Blast-related disinhibition and risk seeking in mice and combat Veterans: Potential role for dysfunctional phasic dopamine release.

Mild traumatic brain injury (mTBI) caused by exposure to high explosives has been called the "signature injury" of the wars in Iraq and Afghanistan. There is a wide array of chronic neurological and behavioral symptoms associated with blast-induced mTBI. However, the underlying mechanisms are not well understood. Here we used a battlefield-relevant mouse model of blast-induced mTBI and in vivo fast-scan cyclic voltammetry (FSCV) to investigate whether the mesolimbic dopamine system contributes to the mechanisms underlying blast-induced behavioral dysfunction. In mice, blast exposure increased novelty seeking, a behavior closely associated with disinhibition and risk for subsequent maladaptive behaviors. In keeping with this, we found that veterans with blast-related mTBI reported greater disinhibition and risk taking on the Frontal Systems Behavior Scale (FrSBe). In addition, in mice we report that blast exposure causes potentiation of evoked phasic dopamine release in the nucleus accumbens. Taken together these findings suggest that blast-induced changes in the dopaminergic system may mediate aspects of the complex array of behavioral dysfunctions reported in blast-exposed veterans.

Lesioning noradrenergic neurons of the locus coeruleus in C57Bl/6 mice with unilateral 6-hydroxydopamine injection, to assess molecular, electrophysiological and biochemical changes in noradrenergic signaling.

The locus coeruleus (LC) is the major loci of noradrenergic innervation to the forebrain. Due to the extensive central nervous system innervation of the LC noradrenergic system, a reduction in the number of LC neurons could result in significant changes in noradrenergic function in many forebrain regions. LC noradrenergic neurons were lesioned in adult male C57Bl/6 mice with the unilateral administration of 6-hydroxydopamine (6OHDA) (vehicle on the alternate side). Noradrenergic markers were measured 3 weeks later to determine the consequence of LC loss in the forebrain. Direct administration of 6OHDA into the LC results in the specific reduction of noradrenergic neurons in the LC (as measured by electrophysiology, immunoreactivity and in situ hybridization), the lateral tegmental neurons and dopaminergic neurons in the substantia nigra (SN) and ventral tegmental region were unaffected. The loss of LC noradrenergic neurons did not result in compensatory changes in the expression of mRNA for norepinephrine (NE)-synthesizing enzymes. The loss of LC noradrenergic neurons is associated with reduced NE tissue concentration and NE transporter (NET) binding sites in the frontal cortex and hippocampus, as well as other forebrain regions such as the amygdala and SN. Adrenoreceptor (AR) binding sites (α(1)- and α(2)-AR) were not significantly affected on the 6OHDA-treated side compared to the vehicle-treated side, although there is a reduction of AR binding sites on both the vehicle- and 6OHDA-treated side in specific forebrain regions. These studies indicate that unilateral stereotaxic injection of 6OHDA into mice reduces noradrenergic LC neurons and reduces noradrenergic innervation to many forebrain regions, including the contralateral side.

ABCB1 genotype and CSF beta-amyloid in Alzheimer disease.

The ABCB1 gene, coding for the efflux transporter P-glycoprotein (PGP), is a candidate gene for Alzheimer disease (AD). P-glycoprotein is heavily expressed at the blood-brain barrier, where it mediates the efflux of ß-amyloid (Aß) from the brain. In this study, we investigated a possible association between 2 common ABCB1 polymorphisms, G2677T/A (Ala893Ser/Thr) and C3435T, AD, and cerebrospinal fluid (CSF) levels of Aß. No strong evidence for association was found.

A comprehensive analysis of the effect of DSP4 on the locus coeruleus noradrenergic system in the rat.

Degeneration of the noradrenergic neurons in the locus coeruleus (LC) is a major component of Alzheimer's (AD) and Parkinson's disease (PD), but the consequence of noradrenergic neuronal loss has different effects on the surviving neurons in the two disorders. Therefore, understanding the consequence of noradrenergic neuronal loss is important in determining the role of this neurotransmitter in these neurodegenerative disorders. The goal of the study was to determine if the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) could be used as a model for either (or both) AD or PD. Rats were administered DSP4 and sacrificed 3 days 2 weeks and 3 months later. DSP4-treatment resulted in a rapid, though transient reduction in norepinephrine (NE) and NE transporter (NET) in many brain regions receiving variable innervation from the LC. Alpha(1)-adrenoreceptors binding site concentrations were unchanged in all brain regions at all three time points. However, an increase in alpha(2)-AR was observed in many different brain regions 2 weeks and 3 months after DSP4. These changes observed in forebrain regions occurred without a loss in LC noradrenergic neurons. Expression of synthesizing enzymes or NET did not change in amount of expression/neuron despite the reduction in NE tissue content and NET binding site concentrations at early time points, suggesting no compensatory response. In addition, DSP4 did not affect basal activity of LC at any time point in anesthetized animals, but 2 weeks after DSP4 there is a significant increase in irregular firing of noradrenergic neurons. These data indicate that DSP4 is not a selective LC noradrenergic neurotoxin, but does affect noradrenergic neuron terminals locally, as evident by the changes in transmitter and markers at terminal regions. However, since DSP4 did not result in a loss of noradrenergic neurons, it is not considered an adequate model for noradrenergic neuronal loss observed in AD and PD.

