Environmental Enrichment during Abstinence Reduces Oxycodone Seeking and c-Fos Expression in a Subpopulation of Medial Prefrontal Cortex Neurons.

BACKGROUND: Several preclinical studies have demonstrated that environmental enrichment (EE) during abstinence reduces drug seeking for psychostimulant and opioid drugs. Drug seeking is dependent on activity within the dorsomedial prefrontal cortex, and enrichment has been able to reduce drug seeking-associated increases in c-Fos in this region. In this study, we tested the hypothesis that EE during abstinence from oxycodone self-administration would reduce drug seeking and c-Fos immunoreactivity within the prefrontal cortex in a cell-type specific manner. METHODS: Male rats self-administered oxycodone in two-hours sessions for three weeks, then underwent an initial drug seeking test under extinction conditions after one week of forced abstinence. Following this test, rats received either EE or remained individually housed in their home cage, then a second drug seeking test, with tissue collection immediately afterward. RESULTS: Compared to rats in standard housing, environmentally enriched rats had lower oxycodone seeking. In the prelimbic and infralimbic prefrontal cortices, the number of c-Fos+ cells was reduced, and this reduction was predominantly in inhibitory cells neurons, as evidenced by a reduction in the proportion of c-Fos+ cells in GAD+, but not CamKII+ cells. There was also a robust positive relationship between the number of c-Fos+ cells and persistence of oxycodone seeking in both the PrL and IL. CONCLUSIONS: These findings further support the effectiveness of enriched environments to reduce reactivity to drug-associated stimuli and contexts and provide a potential mechanism by which this occurs.

The effects of sleep restriction during abstinence on oxycodone seeking: Sex-dependent moderating effects of behavioral and hypothalamic-pituitary-adrenal axis-related phenotypes.

During opioid use and abstinence, sleep disturbances are common and are thought to exacerbate drug craving. In this study, we tested the hypothesis that sleep restriction during abstinence from oxycodone self-administration would increase drug seeking during extinction and footshock reinstatement tests. We also performed behavioral phenotyping to determine if individual variation in responses to stressors and/or pain are associated with oxycodone seeking during abstinence, as stress, pain and sleep disturbance are often co-occurring phenomena. Sleep restriction during abstinence did not have selective effects on oxycodone seeking for either sex in extinction and footshock reinstatement tests. Some phenotypes were associated with drug seeking; these associations differed by sex and type of drug seeking assessment. In female rats, pain-related phenotypes were related to high levels of drug seeking during the initial extinction session. In male rats, lower anxiety-like behavior in the open field was associated with greater drug seeking, although this effect was lost when correcting for oxycodone intake. Adrenal sensitivity prior to oxycodone exposure was positively associated with footshock reinstatement in females. This work identifies sex-dependent relationships between HPA axis function and opioid seeking, indicating that HPA axis function could be a therapeutic target for the treatment of opioid use disorder, with tailored approaches based on sex. Sleep disturbance during abstinence did not appear to be a major contributing factor to opioid seeking.

Sleep restriction during opioid abstinence affects the hypothalamic-pituitary-adrenal (HPA) axis in male and female rats.

Hypothalamic-pituitary-adrenal (HPA) axis dynamics are disrupted by opioids and may be involved in substance abuse; this persists during withdrawal and abstinence and is associated with co-morbid sleep disruption leading to vulnerability to relapse. We hypothesized that chronic sleep restriction (SR) alters the HPA axis diurnal rhythm and the sexually dimorphic response to acute stressor during opioid abstinence. We developed a rat model to evaluate the effect of persistent sleep loss during opioid abstinence on HPA axis dynamics in male and female rats. Plasma ACTH and corticosterone were measured diurnally and in response to acute restraint stress in rats Before (control) compared to During subsequent opioid abstinence without or with SR. Abstinence, regardless of sleep state, led to an increase in plasma ACTH and corticosterone in the morning in males. There was a tendency for higher PM plasma ACTH during abstinence in SR males (p = 0.076). ACTH and corticosterone responses to restraint were reduced in male SR rats whereas there was a failure to achieve the post-restraint nadir in female SR rats. There was no effect of the treatments or interventions on adrenal weight normalized to body weight. SR resulted in a dramatic increase in hypothalamic PVN AVP mRNA and plasma copeptin in male but not female rats. This corresponded to the attenuation of the HPA axis stress response in SR males during opioid abstinence. We have identified a potentially unique, sexually dimorphic role for magnocellular vasopressin in the control of the HPA axis during opioid abstinence and sleep restriction.

Chronicity of repeated blast traumatic brain injury associated increase in oxycodone seeking in rats.

