in the radial-arm maze, in which each arm entry was rewarded once per session. Then, I 3 rats received bilateral knife-cut lesions of the fimbria-fornix, while 14 rats underwent sham surgery. The rats were tested after subcutaneous injections with combinations of clozapine (0 and I .25 mg/kg) and nicotine (0, 0.2, and 0.4 mg/kg). In sham- operated rats, clozapine caused a significant (P<.005) working memory impairment Fimbria-fornix lesions also caused a significant (P<:0.05) memory impairment Interestingly, clozapine had the opposite effect on working memory in the Iesioned vs sham-operated rats. in contrast to its effects in controls, clozapine (I .25 mg/kg) significantly (P < 0.05) attenuated the working memory deficit caused by fimbria-fornix lesions. Nicotine (0.2 mg/kg) did not quite significantly improve memory in lesioned rats. The effects of clozapine and nicotine were not additive in the lesioned rats. This study demonstrates the efficacy of clozapine in improving working memory in fimbria-fornix-lesioned rats, whereas it causes impairments in intact rats, Therapeutic treatment with clozapine in people with malfunctions of the hippocampus such as seen in schizophrenia may improve cognitive performance, whereas the same doses of clozapine may impair memory in individuals without hippocampal malfunction. [ABSTRACT FROM AUTHOR]

Rationale: Both central serotonergic and nicotinic systems play important roles in a variety of neuro-behavioral functions; however, the interactions of these two systems have not been fully characterized. The current study served to determine the impact of a relatively selective 5-HT2A receptor antagonist, ketanserin, on attentional function in rats and the interactions of ketanserin with nicotine administration. Methods: A standard operant visual signal detection task was used to assess sustained attention. In expt 1, adult female Sprague--Dawley rats (n=39) were injected subcutaneously (SC) with a dose range of ketanserin (0, 0.25, 0.5 and 1 mg/kg). In expt 2, the interactions of acute ketanserin (0, 1 and 2 mg/kg, SC) and acute nicotine (0, 25 and 50 µg/kg, SC) were assessed. In expt 3, the interaction of acute ketanserin (0, 1 and 2 mg/kg, SC) and chronic nicotine (5 mg/kg per day, SC for 4 weeks via osmotic pump) was characterized. Using an operant visual signal detection task, three possible outcomes (dependent variables) were measured in each trial: percent hit, percent correct rejection, and response omissions. Results: Ketanserin, when given alone, did not have a significant effect on either percent hit or percent correct rejection. Acute administration of 25 µg/kg nicotine significantly improved percent hit (i.e. improvement in choice accuracy), an effect that was reversed by acute administration of 1 mg/kg ketanserin. Chronic nicotine infusion for 28 consecutive days significantly increased percent correct rejection (i.e. improvement in choice accuracy) without development of tolerance, an effect which was reversed by an acute dose of 2 mg/kg ketanserin. Conclusions: These data suggest a functional interaction between nicotine and 5-HT2A receptor antagonist ketanserin. [ABSTRACT FROM AUTHOR]

Objectives. Chronic transdermal nicotine has been found to improve attentional performance in patients with Alzheimer’s disease (AD), but little is known about chronic nicotine effects in age-associated memory impairment (AAMI), a milder form of cognitive dysfunction. The current study was performed to determine the clinical and neuropsychological effects of chronic transdermal nicotine in AAMI subjects over a 4-week period. Design. The double-blind, placebo-controlled, cross-over study consisted of two 4-week periods separated by a 2-week washout period. Setting. An outpatient setting was used. Participants. The subjects (n=11) met criteria for AAMI. Interventions. The subjects were given nicotine patches (Nicotrol) to wear for 16 h a day at the following doses: 5 mg/day during week 1, 10 mg/day during week 2 and week 3 and 5 mg/day during week 4. Measurements. The effects of nicotine treatment were determined with the clinical global impressions questionnaire, Conners’ Continuous Performance test, and the automated neuropsychologic assessment metrics (ANAM) computerized neuropsychology battery. Results. Nicotine significantly improved the clinical global impression score as assessed by participants, as well as objective tests of attentional function on the Connors’ Continuous Performance Test and decision reaction time on the neuropsychology test battery. Nicotine did not improve performance on other tests measuring motor and memory function. Conclusion. Chronic transdermal nicotine treatment in AAMI subjects caused a sustained improvement in clinical symptoms and objective computerized tests of attention. These results support the further investigation of nicotinic treatment as a promising therapy for AAMI. [ABSTRACT FROM AUTHOR]

