Increasing dietary choline attenuates spatial memory deficits resulting from exposure to the chemotherapeutic agents cyclophosphamide and doxorubicin.

BACKGROUND: Choline supplementation (+Ch) improves cognitive function in impaired animals and humans. Chemotherapy-related cognitive deficits (CRCDs) occur in cancer patients, and these deficits persist following treatment, adversely impacting quality of life. To date, there are no approved treatments for this condition. AIM: Because +Ch improves impaired memory, it was of interest to determine whether +Ch can attenuate spatial memory deficits induced by the chemotherapeutic agents doxorubicin (DOX) and cyclophosphamide (CYP). METHODS: Female BALB/C mice, 64 days of age, were trained in the Morris water maze and baseline performance determined on day 15. Following baseline assessment, mice were placed on +Ch diet (2.0% Ch) or remained on standard diet (0.12% Ch). Mice received intravenous injections of DOX (2.5 mg/kg) and CYP (25 mg/kg), or equivalent volumes of saline (0.9% NaCl), on days 16, 23, 30, and 37, and spatial memory was assessed weekly from day 22 to 71. RESULTS: DOX and CYP produced a prolonged impairment in spatial memory as indicated by an increased latency to the correct zone (p < 0.05), and a decrease in time in the correct zone (p < 0.05), % of total swim distance in the correct zone (p < 0.05) and % entries to the correct zone (p < 0.05). These effects were attenuated by +Ch. CONCLUSION: Although it remains to be determined whether this effect extends to other cognitive domains and whether +Ch is prophylactic or therapeutic, these findings suggest that +Ch may be an effective intervention for CRCDs.

Spatial memory deficits in mice induced by chemotherapeutic agents are prevented by acetylcholinesterase inhibitors.

PURPOSE: These studies determined whether the acetylcholinesterase inhibitors, donepezil and galantamine, both of which are approved for the treatment of cognitive deficits in Alzheimer's disease, can prevent or reverse spatial memory deficits in mice induced by cyclophosphamide and doxorubicin, cytotoxic agents commonly used to treat breast cancer. METHODS: Female BALB/C mice were trained in the Morris water maze to identify the location of a submerged platform, and, following baseline assessment of spatial memory, received injections of cyclophosphamide and doxorubicin once per week for 4 weeks to impair spatial memory. Saline or acetylcholinesterase inhibitors were administered daily either concurrent with the chemotherapy injections (prevention) or beginning 1 week following the final chemotherapy injections (reversal), and spatial memory was assessed weekly. RESULTS: Spatial memory declined during and following weekly injections of cyclophosphamide and doxorubicin, and was unaltered when the acetylcholinesterase inhibitors were administered following the manifestation of chemotherapy-induced deficits. In contrast, spatial memory of mice receiving the acetylcholinesterase inhibitors concurrent with chemotherapy did not differ from that at baseline. CONCLUSIONS: Results indicate that chemotherapy-induced spatial memory deficits in mice can be prevented, but not reversed by the use of acetylcholinesterase inhibitors concomitant with chemotherapy, suggesting that these agents should be investigated further for the prevention of chemobrain.

Doxorubicin and cyclophosphamide lead to long-lasting impairment of spatial memory in female, but not male mice.

Self-reports of chemotherapy-related cognitive deficits (CRCDs) are more prevalent among women than men, suggesting that women may be more vulnerable to the cognitive-impairing effects of chemotherapy. However, there have been no direct comparisons of females and males using objective measures of cognitive function either during or following exposure to the same chemotherapeutic regimen. The present study used an animal model, and a prospective longitudinal design, to assess sex differences in the manifestation and persistence of spatial memory deficits resulting from exposure to doxorubicin (DOX) and cyclophosphamide (CYP), commonly used anticancer drugs. The spatial memory of female and male BALB/C mice was assessed using the Morris water maze prior to, during and following 4 weekly intravenous injections of DOX (2.5mg/kg) and CYP (25mg/kg) or vehicle. Females receiving DOX+CYP experienced significant deficits in spatial memory during and following injections when compared to baseline or females receiving vehicle. These deficits persisted for at least 34 days following the final injection. In contrast, males receiving DOX+CYP injections did not exhibit alterations in spatial memory relative to baseline or males receiving vehicle. These findings indicate that females may be more vulnerable than males to the cognitive-impairing effects of DOX+CYP and demonstrate that deficits in females persist for at least several weeks following drug exposure. Preclinical studies of CRCDs should parallel clinical work by including females and examine sex specific factors as potential mechanisms.

Obstacles and Opportunities for Cholinergic Drug Development in the Treatment of Cognitive Disorders.

