Faculty Bibliography

Recent studies in rodents have suggested a role for the central endocannabinoid system in the regulation of mood and alcohol related behaviors. Alcohol use disorder is often associated with suicidal behavior. In the present study, we examined whether abnormalities in the endocannabinoid system in the ventral striatum are associated with alcohol dependence and suicide. The levels of CB1 receptors, receptor-mediated G-protein signaling, and activity and level of the fatty acid amide hydrolase (FAAH) were analyzed postmortem in the ventral striatum of alcohol-dependent nonsuicides (CA, n=9), alcohol-dependent suicides (AS, n=9) and nonpsychiatric controls (C, n=9). All subjects underwent a psychological autopsy, and toxicological and neuropathological examinations. The levels of the CB1 receptors and the CB1 receptor-mediated G-protein signaling were significantly lower in the ventral striatum of CA compared to the control group. However, these parameters were elevated in AS when compared to CA group. The activity of FAAH enzyme was lower in CA compared to the control group while it was found to be significantly higher in AS compared with CA group. These findings suggest that alcohol dependence is associated with the downregulation of the CB1 receptors, while suicide is linked to the upregulation of these receptors in the ventral striatum. Alteration in the activity of FAAH enzyme that regulates the anandamide (AEA) content might in turn explain differences in the CB1 receptor function in alcohol dependence and suicide. These findings may have etiological and therapeutic implications for the treatment of alcohol addiction and suicidal behavior

Enhanced odor preference learning and attenuated fear learning characterizes rat pups' attachment learning Sensitive Period for learning the maternal odor. This period terminates at 10 days old (PN10) with increasing endogenous levels of the stress hormone, corticosterone. Increasing Sensitive Period pups' corticosterone prematurely terminates the Sensitive Period, while decreasing corticosterone in older pups delays Sensitive Period termination. Here we extend these findings and define the age range corticosterone alters learning and question whether corticosterone permanently terminates the Sensitive Period. Pups were odor-0.5 mA shock conditioned with either corticosterone increased (PN5-6; 4 mg/kg vs. saline) or decreased (PN15-16; naturally by maternal presence or corticosterone synthesis blocker, Metyrapone). Finally, PN7-8 pups were conditioned with corticosterone and reconditioned without corticosterone to assess whether the Sensitive Period was permanently terminated. Results indicate developmental limits for corticosterone regulation of pup learning are PN6 through PN15. Furthermore, inducing precocious corticosterone induced fear learning was not permanent, since reconditioning without corticosterone enabled odor preference learning. Results suggest pups are protected from learning aversions to maternal odor until approaching weaning

OBJECTIVE: The goal of this study was to pilot a randomized controlled trial of OROS methylphenidate (OROS-MPH) to treat attention deficit hyperactivity disorder (ADHD) plus epilepsy. METHODS: Thirty-three patients, 6-18years of age, taking antiepileptic drugs and with a last seizure 1-60months prior were assigned to a maximum daily dose of 18, 36, or 54mg of OROS-MPH in a double-blind placebo-controlled crossover trial. RESULTS: There were no serious adverse events and no carryover effects in the crossover trial. OROS-MPH reduced ADHD symptoms more than did placebo treatment. There were too few seizures during the active (5) and placebo arms (3) to confidently assess seizure risk; however, considering exposure time, we observed an increased daily risk of seizures with increasing dose of OROS-MPH, suggesting that potential safety concerns require further study. CONCLUSION: A larger study to assess the effect of OROS-MPH on seizure risk is needed. A crossover design including subjects with frequent seizures could maximize power and address high patient heterogeneity and recruitment difficulties.