Rationale. Although the great majority of tobacco addiction begins during adolescence, little is known about differential nicotine effects in adolescents versus adults. Objectives. A rat model was used to determine the impact of the age of onset on nicotine self-administration. Methods. In expt 1, nicotine self-administration of female Sprague-Dawley rats over a range of acute doses (0.01–0.08 mg/kg per infusion) was determined in adolescent (beginning at 54–62 days) versus adult (beginning at 84–90 days). In expt 2, chronic nicotine self-administration over 4 weeks from adolescence into adulthood was compared with the chronic self-administration beginning in adulthood. In expt 3, adolescent-adult differences in nicotine effects on body temperature and locomotor responses were determined. Results. Adolescent-onset rats showed a significant main effect of increased nicotine intake compared with adult-onset rats in an eight-fold range of acute unit doses/infusion. Significant age differences were also seen in the chronic level of nicotine self-administration. Over 4 weeks, the adolescent-onset group had nearly double the rate of nicotine self-administration of the benchmark nicotine dose (0.03 mg/kg per infusion) compared to the adult-onset group. This increased nicotine intake persisted into adulthood. Adolescent rats had significantly greater response than adults to the hypothermic effects of nicotine, but had significantly less response than adults to the reduction in locomotor activity seen after nicotine. Conclusions. Adolescent-onset nicotine self-administration in female rats was associated with significantly higher levels of nicotine self-administration versus rats, which began nicotine self-administration in adulthood. This greater self-administration persists into adulthood and may underlie greater propensity of adolescents to nicotine addiction. [ABSTRACT FROM AUTHOR]

Rationale: During the past decade, central nicotinic systems have been shown in both experimental animals and humans to play an important role in cognitive function. However, the way in which specific aspects of cognitive function are affected by nicotinic systems has remained unclear. In humans, the most pronounced action of nicotine is to improve attention, but in rats, memory improvement is more easily seen. This may be due to differences in methods for assessing attention in rats and humans or to species differences in the roles of nicotinic systems in cognitive function. In the current study, we explored the effects of nicotine and mecamylamine using an operant visual signal detection task designed to model sustained attention processes common to rats and humans. Methods: Adult female rats (n=35) were trained to perform the signal detection task to a stable baseline of about 75% accuracy. The rats were then assigned to two subgroups of high and low accuracy based on overall accuracy (hits and correct rejections) at the end of training. All rats were then injected (SC, 10 min before testing) with saline or different doses of nicotine (0.0125, 0.025, 0.05, 0.1, 0.2 and 0.4 mg/kg) or the nicotinic antagonist mecamylamine (1, 2 and 4 mg/kg). Results: A low dose range of nicotine (0.0125, 0.025, and 0.05 mg/ kg) caused a dose-related increase in percent correct rejection. This dose range did not affect correct detections of the signal (percent hit). Higher doses of nicotine (0.1, 0.2 and 0.4 mg/kg) did not affect percent correct rejection, but did have a time-dependent effect on percent hit. Early in the session, the higher doses of nicotine reduced percent hit, whereas during the later part of the session higher doses of nicotine increased percent hit. Effects of nicotine did not differ between the high- and lowaccuracy rats. Mecamylamine decreased choice accuracy, reducing both percent hit and percent correct rejection. Mecamylamine reduced percent hit in... [ABSTRACT FROM AUTHOR]

