Subanesthetic ketamine with an AMPAkine attenuates motor impulsivity in rats.

The concept of 'impulse control' has its roots in early psychiatry and today has progressed into a well-described, although poorly understood, multidimensional endophenotype underlying many neuropsychiatric disorders (e.g., attention deficit hyperactivity disorder, schizophrenia, substance use disorders). There is mounting evidence suggesting that the cognitive and/or behavioral dimensions underlying impulsivity are driven by dysfunctional glutamate (Glu) neurotransmission via targeted ionotropic Glu receptor (GluR) [e.g., N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)] mechanisms and associated synaptic alterations within key brain nodes. Ketamine, a noncompetitive NMDAR antagonist and FDA-approved for treatment-resistant depression, induces a 'glutamate burst' that drives resculpting of the synaptic milieu, which lasts for several days to a week. Thus, we hypothesized that single and repeated treatment with a subanesthetic ketamine dose would normalize motor impulsivity. Next, we hypothesized that AMPAR positive allosteric modulation, alone or in combination with ketamine, would attenuate impulsivity and provide insight into the mechanisms underlying GluR dysfunction relevant to motor impulsivity. To measure motor impulsivity, outbred male Sprague-Dawley rats were trained on the one-choice serial reaction time task. Rats pretreated with single or repeated (3 days) administration of ketamine (10 mg/kg; i.p.; 24-h pretreatment) or with the AMPAkine HJC0122 (1 or 10 mg/kg; i.p.; 30-min pretreatment) exhibited lower levels of motor impulsivity vs. control. Combination of single or repeated ketamine plus HJC0122 also attenuated motor impulsivity vs. control. We conclude that ligands designed to promote GluR signaling represent an effective pharmacological approach to normalize impulsivity and subsequently, neuropsychiatric disorders marked by aberrant impulse control.

Can Discipline Education be Culturally Sensitive?

Objectives Inappropriate discipline such as harsh physical punishment is a social determinant of health. The objective was to determine if a brief parent training intervention that teaches discipline strategies is culturally sensitive. Methods English or Spanish-speaking parents of 1-5 year old children viewed a multimedia program that teaches appropriate discipline strategies. The intervention, Play Nicely, was viewed in the exam room before the physician's visit. Parents viewed 4 of 20 discipline strategies of their choosing; the average viewing time was 7 min. Results Of 204 parents eligible to participate, 197 (96 %) completed the study; 41 % were Black, 31 % were White, and 21 % were Hispanic. At least 80 % of parents from each racial/ethnic group reported that the program built their confidence to care for their child, addressed their family needs, explained things in a way they could understand, respected their family values, and was sensitive to their personal beliefs. Overall, 80 % of parents reported that the program answered individual questions. One parent (0.5 %) reported that the program did not respect her family values. Conclusions for Practice Discipline education can be integrated into the pediatric primary care clinic in a way that is family-centered and culturally sensitive for the majority of parents. The results have implications for the development and implementation of population-based parenting programs and the primary prevention of child abuse and violence.

Newborn pulse oximetry screening to detect critical congenital heart disease.

OBJECTIVES: To describe current practice and clarify provider opinion in the US with regard to newborn pulse oximetry screening (NPOx) for critical congenital heart disease. STUDY DESIGN: An internet-based questionnaire was forwarded to general pediatricians, neonatologists, and family medicine physicians. Physicians were surveyed regarding involvement in newborn medicine, knowledge of NPOx recommendations, and opinions regarding screening. NPOx protocol specifics were also queried. RESULTS: Survey responses (n = 481) were received with 349 respondents involved in newborn medicine. Forty-nine percent (95% CI 44%-54%) of those involved in newborn medicine practice at a hospital with a NPOx protocol. Sixty-six percent of providers endorsed it as an effective tool, 20% required more education, 11% questioned its sensitivity, and 3% had no opinion. Sixty-five percent of providers were aware of recent state legislation mandating its use and 46% reported awareness of the addition of NPOx to the Recommended Uniform Screening Panel. Eighty-four percent of providers who practice at a hospital without a NPOx protocol were interested in its implementation. NPOx protocols varied and were not uniform with differences in time of test, location of probe, and values considered positive. CONCLUSIONS: NPOx has grown in its prevalence and acceptance in clinical practice, yet is far from universal in its application and design despite the recent American Academy of Pediatrics endorsement and its addition to the Recommended Uniform Screening Panel. The majority of physicians involved in newborn medicine deemed it an effective tool.

