Leslie Renee Amodeo

Children with attention-deficit/hyperactivity disorder (ADHD) experience more sleep problems than their peers. As stimulant medications, particularly methylphenidate (MPH), are the most common treatment for pediatric ADHD, there has been growing interest in whether such medications contribute to sleep disturbances and the development of sleep disorders later in life. Despite ongoing interest, evidence related to MPH on sleep functioning in children remains mixed. The present study investigated the effects of MPH on 24-hour rest/wake activity patterns and circadian rhythms in adolescent versus adult rats. Male and female Long-Evans rats were administered MPH (1 or 2 mg/kg, i.p.) or control twice daily for 10 days during either adolescence (PD 30–39) or adulthood (PD 80–89). Non-invasive activity monitors, secured to each rat using custom-fitted jackets, were used to assess circadian rhythms and detailed activity patterns over a 24-hour reverse light/dark cycle. Microanalysis of activity patterns were assessed on the last day of MPH treatment, during acute discontinuation, and after 10 days of prolonged discontinuation. Results showed that repeated MPH administration produced dose- and age-specific increases in activity across the light/dark cycle on the last day of treatment. In adults, this was associated with longer and more frequent active episodes during the dark period, and transient increases in fragmented activity during early withdrawal. MPH also impaired rest quality in female rats, reflected by fewer rest episodes and increased fragmentation during the light period. While some of these disruptions persisted immediately after discontinuation, more pronounced impairments in rest quality emerged after 10 days of withdrawal. These findings suggest that while MPH may enhance activity during treatment in an age- and sex-dependent manner, its discontinuation may lead to lasting reductions in sleep quality in both adolescents and adults who are transiently exposed to the psychostimulants.

Background: Sleep difficulties and rhythm disturbances are some of the problems associated with adolescent binge drinking. Recently, animal models of alcohol‐induced insomnia have been developed. However, studies in human subjects have recently focused not only on nighttime EEG findings but also on daytime sleepiness and disrupted activity levels as typically measured by activity tracking devices such as the “Fitbit.” We sought to develop and test a Fitbit‐like device (the “FitBite”) in rats and use it to track rest‐activity cycles following adolescent alcohol exposure.Methods: The effects of 5 weeks of adolescent ethanol vapor or control conditions were evaluated in 48 male and female Wistar rats using FitBite activity while intoxicated, and during acute (24 h post‐vapor exposure) and chronic withdrawal (4 weeks post‐vapor exposure). Data were analyzed using activity count and cosinor analyses. Fourteen rats were subsequently implanted with cortical electrodes, and data from the FitBite were compared with EEG data to determine how well the FitBite could identify sleep and activity cycles.Results: Female rats were generally more active than males, with higher circadian rhythm amplitudes and mesors (rhythm‐adjusted means) across a 24‐h period. There were significant correlations between EEG‐estimated sleep and activity counts using the FitBite. When the rats were tested during intoxication after 4 weeks of ethanol vapor exposure, they had significantly less overall activity. Disruptions in circadian rhythm were also found with significant decreases in the circadian amplitude, mesor, and a later shift in the acrophase. At 24 h of ethanol withdrawal, rats had more episodes of activity with shorter durations during the daytime, when rats are expected to spend more of their time sleeping. This effect remained at 4 weeks following withdrawal, but circadian rhythm disruptions were no longer present.Conclusions: A Fitbit‐like device can be successfully used in rats to assess rest‐activity cycles. Adolescent alcohol exposure produced circadian rhythm disturbances that were not observed after withdrawal. Fragmentation of ultradian rest‐activity cycles during the light period was found at 24 h and 4 weeks after withdrawal and support data demonstrating the presence of sleep disturbance long after alcohol withdrawal.

Background: Alcohol use is on the rise among women in the United States which is especially concerning since women who drink have a higher risk of alcohol‐related problems. Orexin (hypocretin) receptor antagonists may have some therapeutic value for alcohol‐induced insomnia; however, the use of this class of drugs following female adolescent binge drinking is limited. The current study will address whether adolescent intermittent ethanol (AIE) in female rats can result in lasting changes in sleep pathology and whether orexin‐targeted treatment can alleviate these deficits.Methods: Following a 5‐week AIE vapor model, young adult rats were evaluated on waking event‐related oscillations (EROs) and EEG sleep. Subsequently, AIE rats were treated with orexin receptor 2 (OX₂R) antagonist (MK‐1064; 10, 20mg/kg) to test for modifications in sleep pathology and waking ERO.Results: Female AIE rats exhibited lasting changes in sleep compared to controls. This was demonstrated by increased fragmentation of slow wave sleep (SWS) and rapid eye movement sleep, as well as reductions in delta and theta power during SWS. There was no impact of AIE on waking EROs. Acute MK‐1064 hastened SWS onset and increased the number of SWS episodes, without increasing sleep fragmentation in AIE and controls. While treatment with MK‐1064 did not impact sleep EEG spectra, waking ERO energy was increased in delta, theta, and beta frequency bands.Conclusions: These results demonstrate that AIE can produce lasting changes in sleep in female rats, highly similar to what we previously found in males. Additionally, while the OX₂R antagonist promoted sleep in both alcohol‐exposed and unexposed rats, it did not reverse most of the alcohol‐induced disruptions in sleep. Thus, OX₂R antagonism may serve as a potential therapeutic strategy for the treatment of insomnia, but not the specific signs of alcohol‐induced insomnia.

Drugs of abuse are known to reduce intake of a taste conditioned stimulus (conditional stimulus, CS), a behavioral response sometimes seen as paradoxical because the same drugs also serve as rewards in other behavioral procedures. In the present study we compared patterns of intake and palatability (assessed using microstructural analysis of licking) for a standard saccharin CS paired with the following: lithium chloride, morphine, amphetamine, or sucrose. We found that morphine and amphetamine, like lithium-induced illness, each suppressed CS intake and caused a reduction in saccharin palatability. Sucrose, a rewarding stimulus, did not reduce the palatability of the saccharin CS. We interpret these finds as evidence that drugs of abuse induce conditioned taste aversions.

Like illness-inducing agents (e.g., lithium chloride), drugs of abuse also suppress intake of a taste solution. To explore the nature of this drug-induced intake reduction, in the current study three aqueous stimuli with different initial values served as the conditioned stimuli (CSs) that were paired with a standard dose of amphetamine in a voluntary intake procedure and lick patterns were analyzed. Consistent with earlier studies, amphetamine significantly reduced intake of all three CSs (quinine, sodium chloride, and orange odor). In contrast to studies that analyze orofacial responses, we found that lick cluster size was significantly lowered by amphetamine, indicating that the psychoactive drug induced a conditioned reduction in taste palatability.