The frequency of neuropsychiatric disorders is greater than that of cancer, cardiovascular disease, and diabetes combined, and is growing at a faster rate than any other ailments in the United States or Europe. Despite a considerable need for the development of treatments for central nervous system disorders, pharmaceutical companies continue to reduce investment in this area of research. Of particular concern is the treatment of diseases and disorders that affect cognitive function, which are often given a lower priority for research investment than life threatening conditions or those with overt physical symptoms. Several reasons exist for this reduced investment, including a poor understanding of the mechanisms underlying impaired cognitive function, costly and long periods of development for these medications, disproportionately lower success rates, and a stigma associated with the medical treatment of mental illness. This paper will discuss these issues, review some of the successes resulting from research investment and discuss opportunities that should encourage increased research investment in cognitive disorders and their treatment.

Potential Use of Nicotinic Receptor Agonists for the Treatment of Chemotherapy-Induced Cognitive Deficits.

Over the past several decades, research in both humans and animals has established the existence of persistent cognitive deficits resulting from exposure to chemotherapeutic agents. Nevertheless, there has been very little research addressing the treatment of chemotherapy-induced cognitive deficits and there is currently no approved treatment for this condition, often referred to as 'chemo-brain.' Several drugs that enhance cholinergic function and/or increase nicotinic acetylcholine receptor (nAChR) activity have been demonstrated to improve cognitive performance and/or reverse cognitive deficits in animals, findings that have led to the use of these compounds to treat the cognitive deficits present in a variety of disorders including attention deficit disorder, Alzheimer's disease, Parkinson's disease and schizophrenia. Although nAChR agonists have not been assessed for their efficacy in treating chemotherapy-induced cognitive deficits, these drugs have been shown to produce measureable increases in performance on several behavioral tasks known to be disrupted by exposure to chemotherapeutic agents. While the processes underlying chemotherapy-induced cognitive deficits may differ from those underlying other disorders, there appears to be a broad spectrum of application for the use of nAChR agonists to improve cognitive function. Therefore, studies examining the use of these drugs in the treatment of chemotherapy-induced cognitive deficits should be conducted as they may be of benefit for the treatment of 'chemo-brain.'

An open-label pilot trial of minocycline in children as a treatment for Angelman syndrome.

BACKGROUND: Minocycline, a member of the tetracycline family, has a low risk of adverse effects and an ability to improve behavioral performance in humans with cognitive disruption. We performed a single-arm open-label trial in which 25 children diagnosed with Angelman syndrome (AS) were administered minocycline to assess the safety and tolerability of minocycline in this patient population and determine the drug's effect on the cognitive and behavioral manifestations of the disorder. METHODS: Participants, age 4-12 years old, were randomly selected from a pool of previously screened children for participation in this study. Each child received 3 milligrams of minocycline per kilogram of body weight per day for 8 weeks. Participants were assessed during 3 study visits: baseline, after 8-weeks of minocycline treatment and after an 8-week wash out period. The primary outcome measure was the Bayley Scales of Infant and Toddler Development 3rd Edition (BSID-III). Secondary outcome measures included the Clinical Global Impressions Scale (CGI), Vineland Adaptive Behavior Scales 2nd Edition (VABS-II), Preschool Language Scale 4th Edition (PLS-IV) and EEG scores. Observations were considered statistically significant if p < 0.05 using ANOVA and partial eta squared (η(2)) was calculated to show effect size. Multiple comparisons testing between time points were carried out using Dunnett's post hoc testing. RESULTS: Significant improvement in the mean raw scores of the BSID-III subdomains communication and fine motor ability as well as the subdomains auditory comprehension and total language ability of the PLS-IV when baseline scores were compared to scores after the washout period. Further, improvements were observed in the receptive communication subdomain of the VABS-II after treatment with minocycline. Finally, mean scores of the BSID-III self-direction subdomain and CGI scale score were significantly improved both after minocycline treatment and after the wash out period. CONCLUSION: The clinical and neuropsychological measures suggest minocycline was well tolerated and causes improvements in the adaptive behaviors of this sample of children with Angelman syndrome. While the optimal dosage and the effects of long-term use still need to be determined, these findings suggest further investigation into the effect minocycline has on patients with Angelman syndrome is warranted. TRIAL REGISTRATION: NCT01531582 - clinicaltrials.gov.

The need to expand access to electroconvulsive therapy: a retrospective analysis of a new academic service.