Protective Behavioral Strategies, Social Norms, and Alcohol-Related Outcomes.

The present study examined the unique contributions of protective behavioral strategies and social norms in predicting alcohol-related outcomes. Participants were 363 students from a large public university in the Midwest who reported at least one binge-drinking episode (5+/4+ drinks for men/women in one sitting) in the past 30 days. Data were collected 1/2010-3/2011. We used SEM to test models where protective behavioral strategies (PBS) and social norms were predictors of both alcohol use and alcohol-related problems, after controlling for the effects of gender. Both PBS and descriptive norms had relationships with alcohol use. PBS also had a relationship with alcohol-related problems. Overall, the findings suggest that PBS and social norms have unique associations with distinct alcohol-related outcomes.

Examining a curvilinear model of readiness to change and alcohol consumption.

Research examining the relationship between readiness to change and alcohol consumption among college students is inconsistent. The purpose of the present study was to extend these findings, using two different measures of readiness to change. We hypothesized a curvilinear effect would occur such that the relationship between readiness to change and alcohol use would be relatively low for students low and high on readiness to change, whereas the relationship would be relatively high for those with moderate levels of readiness to change. Data were collected from two studies: Study 1 consisted of 263 undergraduate students and Study 2 consisted of 245 undergraduates participating in either intercollegiate or recreational athletics at three US universities. In Study 1, we examined the association between both linear and quadratic scores on a readiness to change measure and alcohol use. In Study 2, we examined the relationship between scores on a stage of change measure that included subscales indicative of different levels of readiness to change and alcohol use. The pattern of relationships supported the existence of an effect where the highest levels of alcohol use occurred among those with scores representing moderate levels of readiness to change.

Psychotropic Medication Prescribing: Youth in Foster Care Compared with Other Medicaid Enrollees.

Objective: To compare the prevalence of psychotropic medication prescriptions among youth in foster care with those among nonfoster youth on Medicaid. Methods: Children ages 1-18 years in a region of a large southern state who were enrolled in their respective Medicaid plan for at least 30 days between 2014 and 2016 and had at least one health care claim were included. Medicaid prescription claims were categorized by class: alpha agonists, anxiolytics, antidepressants, antipsychotics, mood stabilizers, and stimulants. Primary mental health (MH) or developmental disorder (DD) diagnostic groups were identified for each class. Analyses included chi-square tests, t-tests, Wilcoxon sign rank tests, and logistic regression. Results: A total of 388,914 nonfoster and 8426 children in foster care were included. Overall, 8% of nonfoster and 35% of foster youth were dispensed at least one prescription for a psychotropic medication. Prevalence was higher for youth in care within each drug class and, with one exception, across all age groups. Among children prescribed a psychotropic medication, the mean number of drug classes prescribed was 1.4 (SD 0.8) and 2.9 (SD 1.4) for nonfoster and foster youth, respectively (p < 0.000). Except for anxiolytics and mood stabilizers, more children in foster care were prescribed psychotropic medications without an MH or DD diagnosis. Finally, children in foster care experienced 6.8 (95% CI: 6.5-7.2) times higher odds of being prescribed a psychotropic medication than their nonfoster peers, after controlling for age group, gender, and number of mental and developmental diagnoses. Conclusions: Across all age groups, children in foster care on Medicaid were prescribed psychotropic medications disproportionately more than their nonfoster peers on Medicaid. In addition, children in foster care were significantly more likely to be prescribed psychotropic medication absent an MH or DD diagnosis.

Assessing the Dependability of Drinking Motives via Generalizability Theory.