Numerous epidemiological studies have found co-morbidity between non-severe traumatic brain injury (TBI) and substance misuse in both civilian and military populations. Preclinical studies have also identified this relationship for some misused substances. We have previously demonstrated that repeated blast traumatic brain injury (rbTBI) increased oxycodone seeking without increasing oxycodone self-administration, suggesting that the neurological sequelae of traumatic brain injury can elevate opioid misuse liability. Here, we determined the chronicity of this effect by testing different durations of time between injury and oxycodone self-administration and durations of abstinence. We found that the subchronic (four weeks), but not the acute (three days) or chronic (four months) duration between injury and oxycodone self-administration was associated with increased drug seeking and re-acquisition of self-administration following a 10-day abstinence. Examination of other abstinence durations (two days, four weeks, or four months) revealed no effect of rbTBI on drug seeking at any of the abstinence durations tested. Together, these data indicate that there is a window of vulnerability after TBI when oxycodone self-administration is associated with elevated drug seeking and relapse-related behaviors.

Effects of photon irradiation in the presence and absence of hindlimb unloading on the behavioral performance and metabolic pathways in the plasma of Fischer rats.

Introduction: The space environment astronauts experience during space missions consists of multiple environmental challenges, including microgravity. In this study, we assessed the behavioral and cognitive performances of male Fisher rats 2 months after sham irradiation or total body irradiation with photons in the absence or presence of simulated microgravity. We analyzed the plasma collected 9 months after sham irradiation or total body irradiation for distinct alterations in metabolic pathways and to determine whether changes to metabolic measures were associated with specific behavioral and cognitive measures. Methods: A total of 344 male Fischer rats were irradiated with photons (6 MeV; 3, 8, or 10 Gy) in the absence or presence of simulated weightlessness achieved using hindlimb unloading (HU). To identify potential plasma biomarkers of photon radiation exposure or the HU condition for behavioral or cognitive performance, we performed regression analyses. Results: The behavioral effects of HU on activity levels in an open field, measures of anxiety in an elevated plus maze, and anhedonia in the M&M consumption test were more pronounced than those of photon irradiation. Phenylalanine, tyrosine, and tryptophan metabolism, and phenylalanine metabolism and biosynthesis showed very strong pathway changes, following photon irradiation and HU in animals irradiated with 3 Gy. Here, 29 out of 101 plasma metabolites were associated with 1 out of 13 behavioral measures. In the absence of HU, 22 metabolites were related to behavioral and cognitive measures. In HU animals that were sham-irradiated or irradiated with 8 Gy, one metabolite was related to behavioral and cognitive measures. In HU animals irradiated with 3 Gy, six metabolites were related to behavioral and cognitive measures. Discussion: These data suggest that it will be possible to develop stable plasma biomarkers of behavioral and cognitive performance, following environmental challenges like HU and radiation exposure.

Repeated blast mild traumatic brain injury and oxycodone self-administration produce interactive effects on neuroimaging outcomes.

Traumatic brain injury (TBI) and drug addiction are common comorbidities, but it is unknown if the neurological sequelae of TBI contribute to this relationship. We have previously reported elevated oxycodone seeking after drug self-administration in rats that received repeated blast TBI (rbTBI). TBI and exposure to drugs of abuse can each change structural and functional neuroimaging outcomes, but it is unknown if there are interactive effects of injury and drug exposure. To determine the effects of TBI and oxycodone exposure, we subjected rats to rbTBI and oxycodone self-administration and measured drug seeking and several neuroimaging measures. We found interactive effects of rbTBI and oxycodone on fractional anisotropy (FA) in the nucleus accumbens (NAc) and that FA in the medial prefrontal cortex (mPFC) was correlated with drug seeking. We also found an interactive effect of injury and drug on widespread functional connectivity and regional homogeneity of the blood oxygen level dependent (BOLD) response, and that intra-hemispheric functional connectivity in the infralimbic medial prefrontal cortex positively correlated with drug seeking. In conclusion, rbTBI and oxycodone self-administration had interactive effects on structural and functional magnetic resonance imaging (MRI) measures, and correlational effects were found between some of these measures and drug seeking. These data support the hypothesis that TBI and opioid exposure produce neuroadaptations that contribute to addiction liability.

Effects of 5-Ion Beam Irradiation and Hindlimb Unloading on Metabolic Pathways in Plasma and Brain of Behaviorally Tested WAG/Rij Rats.

A limitation of simulated space radiation studies is that radiation exposure is not the only environmental challenge astronauts face during missions. Therefore, we characterized behavioral and cognitive performance of male WAG/Rij rats 3 months after sham-irradiation or total body irradiation with a simplified 5-ion mixed beam exposure in the absence or presence of simulated weightlessness using hindlimb unloading (HU) alone. Six months following behavioral and cognitive testing or 9 months following sham-irradiation or total body irradiation, plasma and brain tissues (hippocampus and cortex) were processed to determine whether the behavioral and cognitive effects were associated with long-term alterations in metabolic pathways in plasma and brain. Sham HU, but not irradiated HU, rats were impaired in spatial habituation learning. Rats irradiated with 1.5 Gy showed increased depressive-like behaviors. This was seen in the absence but not presence of HU. Thus, HU has differential effects in sham-irradiated and irradiated animals and specific behavioral measures are associated with plasma levels of distinct metabolites 6 months later. The combined effects of HU and radiation on metabolic pathways in plasma and brain illustrate the complex interaction of environmental stressors and highlights the importance of assessing these interactions.