Nicotine has been shown in a variety of studies to improve memory performance. The cognitive effects of nicotine are particularly important with regard to schizophrenia. In the current studies nicotine interactions with three different antipsychotic drugs, haloperidol, clozapine and risperidone, were assessed with regard to memory function. Female Sprague-Dawley rats were trained on the radial-arm maze to asymptotic levels of choice accuracy. They were then administered nicotine alone or in combination with haloperidol, clozapine or risperidone. Acute haloperidol (0.04 mg/kg) did not by itself affect memory performance. Co-administration of haloperidol with nicotine, however, decreased memory performance compared with nicotine administration in isolation. Acute clozapine (1.25 and 2.5 mg/kg) caused a significant memory impairment, an effect reversed by acute nicotine co-treatment. Risperidone (0.05 mg/kg), like haloperidol, did not by itself affect memory performance. Risperidone co-administration with nicotine, however, did significantly attenuate the improvement caused by nicotine administration in isolation. The similar interaction of haloperidol and risperidone with nicotine may be due to their common action of blocking D2 receptors, a mechanism of action not shared by clozapine. In contrast to the interaction of nicotine with haloperidol or risperidone, nicotine effectively reversed clozapine-induced memory impairment. These studies demonstrate interactions between nicotine and antipsychotic drugs in terms of memory, which may have important impacts on the treatment of schizophrenia. [Copyright &y& Elsevier]

Abstract Rationale: Acute and chronic systemic nico-tine administration has been shown to cause significant spatial memory improvement. The critical nicotinic re-ceptor subtypes for this effect and their location are still being determined. Nicotinic receptors in the ventral hip-pocampus have been found to be critically involved in memory. Acute ventral hippocampal infusions of dihy-dro- α -erythroidine (DH E), an α4β2 nicotinic receptor antagonist, impaired spatial memory of rats in the radial-arm maze. Objectives: The current study used chronic ventral hippocampal infusion of DH E as a model of nicotinic receptor loss such as that which occurs in Alz-heimer's disease. The therapeutic effect of systemic nic-otine treatment in reversing the DH E-induced memory impairment was determined. Methods: Rats were pre-trained to asymptotic levels of performance on the eight-arm radial maze. Then, they were implanted with bilater-al infusion cannulae in the ventral hippocampus, through which 0, 33.3, or 100 µg/side/day of DH E was continu-ously infused for 4 weeks. The rats were retested on the eight-arm maze throughout infusion period and after withdrawal, and the interaction of acute systemic nico-tine injections on memory was tested. Results: The high-er (100 µg/side/day) but not the lower (33.3 µg/side/day) DH E dose caused a significant spatial memory impair-ment. Acute systemic nicotine injections (0, 0.1, 0.2, and 0.4 mg/kg, subcutaneous) attenuated the memory impair-ing effects of 100 µg/side/day of DH E. There was no significant effect on response latency with the chronic DH E infusion. Acute systemic nicotine infusions did significantly speed responding, an effect which was re-versed by chronic hippocampal infusions of DH E. Af-ter withdrawal there were no significant lasting effects on choice accuracy or response latency. Wet-dog shakes were significantly elevated during chronic... [ABSTRACT FROM AUTHOR]

Extracellular superoxide dismutase (EC-SOD) controls the availability of extracellular superoxide and appears to play a role in controlling oxidative stress and intercellular signaling. Whether EC-SOD overexpression would help or hinder neurobehavioral function appears to depend on the age of the individual. In young adult mice, we have found that EC-SOD overexpression can interfere with learning on the radial-arm maze, possibly by reducing control over nitric oxide neurotransmission. In aged mice, we found, in the current study, that EC-SOD overexpression greatly improves learning on the radial-arm maze. Control (N = 17) and EC-SOD overexpressing mice (N = 13) acquired the 8-arm radial maze over 21 sessions of training. The EC-SOD overexpressing mice had significantly better choice accuracy than the control mice (p < 0.005). The EC-SOD overexpressing mice averaged 6.34 ± 0.22 correct arm entries before an error (entries to repeat) during the acquisition phase, while the control mice averaged 5.18 ± 0.22 entries to repeat. EC-SOD genotype did not cause a main effect on response latency. The advantage held by the EC-SOD overexpressing mice persisted during the eight-session post-acquisition phase of testing (p < 0.01). When there was a shift from high to low levels of motivation by reducing the period of food restriction before testing, the EC-SOD overexpression-induced improvement was reduced slightly, but it was still significant compared with the wild-type controls (p < 0.025). Then, after 4 months of no testing, the mice were tested for retention and reacquisition of performance on the radial-arm maze. The EC-SOD overexpressing mice maintained their significantly better choice accuracy (p < 0.05). Enhancement of EC-SOD activity appears to improve learning and memory performance, specifically in aging mice. EC-SOD mimetic treatment during the course of aging may hold promise for aging-induced cognitive impairment. [ABSTRACT FROM AUTHOR]