This study assessed the score reliability of the Drinking Motives Questionnaire-Revised (DMQ-R) via generalizability theory. Participants (n = 367 college students) completed the DMQ-R at three time points. Across subscale scores, persons, persons × occasions, and persons × items interactions accounted for meaningful variance. Findings illustrate advantages of generalizability theory-based techniques.

Heightened cocaine-seeking in male rats associates with a distinct transcriptomic profile in the medial prefrontal cortex.

Drug overdose deaths involving cocaine have skyrocketed, an outcome attributable in part to the lack of FDA-approved medications for the treatment of cocaine use disorder (CUD), highlighting the need to identify new pharmacotherapeutic targets. Vulnerability to cocaine-associated environmental contexts and stimuli serves as a risk factor for relapse in CUD recovery, with individual differences evident in the motivational aspects of these cues. The medial prefrontal cortex (mPFC) provides top-down control of striatal circuitry to regulate the incentive-motivational properties of cocaine-associated stimuli. Clinical and preclinical studies have identified genetic variations that impact the degree of executive restraint over drug-motivated behaviors, and we designed the present study to employ next-generation sequencing to identify specific genes associated with heightened cue-evoked cocaine-seeking in the mPFC of male, outbred rats. Rats were trained to stably self-administer cocaine, and baseline cue-reinforced cocaine-seeking was established. Rats were phenotyped as either high cue (HC) or low cue (LC) responders based upon lever pressing for previously associated cocaine cues and allowed 10 days of abstinence in their home cages prior to mPFC collection for RNA-sequencing. The expression of 309 genes in the mPFC was significantly different in HC vs. LC rats. Functional gene enrichment analyses identified ten biological processes that were overrepresented in the mPFC of HC vs. LC rats. The present study identifies distinctions in mPFC mRNA transcripts that characterizes individual differences in relapse-like behavior and provides prioritized candidates for future pharmacotherapeutics aimed to help maintain abstinence in CUD. In particular the Htr2c gene, which encodes the serotonin 5-HT2C receptor (5-HT2CR), is expressed to a lower extent in HC rats, relative to LC rats. These findings build on a plethora of previous studies that also point to the 5-HT2CR as an attractive target for the treatment of CUD.

Role of neuropeptide neuromedin U in the nucleus accumbens shell in cocaine self-administration in male rats.

The nucleus accumbens shell (NAcSh) and its afferent and efferent neuronal projections control key aspects of motivation for cocaine. A recently described regulator of γ-aminobutyric acid (GABA) projections from the dorsal raphe nucleus (DRN) to the NAcSh (DRN → NAcSh) is the neuropeptide neuromedin U (NMU). Here, we find that systemic administration of NMU decreases breakpoint for cocaine on a progressive ratio schedule of reinforcement in male rats. Employing a retrograde adeno-associated virus (AAV), we found that RNAi-mediated knockdown of the NMU receptor 2 (NMUR2) in afferent DRN projections to the NAcSh increases the breakpoint for cocaine. Our previous studies demonstrated that NMU regulates GABA release in the NAcSh, and our current investigation found that systemic NMU administration suppresses cocaine-evoked GABA release in the NAcSh and increases phosphorylated c-Fos expression in neurons projecting from the NAcSh to the ventral pallidum (VP). To further probe the impact of NMU/NMUR2 on neuroanatomical pathways regulating motivation for cocaine, we employed multi-viral transsynaptic studies. Using a combination of rabies virus and retrograde AAV helper virus, we mapped the impact of NMU across three distinct brain regions simultaneously and found a direct connection of GABAergic DRN neurons to the NAcSh → VP pathway. Together, these data reveal that NMU/NMUR2 modulates a direct connection within the GABAergic DRN → NAcSh → VP circuit that diminishes breakpoints for cocaine. These findings importantly advance our understanding of the neurochemical underpinnings of pathway-specific regulation of neurocircuitry that may regulate cocaine self-administration, providing a unique therapeutic perspective.