BACKGROUND: Studies have long described the efficacy of electroconvulsive therapy (ECT); however, access to care continues to be an obstacle to treatment. Despite national trends resulting in declining availability of ECT, a new academic service was created to serve the needs of an area with limited resources. In this study, the characteristics and outcomes of patients receiving treatment during the first year of a new ECT program were assessed. The goals were to analyze treatment outcomes in this population and to identify associations between patient characteristics, treatment parameters, and clinical response. METHODS: Medical charts from the first 49 patients undergoing ECT between October 2010 and September 2011 were retrospectively reviewed. Patient characteristics, indications for ECT, and treatment parameters were compared with clinical improvement as defined by the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Of the 46 patients included in this study, the majority were female (63%), Caucasian (89%), and diagnosed with major depressive disorder (63%). The acute series duration ranged from 3 to 29 treatments (median of 13), with 50% (n=23) of patients achieving remission (MADRS<10) and 78% (n=36) achieving response (MADRS reduction > 50%) at the completion of the acute series. Positive outcomes were found to be associated with a history of medication-resistant conditions. CONCLUSIONS: ECT is a highly effective intervention for the treatment of depression and continues to be a sought-after therapy. Efficacy rates in the first year of this service were comparable to what has been reported in the general population and emphasize the need for the continued availability of ECT as a treatment option.

Postpartum depression in rats: differences in swim test immobility, sucrose preference and nurturing behaviors.

Postpartum depression (PPD) is a common disorder affecting both mothers and their offspring. Studies of PPD in laboratory animals have typically assessed either immobility on forced swim testing or sucrose preference in ovariectomized rats following hormone supplementation and withdrawal or in stress models. To date, few studies have related these measures to maternal behaviors, a potential indicator of depressive-like activity postpartum. Because a single measure may be insufficient to characterize depression, the present study determined the distribution of depressive-like behaviors in Sprague-Dawley rats postpartum. Nurturing and non-nurturing behaviors exhibited by undisturbed dams were recorded during the first 12 days postpartum, and immobility in the forced swim test and sucrose preference were determined thereafter. A median-split analysis indicated that 19% of dams exhibited high sucrose preference and low immobility, 30% exhibited either only high immobility or only low sucrose preference, and 21% exhibited both high immobility and low preference. Dams exhibiting depressive-like activity on either or both tests displayed increased self-directed behaviors and decreased active nurturing during the dark phase of the diurnal cycle. This is the first study to characterize undisturbed nurturing and non-nurturing behaviors, and use both sucrose preference and immobility in the forced swim test, to classify PPD endophenotypes exhibited by rat dams following parturition. The present study underscores the idea that multiple tests should be used to characterize depressive-like behavior, which is highly heterogeneous in both the human and laboratory animal populations.

Ethanol conditioned place preference and alterations in ΔFosB following adolescent nicotine administration differ in rats exhibiting high or low behavioral reactivity to a novel environment.

This study determined the effects of adolescent nicotine administration on adult alcohol preference in rats exhibiting high or low behavioral reactivity to a novel environment, and ascertained whether nicotine altered ΔFosB in the ventral striatum (vStr) and prefrontal cortex (PFC) immediately after drug administration or after rats matured to adulthood. Animals were characterized as exhibiting high (HLA) or low (LLA) locomotor activity in the novel open field on postnatal day (PND) 31 and received injections of saline (0.9%) or nicotine (0.56 mg free base/kg) from PND 35 to 42. Ethanol-induced conditioned place preference (CPP) was assessed on PND 68 following 8 days conditioning in a biased paradigm; ΔFosB was measured on PND 43 or PND 68. Following adolescent nicotine exposure, HLA animals demonstrated a CPP when conditioned with ethanol; LLA animals were unaffected. Further, adolescent nicotine exposure for 8 days increased levels of ΔFosB in limbic regions in both HLA and LLA rats, but this increase persisted into adulthood only in LLA animals. Results indicate that adolescent nicotine exposure facilitates the establishment of an ethanol CPP in HLA rats, and that sustained elevations in ΔFosB are not necessary or sufficient for the establishment of an ethanol CPP in adulthood. These studies underscore the importance of assessing behavioral phenotype when determining the behavioral and cellular effects of adolescent nicotine exposure.

Effects of nicotine exposure on locomotor activity and pCREB levels in the ventral striatum of adolescent rats.

Behavioral reactivity to novel stimuli, which is greater in the adolescent than young adult population, is associated with drug abuse liability, suggesting that the increased addiction vulnerability of adolescents may be related to heightened novel stimulus reactivity and underlying cellular processes. We examined the hypothesis that adolescent animals who exhibit higher novel stimulus reactivity, exhibit greater locomotor activity in response to nicotine than adolescents who exhibit lower novel stimulus reactivity, and that this difference is associated with alterations in CREB expression and activity in the ventral striatum (vStr) and prefrontal cortex (PFC). Adolescents exhibiting high locomotor activity (HLA) in the novel open field developed tolerance to the locomotor depressant effects of nicotine with fewer exposures and at lower doses than adolescents with low locomotor activity (LLA). Further, HLA adolescents exhibited lower CREB activity in the vStr than LLA adolescents and this difference was attenuated by repeated exposure to high, but not low doses of nicotine. Thus, inherent differences in the reactivity to novel stimulation during the adolescent period appear to predict sensitivity to the behavioral and cellular effects of nicotine and may underlie differences in progression to addiction.