Screening for ADHD in adults with cystic fibrosis: Prevalence, health-related quality of life, and adherence.

BACKGROUND: International guidelines recommend depression and anxiety screening in individuals with cystic fibrosis (CF), but Attention-Deficit Hyperactivity Disorder (ADHD) remains understudied. METHODS: Adults with CF (n=53) were screened using the Adult ADHD Self-Report Scale-v1.1 Symptom Checklist (ASRS-v1.1), Cystic Fibrosis Questionnaire-Revised (CFQ-R), and a self-report measure of treatment adherence. RESULTS: Elevated ADHD symptoms on the ASRS-v1.1 screener were reported by 15% of participants. Self-reported adherence, Body Mass Index in kg/m2 (BMI), and Forced Expiratory Volume in 1 Second, Percent Predicted (FEV1%pred) did not differ between participants with vs. without elevated ADHD scores. Three CFQ-R scales, Physical Functioning, Role Functioning, and Respiratory Symptoms, were significantly lower in participants with elevated ADHD screens (unadjusted p<0.05). This difference remained statistically significant for the Role Functioning and Respiratory Symptoms scales following correction for multiple comparisons. CONCLUSIONS: The highly specific screening tool ASRS-v1.1 can ascertain previously undetected ADHD symptoms in adults with CF. ADHD was substantially more prevalent than expected in this population. Elevated ASRS-v1.1 screens correlated with poorer Health-Related Quality of Life (HRQoL) in some domains, but not with BMI, FEV1%pred, or self-reported CF treatment adherence. Additional research will elucidate the impact of ADHD and its treatment on HRQoL, CF self-care and health outcomes.

Effect of altitude on brain intracellular pH and inorganic phosphate levels.

Normal brain activity is associated with task-related pH changes. Although central nervous system syndromes associated with significant acidosis and alkalosis are well understood, the effects of less dramatic and chronic changes in brain pH are uncertain. One environmental factor known to alter brain pH is the extreme, acute change in altitude encountered by mountaineers. However, the effect of long-term exposure to moderate altitude has not been studied. The aim of this two-site study was to measure brain intracellular pH and phosphate-bearing metabolite levels at two altitudes in healthy volunteers, using phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS). Increased brain pH and reduced inorganic phosphate (Pi) levels were found in healthy subjects who were long-term residents of Salt Lake City, UT (4720ft/1438m), compared with residents of Belmont, MA (20ft/6m). Brain intracellular pH at the altitude of 4720ft was more alkaline than that observed near sea level. In addition, the ratio of inorganic phosphate to total phosphate signal also shifted toward lower values in the Salt Lake City region compared with the Belmont area. These results suggest that long-term residence at moderate altitude is associated with brain chemical changes.

A prospective open-label trial of quetiapine monotherapy in preschool and school age children with bipolar spectrum disorder.

BACKGROUND: Although bipolar disorder frequently onsets in the preschool years, treatment studies to guide management of these highly dysfunctional children are limited. This study evaluates the response to quetiapine monotherapy in preschool and school age children with bipolar spectrum disorder (BSD). METHOD: Two eight-week, prospective, open-label trials utilizing identical methodology to assess the effectiveness and tolerability of quetiapine monotherapy in the treatment of BSD in preschool (age 4-6 years) and school age children (age 6-15 years). RESULTS: Forty-nine children (30 preschool and 19 school age) with BSD (Young Mania Rating Scale [YMRS] at entry: 34.5±5.5 and 30±6.5 respectively) were enrolled and 34 (20 preschool and 14 school age) completed the trial. Quetiapine was titrated to a mean endpoint dose of 175.8±63.8 mg/day in preschool and 248.7±153.1 mg/day in school age children. At endpoint, treatment with quetiapine was associated with similar and statistically significant improvement in mean YMRS scores in preschool (-14.5±11.5, p<0.001) and school age (-13±9.8, p<0.001) children. Quetiapine was generally well tolerated with treatment limiting adverse-events observed in 3/30 preschool and 1/19 school age children. Quetiapine monotherapy in preschool and school age children was associated with significant weight gain (+3.1±1.8 and +7.4±7.7 lb respectively, p<0.001) and with clinically insignificant changes in vital signs. LIMITATIONS: As an uncontrolled study, the assessments were not blind to treatment and the effects of treatment cannot be separated from time. CONCLUSIONS: Open-label quetiapine treatment was beneficial for the treatment of BSD in preschool and school age children. Further controlled trials are warranted.