The use of newborn screening pulse oximetry to detect cyanotic congenital heart disease: a survey of current practice at Army, Navy, and Air Force hospitals.

OBJECTIVE: To determine the prevalence of newborn screening pulse oximetry (+POx) among military hospitals, including barriers to instituting protocols. METHODS: An internet-based questionnaire was forwarded to the senior pediatricians at military hospitals worldwide supporting newborn deliveries. RESULTS: Forty seven of 53 hospitals (88%) supporting deliveries responded to the survey. Thirty percent of hospitals utilize a +POx protocol. Eight centers cited no problems with implementation. All hospitals screened at > or = 24 hours of life. The site of recording, positive values, and follow-up for positive screens varied. Cardiology consult and echocardiogram were not mandated. Most hospitals (34/47) are unable to obtain a pediatric cardiology consult without transfer. Few hospitals (9/47) utilize a telemedicine system. Seventy-five percent (24/32) of hospitals not utilizing a protocol are interested in instituting one. CONCLUSION: Though slightly less than one-third of military hospitals use a +POx, there is a greater interest in its use. More reliable consultative services and a robust telemedicine system may aid its implementation.

Glutamatergic projections from homeostatic to hedonic brain nuclei regulate intake of highly palatable food.

Food intake is a complex behavior regulated by discrete brain nuclei that integrate homeostatic nutritional requirements with the hedonic properties of food. Homeostatic feeding (i.e. titration of caloric intake), is typically associated with hypothalamic brain nuclei, including the paraventricular nucleus of the hypothalamus (PVN). Hedonic feeding is driven, in part, by the reinforcing properties of highly palatable food (HPF), which is mediated by the nucleus accumbens (NAc). Dysregulation of homeostatic and hedonic brain nuclei can lead to pathological feeding behaviors, namely overconsumption of highly palatable food (HPF), that may drive obesity. Both homeostatic and hedonic mechanisms of food intake have been attributed to several brain regions, but the integration of homeostatic and hedonic signaling to drive food intake is less clear, therefore we aimed to identify the neuroanatomical, functional, and behavioral features of a novel PVN → NAc circuit. Using viral tracing techniques, we determined that PVN → NAc has origins in the parvocellular PVN, and that PVN → NAc neurons express VGLUT1, a marker of glutamatergic signaling. Next, we pharmacogenetically stimulated PVN → NAc neurons and quantified both gamma-aminobutyric acid (GABA) and glutamate release and phospho-cFos expression in the NAc and observed a robust and significant increase in extracellular glutamate and phospho-cFos expression. Finally, we pharmacogenetically stimulated PVN → NAc which decreased intake of highly palatable food, demonstrating that this glutamatergic circuitry regulates aspects of feeding.

Binge-Type Eating in Rats is Facilitated by Neuromedin U Receptor 2 in the Nucleus Accumbens and Ventral Tegmental Area.

Binge-eating disorder (BED) is the most common eating disorder, characterized by rapid, recurrent overconsumption of highly palatable food in a short time frame. BED shares an overlapping behavioral phenotype with obesity, which is also linked to the overconsumption of highly palatable foods. The reinforcing properties of highly palatable foods are mediated by the nucleus accumbens (NAc) and the ventral tegmental area (VTA), which have been implicated in the overconsumption behavior observed in BED and obesity. A potential regulator of binge-type eating behavior is the G protein-coupled receptor neuromedin U receptor 2 (NMUR2). Previous research demonstrated that NMUR2 knockdown potentiates binge-type consumption of high-fat food. We correlated binge-type consumption across a spectrum of fat and carbohydrate mixtures with synaptosomal NMUR2 protein expression in the NAc and VTA of rats. Synaptosomal NMUR2 protein in the NAc demonstrated a strong positive correlation with binge intake of a "lower"-fat (higher carbohydrate) mixture, whereas synaptosomal NMUR2 protein in the VTA demonstrated a strong negative correlation with binge intake of an "extreme" high-fat (0% carbohydrate) mixture. Taken together, these data suggest that NMUR2 may differentially regulate binge-type eating within the NAc and the VTA.