BACKGROUND: Dermatomyositis is an autoimmune disease of unknown etiology characterized by inflammation of the skin and muscles. Several medications have been implicated in the development of dermatomyositis; however, the disease has rarely been linked to the use of tumor necrosis factor (TNF) inhibitors. We report 4 cases of dermatomyositis that developed or were exacerbated by exposure to the TNF inhibitors etanercept and adalimumab. Observation Four patients with symptoms of inflammatory arthritis were treated with TNF inhibitors for a duration ranging from 2 months to 2 years. All 4 patients developed symptoms consistent with dermatomyositis, including inflammatory rash and muscle weakness. Their symptoms persisted after discontinuation of the treatment with the TNF inhibitors but responded to treatment with corticosteroids and immunosuppressive medications. CONCLUSIONS: Tumor necrosis factor inhibitors have been associated with the onset of a number of autoimmune disorders, most commonly vasculitis and a lupuslike syndrome. Rarely have they been associated with dermatomyositis. The 4 cases reported herein indicate that TNF inhibitor use can be associated with either induction or exacerbation of dermatomyositis.

STUDY OBJECTIVES: To explore the relationship between sleep duration in adolescence and hypercholesterolemia in young adulthood. Experimental sleep restriction has been shown to significantly increase total cholesterol and LDL cholesterol levels in women. Short sleep duration has been found in cross sectional studies to be associated with higher total cholesterol and lower HDL cholesterol levels. Sleep deprivation could increase the risk for hypercholesterolemia by increasing appetite and dietary consumption of saturated fats, decreasing motivation to engage in regular physical activity, and increasing stress and resultant catecholamine induced lipolysis. No previous published population studies have examined the longitudinal relationship between sleep duration and high cholesterol. DESIGN: Multivariate longitudinal analyses stratified by sex of the ADD Health using logistic regression. SETTING: United States nationally representative, school-based, probability-based sample. PARTICIPANTS: Adolescents (n = 14,257) in grades 7 to 12 at baseline (1994-95) and ages 18 to 26 at follow-up (2001-02). MEASUREMENTS AND RESULTS: Among females, each additional hour of sleep was associated with a significantly decreased odds of being diagnosed with high cholesterol in young adulthood (OR = 0.85, 95% CI 0.75-0.96) after controlling for covariates. Additional sleep was associated with decreased, yet not statistically significant, odds ratios for hypercholesterolemia in males (OR = 0.91, 95% CI 0.79-1.05). CONCLUSIONS: Short sleep durations in adolescent women could be a significant risk factor for high cholesterol. Interventions that lengthen sleep could potentially serve as treatments and as primary preventative measures for hypercholesterolemia

Family-based interventions with children who are affected by HIV and AIDS are not well established. The Collaborative HIV Prevention and Adolescent Mental Health Program (CHAMP) represents one of the few evidence-based interventions tested in low-income contexts in the US, Caribbean and South Africa. This paper provides a description of the theoretical and empirical bases of the development and implementation of CHAMP in two of these countries, the US and South Africa. In addition, with the advent of increasing numbers of children infected with HIV surviving into adolescence and young adulthood, a CHAMP+ family-based intervention, using the founding principles of CHAMP, has been developed to mitigate the risk influences associated with being HIV positive.

The lateral hypothalamus and the nucleus accumbens shell (AcbSh) are brain regions important for food intake. The AcbSh contains high levels of receptor for melanin-concentrating hormone (MCH), a lateral hypothalamic peptide critical for feeding and metabolism. MCH receptor (MCHR1) activation in the AcbSh increases food intake, while AcbSh MCHR1 blockade reduces feeding. Here biochemical and cellular mechanisms of MCH action in the rodent AcbSh are described. A reduction of phosphorylation of GluR1 at serine 845 (pSer(845)) is shown to occur after both pharmacological and genetic manipulations of MCHR1 activity. These changes depend upon signaling through G(i/o), and result in decreased surface expression of GluR1-containing AMPA receptors (AMPARs). Electrophysiological analysis of medium spiny neurons (MSNs) in the AcbSh revealed decreased amplitude of AMPAR-mediated synaptic events (mEPSCs) with MCH treatment. In addition, MCH suppressed action potential firing MSNs through K(+) channel activation. Finally, in vivo recordings confirmed that MCH reduces neuronal cell firing in the AcbSh in freely moving animals. The ability of MCH to reduce cell firing in the AcbSh is consistent with a general model from other pharmacological and electrophysiological studies whereby reduced AcbSh neuronal firing leads to food intake. The current work integrates the hypothalamus into this model, providing biochemical and cellular mechanisms whereby metabolic and limbic signals converge to regulate food intake.