Repeated ethanol exposure during adolescence alters the developmental trajectory of dopaminergic output from the nucleus accumbens septi.

Individuals who begin using alcohol prior to 14 years of age are 4 times more likely to progress to addiction than those who do not initiate use until 21 years of age. The nucleus accumbens septi undergoes dramatic developmental transitions during the adolescent period, and dopaminergic activity within this region has been identified as a central neurochemical mediator of drug reward, addiction and dependence. Thus, alcohol-induced neurochemical alterations in dopaminergic activity within this brain region likely mediate the heightened vulnerability to addiction observed in adolescent alcohol users. To investigate this idea, Sprague-Dawley rats were exposed to intraperitoneal injections of either saline or ethanol (0.5, 1.0 or 2.0 g/kg) twice daily over four days beginning on postnatal day 21, 31, 41 or 56. Cannulas were implanted toward the nucleus accumbens septi, subsequent in vivo microdialysis was used to collect samples, and both basal and ethanol-stimulated dopamine overflow was measured using high performance liquid chromatography with electrochemical detection. A developmental transition in basal levels of dopamine in the nucleus accumbens septi was apparent with peak levels at postnatal day 45. An ethanol challenge produced unique responses across ages, with greater peak effects relative to baseline in younger animals (postnatal day 25 and 35). Following repeated exposure to ethanol, a significant increase in basal dopamine was apparent for all ages, and when these animals were challenged with ethanol, peak effects relative to baseline were decreased in younger animals, but unchanged in older animals (postnatal day 45 and 60). Results indicate that there is a key developmental transition in the ability of rats to adapt to the effects of repeated ethanol exposure, which occurs between postnatal day 35 and 45. This alteration may explain the increased addiction vulnerability observed in individuals who initiate alcohol use during early adolescence.

Dependence of adolescent novelty-seeking behavior on response phenotype and effects of apparatus scaling.

Adult rats have been phenotyped as high (HRs) or low (LRs) responders to novelty, the former associated with high-risk behaviors. Data indicating that adolescent rodents exhibit increased novelty-seeking relative to adults are equivocal, and phenotypic variations in adolescent novel stimulus reactivity are unknown. To determine whether novelty-seeking differs between adolescent and adult rats, reflecting phenotypic variations within each age, activities in an inescapable novel environment and novel object exploration were measured. Adolescents moved further, faster, and more continuously than adults, and exhibited a greater variability and range of activity in the novel environment. Both adolescent and adult LRs habituated to the environment by the second trial, but HRs maintained increased activity throughout 8 trials. In the free-choice paradigm, adolescents approached the novel object more frequently and spent more time in proximity to the object than adults. Similar results were obtained using arenas and objects of the same size or scaled to animal size. Results confirm that novelty-seeking by adolescents is greater than by adults, a behavior attributed primarily to the response magnitude exhibited by adolescents with the HR phenotype.

Developmental differences in nicotine place conditioning.

To understand the motivations and implications of the prevalence of smoking, studies have compared the behavioral effects of nicotine, the psychoactive drug in tobacco, in adolescent and adult animals. The present study used a biased three-chambered conditioned-place preference procedure without prior habituation to examine the potential rewarding and anxiolytic effects of nicotine across adolescence and adulthood to assess the presence of age-dependent differences in response to nicotine.

An animal model of sensation seeking: the adolescent rat.

Previous research has established a strong relationship between a rodent's preference for novelty and sensitivity to psychomotor stimulants. Rats with greater sensitivity to the motoric effects of amphetamine exhibit higher preferences for novelty. Additionally, animals with high novelty preference scores are more easily drug conditioned and are more sensitive to, and can more accurately discriminate, amphetamine doses. Novelty preference in animals has been compared to sensation seeking in humans and is strongly correlated with drug use and addiction vulnerability. Thus, the present studies employed a playground maze procedure to measure changes in novelty preference across age following either four or eight habituation trials using eight distinct objects. Early-adult (postnatal day [PND] 59) animals did not exhibit a significant preference for a novel object regardless of total number of habituation trials. Early-adolescent animals (PND 34) exhibited a preference for the novel object in fewer than four habituation trials, but exhibited no preference with increased habituation trials. These results are counterintuitive and may demonstrate an overgeneralization of the habituation trials specific to adolescent animals. Given that adolescence is a period of heightened exploration, one would expect adolescent animals to demonstrate an enhanced preference for novel stimuli using this paradigm. However, it is possible that the complexity of the task, as presented, reveals differences in the establishment and behavioral manifestation of associations during adolescence. To address this issue, a separate novelty paradigm was implemented using an open-field habituation procedure followed by the introduction of a single novel object during the testing period. This revised design provides the foundation needed to better assess novelty-induced locomotor activity and novelty preference in adolescent rats.