Cocaine-Evoked Locomotor Activity Negatively Correlates With the Expression of Neuromedin U Receptor 2 in the Nucleus Accumbens.

Cocaine use disorder (CUD) is characterized by repeated cycles of drug seeking and drug taking. Currently, there are no available pharmacotherapies to treat CUD, partially due to a lack of a mechanistic understanding of cocaine-evoked alterations in the brain that drive drug-related behaviors. Repeated cocaine use alters expression of numerous genes in addiction-associated areas of the brain and these alterations are in part driven by inter-subject genetic variability. Recent findings have shown the neuropeptide neuromedin U (NMU) and its receptor NMU receptor 2 (NMUR2) decrease drug-related behaviors, but it is unknown if substances of abuse alter NMU or NMUR2 expression. Here, rats were given twice daily saline or cocaine (15 mg/kg, intraperitoneal (IP)) for 5 days and then 7 days with no treatment. All rats were then given a single cocaine treatment and locomotor activity was measured in the acute (non-sensitized) and repeated drug exposure (sensitized) groups. Immediately following locomotor assay, tissue was taken and we demonstrate that accumbal NMUR2 mRNA expression, but not NMU mRNA expression, is negatively correlated with non-sensitized cocaine-evoked locomotor activity, but the correlation is lost following cocaine sensitization. Furthermore, in a separate cohort NMUR2 protein levels also negatively correlated with cocaine-evoked locomotor activity based on immunohistochemical stereology for NMUR2 protein expression. These findings are the first to demonstrate that repeated cocaine exposure causes dysregulated expression of NMUR2 and highlight the deleterious effects of repeated cocaine exposure on neurobiological receptor systems. Restoring the normal function of NMUR2 could be beneficial to the treatment of CUD.

Environmental Enrichment and Social Isolation Mediate Neuroplasticity of Medium Spiny Neurons through the GSK3 Pathway.

Resilience and vulnerability to neuropsychiatric disorders are linked to molecular changes underlying excitability that are still poorly understood. Here, we identify glycogen-synthase kinase 3ß (GSK3ß) and voltage-gated Na+ channel Nav1.6 as regulators of neuroplasticity induced by environmentally enriched (EC) or isolated (IC) conditions-models for resilience and vulnerability. Transcriptomic studies in the nucleus accumbens from EC and IC rats predicted low levels of GSK3ß and SCN8A mRNA as a protective phenotype associated with reduced excitability in medium spiny neurons (MSNs). In vivo genetic manipulations demonstrate that GSK3ß and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3ß prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3ß with Nav1.6 and phosphorylation at Nav1.6T1936 by GSK3ß. A GSK3ß-Nav1.6T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3ß regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity.

The efficacy of single-component brief motivational interventions among at-risk college drinkers.

OBJECTIVE: College students are an at-risk population for heavy drinking and negative alcohol-related outcomes. Research has established that brief, multicomponent motivational interviewing-based interventions can be effective at reducing alcohol use or related problems, but less is known about the efficacy of individual components within these interventions. The purpose of this study was to test the efficacy of 2 single-component, in-person, brief (15-20 min) alcohol interventions: personalized normative feedback (PNF) and protective behavioral strategies feedback (PBSF). METHOD: Data were collected on 365 undergraduate students from a large Midwestern university (65% women; 89% White) who were randomly assigned to 1 of 3 conditions: PNF, PBSF, or alcohol education (AE). Participants completed measures of alcohol use, alcohol-related problems, social norms, and protective behavioral strategies. RESULTS: Results indicated that the PNF intervention was efficacious relative to the other conditions at reducing alcohol use and that its effects at 6-month follow-up were mediated by changes in perceived norms at the 1-month follow-up. The PBSF intervention was not efficacious at reducing alcohol use or alcohol-related problems. CONCLUSIONS: These findings provide support for the efficacy of an in-person PNF intervention and theoretical support for the hypothesized mechanisms of change in the intervention. Implications for researchers and clinicians are discussed.