BACKGROUND: Both abused and well cared for infants show attachment to their caregivers, although the quality of that attachment differs. Moreover, the infant's attachment to the abusive caregiver is associated with compromised mental health, especially under stress. In an attempt to better understand how abuse by the caregiver can compromise mental health, we explore the neural basis of attachment in both typical and abusive environments using infant rats, which form attachments to the mother through learning her odor. Here, we hypothesize that the neural circuitry for infant attachment differs based on the quality of the attachment, which can be uncovered during stressful situations. METHODS: We used infant rats to compare infant attachment social behaviors and supporting neurobiology using natural maternal odor, as well as two odor-learning attachment paradigms: odor-stroke (mimics typical attachment) and odor-.5 mA shock conditioning (mimics abusive attachment). Next, to uncover differences in behavior and brain, these pups were injected with systemic corticosterone. Finally, pups were reared with an abusive mother to determine ecological relevance. RESULTS: Our results suggest that the natural and learned attachment odors indistinguishably control social behavior in infancy (approach to the odor and interactions with the mother). However, with corticosterone injection, pups with an abusive attachment show disrupted infant social behavior with the mother and engagement of the amygdala. CONCLUSIONS: This animal model of attachment accommodates both abusive and typical attachment and suggests that pups' social behavior and underlying neural circuitry may provide clues to understanding attachment in children with various conditions of care

BACKGROUND: The lateral (LA) and central (CE), but not basal (B), amygdala nuclei are necessary for reactive Pavlovian fear responses such as freezing. The amygdala also plays a key role in the acquisition and expression of active instrumental defensive behaviors, but little is known about the specific roles of amygdala nuclei. Using a Sidman active avoidance (AA) task, we examined the necessity of LA, B, and CE for learning and performance. Pavlovian freezing was simultaneously assessed to examine the contributions of amygdala nuclei to the transition from reactive to active defensive responding. METHODS: Rats received electrolytic lesions of LA, CE, or B before AA training, or following overtraining. Rats that expressed low levels of AA performance during training received bilateral electrolytic lesions to CE to eliminate competing freezing reactions and rescue AA. AA performance and freezing were assessed. RESULTS: Damage to LA and B, but not CE, impaired the acquisition of AA. Performance of AA became amygdala-independent following overtraining. CE lesions abolished Pavlovian freezing and rescued instrumental AA performance in rats that expressed low levels of avoidance responses and high levels of freezing during training. CONCLUSIONS: Although the acquisition of Pavlovian fear depends on LA and CE, but not B, acquisition of instrumental AA is dependent on LA and B, but not CE. CE-dependent Pavlovian processes that control freezing can constrain avoidance behavior. Performance of well-trained AA becomes independent of all three amygdala nuclei. Thus, it appears that different output pathways of LA mediate reactive and active conditioned defensive responding

BACKGROUND: Similar patterns of vulnerability to carbon dioxide (CO(2)) inhalation have been reported in adults with panic disorder (PD) and children with separation anxiety disorder (SAD), suggesting a link between the adult and child conditions. This study examines the influence of familial risk for PD on CO(2) responses in children with SAD. We hypothesized that offspring with SAD of parents with PD would have distinct CO(2) responses. METHODS: Two hundred twelve 9- to 20-year-old offspring of parents with or without PD were exposed to maintained 5% CO(2) inhalation in the participants' homes. Anxiety symptoms, panic attacks, and respiratory physiology (respiratory frequency and tidal volume) were monitored during baseline and 15-min maintained CO(2) breathing. RESULTS: As hypothesized, significant offspring SAD x parent PD interactions were obtained for anxiety symptoms, respiratory frequency, tidal volume, and a panting index during CO(2) inhalation. Offspring with both SAD and parental PD exhibited more anxiety symptoms at termination of 5% CO(2) breathing than the other offspring groups and had the most extreme values on measures of respiratory physiology. CONCLUSIONS: Youth with both SAD and parental PD have respiratory responses to CO(2) similar to adult PD. They might be a subtype of SAD at particularly high risk for adult PD