Extracellular superoxide dismutase (EC-SOD) controls the availability of extracellular superoxide and appears to play a role in controlling intercellular signaling. In this role EC-SOD can have potent effects on neurobehavioral function. In previous studies, we have found that either over- or under-expression of EC-SOD in mice significantly impairs spatial learning on the radial-arm maze. In the current study, the neurobehavioral nature of the EC-SOD role in cognitive function was determined. EC-SOD overexpression altered the relationship between both learning and memory with motivational state. Mice were tested in the radial-arm maze under a high motivational state (22–24 hours of food restriction) or a low motivational state (4–6 hours of food restriction). Under a high motivational state, the EC-SOD overexpressing mice were able to learn in the radial-arm maze, albeit at a slightly lower rate than wild-type controls. This contrasts with the failure to learn by EC-SOD overexpressing mice in our previous study conducted with the low motivational state. The change in motivational state did not significantly alter the learning rate of controls. Similarly, during postacquisition memory phase of testing, the EC-SOD overexpressing mice were significantly worse than controls when tested in a low motivational state but not under a high motivation state. As with learning, motivational state did not significantly affect memory performance in controls. This study shows that mice with EC-SOD overexpression are not incapable of learning and memory in the radial-arm maze, but that the mechanisms which allow control animals to perform this task well under low motivational states are deficient in the mice with EC-SOD overexpression. [ABSTRACT FROM AUTHOR]

Extracellular superoxide dismutase (EC-SOD) controls the availability of extracellular superoxide $(\{\backslash rm\; O\}\_2^\{\{\backslash cdot\}-\})$, which is important for a variety of physiological pathways, including the primary means of inactivating nitric oxide (NO). The role of EC-SOD in neurobehavioral function has been until now unexplored. In the current studies, the phenotypic expression of genotypic alterations of EC-SOD production in mice were characterized for spatial learning and memory. Dramatic impairments in spatial learning in the win-shift 8-arm radial maze were seen in both EC-SOD knockout mice and EC-SOD overexpressing mice. The EC-SOD overexpressing mice were further characterized as having significant deficits in a repeated acquisition task in the radial-arm maze, which permitted the dissociation of long and short-term learning. Long-term learning was significantly impaired by EC-SOD overexpression, whereas short-term learning was not significantly affected by EC-SOD overexpression. NO systems have been shown to be importantly involved in learning and memory. This may be important in the current studies because EC-SOD has primary control over the inactivation of NO. We found that EC-SOD overexpressing mice were resistant to the cognitive effects of L-NAME (N[sup G] -nitro-L-arginine methyl ester hydrochloride), an NO synthase inhibitor. Decreased NO catabolism in these mice may have served to counter the effects of NOS inhibition by L-NAME. The current finding that EC-SOD levels that were either higher or lower than controls impaired learning demonstrates that the proper control of brain extracellular $\{\backslash rm\; O\}\_2^\{\{\backslash cdot\}-\}$ may be more vital than merely reduction of brain extracelluar $\{\backslash rm\; O\}\_2^\{\{\backslash cdot\}-\}$ in maintaining adequate learning function. [ABSTRACT FROM AUTHOR]

A Correction to this paper has been published: https://doi.org/10.1007/s00213-021-05794-y [ABSTRACT FROM AUTHOR]

Men consume the most nicotine and cannabis products but impacts on sperm epigenetics are poorly characterized. Evidence suggests that preconception exposure to these drugs alters offspring neurodevelopment. Epigenetics may in part facilitate heritability. We therefore compared effects of exposure to tetrahydrocannabinol (THC) and nicotine on DNA methylation in rat sperm at genes involved in neurodevelopment. Reduced representation bisulfite sequencing data from sperm of rats exposed to THC via oral gavage showed that seven neurodevelopmentally active genes were significantly differentially methylated versus controls. Pyrosequencing data revealed majority overlap in differential methylation in sperm from rats exposed to THC via injection as well as those exposed to nicotine. Neurodevelopmental genes including autism candidates are vulnerable to environmental exposures and common features may mediate this vulnerability. We discovered that autism candidate genes are significantly enriched for bivalent chromatin structure, suggesting this configuration may increase vulnerability of genes in sperm to disrupted methylation. [ABSTRACT FROM AUTHOR]