Marijuana use, driving, and related cognitions.

The purpose of the present study was to examine cognitive risk factors for driving after use of marijuana. We tested whether marijuana outcome expectancies and specific cognitions about driving after marijuana use were uniquely associated with the likelihood and frequency of driving while high (DWH) and riding with a high driver (RWHD). Participants were college students recruited from introductory psychology classes at a Midwestern university who reported ever using marijuana in their lifetime and reported having access to a car or driving at least once a month (n = 506). Greater perceived dangerousness of DWH was associated with decreased likelihood of DWH and RWHD. Negative marijuana expectancies were associated with decreased likelihood of DWH, and social norms were associated with decreased likelihood of RWHD. All cognitive predictors were associated with decreased frequency of DWH and RWHD for individuals with the propensity to engage in these behaviors. Findings suggest interventions to reduce risk of DWH and RWHD may benefit from targeting general expectancies about the negative effects of marijuana. Similarly, results suggest increasing students' knowledge of the potential danger of DWH may help to reduce the likelihood and frequency of DWH and RWHD.

Do protective behavioral strategies moderate the relationship between negative urgency and alcohol-related outcomes among intercollegiate athletes?

OBJECTIVE: The purpose of this study was to examine the moderating effect of protective behavioral strategies on the relationship between negative urgency and alcohol outcomes. METHOD: Participants were college students who endorsed participating in club/intramural or varsity athletics. The students (N = 234; 73.9% female) completed measures of negative urgency, protective behavioral strategies, alcohol use, and alcohol-related problems. Separate hierarchical multiple regression analyses were conducted for each subscale of the Protective Behavioral Strategies Scale to test for moderation. RESULTS: Results indicated that protective behavioral strategies aimed at serious harm reduction moderated the relationship between negative urgency and alcohol use, whereas strategies aimed at avoiding excessive or rapid drinking moderated the relationship between negative urgency and alcohol-related problems. Strategies that involved planning drinking activities in advance did not moderate the relationship between negative urgency and alcohol outcomes. CONCLUSIONS: The current investigation provides further evidence for the role of protective behavioral strategies against known risk factors for alcohol use and related problems. Further, the paper suggests that type of strategy used matters when attempting to mitigate the relationship between negative urgency and alcohol outcomes. Limitations and future directions are discussed.

The short-term efficacy of a brief motivational intervention designed to increase physical activity among college students.

BACKGROUND: Research has shown that many college students do not meet recommended national guidelines for physical activity. The objective of this pilot study was to examine the short-term efficacy of a brief motivational intervention (BMI) designed to increase physical activity. METHODS: Participants were 70 college students who reported low physical activity (83% women, 60% African American). Participants were randomly assigned to either the BMI condition or to an education-only (EO) condition. They completed measures of physical activity at baseline and 1-month follow-up. RESULTS: Those in the BMI condition reported more vigorous-intensity physical activity at a 1-month follow-up than those in the EO condition. CONCLUSIONS: The findings from this study provide preliminary support for the efficacy of a BMI designed to increase physical activity among college students. Future studies should continue to examine and refine the intervention in an effort to improve health-related behaviors among this group.

Moderators of the relationship between physical activity and alcohol consumption in college students.

OBJECTIVE: Among college students, several studies have found a positive relationship between physical activity and alcohol use. The current study tested gender, Greek status, and ethnicity as potential moderators of the physical activity-alcohol use relationship. PARTICIPANTS: Participants were college freshmen (n = 310) endorsing alcohol/drug use. METHODS: Students completed questionnaires assessing a number of health behaviors. RESULTS: Results indicated that gender and Greek status were significant moderators of the relationship between physical activity and alcohol consumption. There was a positive relationship between physical activity and alcohol use for men and Greeks, but not for females and non-Greeks. CONCLUSIONS: These findings suggest that exercise does not serve as a protective factor for any of the subgroups of college students studied and is positively associated with drinking among college students who are men and/or involved with the Greek system.