Technical note: An improved surgical model for the long-term studies of kinetics and quantification of nutrient absorption in swine.

An improved technique to study kinetics and quantitative absorption of nutrients in pigs is described. Three female pigs (35 kg of BW) were surgically modified with catheters in the hepatic portal vein and carotid artery and an ultrasonic flow probe around the portal vein. Catheter placement and patency was secured using distal modifications (rings and holes) and nonabsorbable suture. Catheters and flow probe cable were tunneled subcutaneously after exteriorization for further protection. Fibrosis and adhesions in the body cavity were minimized by avoiding excessive manipulation and drying of viscera. Pigs were supported during recovery by intravenous fluid therapy of AA and electrolytes until regular feeding resumed. Catheters were flushed daily with heparinized saline (200 IU/L). After 10 d, pigs were fed a diet based on wheat and soybean meal for 6 consecutive 7-d periods. On d 7, blood was collected postprandially every 15 min from -15 to 60 min, 30 to 240 min, 60 to 480 min, and 120 to 720 min. Blood flow was measured simultaneously. Plasma was analyzed for glucose, and net glucose absorption was calculated from plasma portal-arterial differences x plasma flow [blood flow x (1 - hematocrit)]. The specific improvements for long-term use of this model are distal modifications of the catheters, postoperative treatment using parental nutrition and gut motility drug, prevention of infection of body cavity by further tunneling of catheters and blood flow probe cable, and use of ultrasonic blood flow probes and meter. Blood flow measurements using an ultrasonic blood flow probe was not changed after 52 d compared with 10 d post-surgery, indicating the reliability of this model. This catheterized pig model, thus, will allow the long-term study of the kinetics of nutrient absorption.

Intranasal insulin improves cognition and modulates beta-amyloid in early AD.

BACKGROUND: Reduced brain insulin signaling and low CSF-to-plasma insulin ratios have been observed in patients with Alzheimer disease (AD). Furthermore, intracerebroventricular or IV insulin administration improve memory, alter evoked potentials, and modulate neurotransmitters, possibly by augmenting low brain levels. After intranasal administration, insulin-like peptides follow extracellular pathways to the brain within 15 minutes. OBJECTIVE: We tested the hypothesis that daily intranasal insulin treatment would facilitate cognition in patients with early AD or its prodrome, amnestic mild cognitive impairment (MCI). The proportion of verbal information retained after a delay period was the planned primary outcome measure. Secondary outcome measures included attention, caregiver rating of functional status, and plasma levels of insulin, glucose, beta-amyloid, and cortisol. METHODS: Twenty-five participants were randomly assigned to receive either placebo (n = 12) or 20 IU BID intranasal insulin treatment (n = 13) using an electronic atomizer, and 24 participants completed the study. Participants, caregivers, and all clinical evaluators were blinded to treatment assignment. Cognitive measures and blood were obtained at baseline and after 21 days of treatment. RESULTS: Fasting plasma glucose and insulin were unchanged with treatment. The insulin-treated group retained more verbal information after a delay compared with the placebo-assigned group (p = 0.0374). Insulin-treated subjects also showed improved attention (p = 0.0108) and functional status (p = 0.0410). Insulin treatment raised fasting plasma concentrations of the short form of the beta-amyloid peptide (A beta 40; p = 0.0471) without affecting the longer isoform (A beta 42), resulting in an increased A beta 40/42 ratio (p = 0.0207). CONCLUSIONS: The results of this pilot study support further investigation of the benefits of intranasal insulin for patients with Alzheimer disease, and suggest that intranasal peptide administration may be a novel approach to the treatment of neurodegenerative disorders.

Temperament and response to the Trier Social Stress Test.

OBJECTIVE: The personality characteristics behavioural inhibition and neuroticism have been associated with mood and anxiety disorders and, in some studies, hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. We recently reported that low levels of Novelty Seeking were associated with elevated plasma cortisol responses to the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test in healthy adults with no psychiatric disorder. The present study tested the association between temperament and HPA axis function in the same group of subjects using a standardized psychosocial neuroendocrine stress test. METHOD: Subjects completed diagnostic interviews, questionnaires, and the Trier Social Stress Test (TSST). RESULTS: Novelty Seeking was inversely associated with plasma cortisol concentrations at baseline and throughout the TSST, but was not related to adrenocorticotropic hormone (ACTH) levels. CONCLUSION: Results of this study extend our previous finding in the Dex/CRH test to a psychosocial stress test. Future investigations are needed to replicate these findings and further elucidate how temperament and personality are linked to HPA function.

Chronic cortisol suppresses pituitary and hypothalamic peptide message expression in pigtailed macaques.

The effects of chronic elevations in circulating glucocorticoids on the expression of peptides and peptide receptors of the hypothalamic-pituitary-adrenal (HPA) axis have been studied extensively in rodents, but they have not been examined in primates. To determine the responses of the HPA axis in primates to elevated cortisol, hypothalamic and pituitary tissue from normal older pigtailed macaques (Macaca nemestrina) that had received daily oral administration of cortisol or placebo for 1 year were studied. Pro-opiomelanocortin in the anterior pituitary and corticotropin-releasing factor (CRF) mRNA expression in the hypothalamic paraventricular nucleus (PVN) were significantly reduced in cortisol-treated monkeys in comparison with controls. CRF receptor 1 (CRF-R1) expression in the anterior pituitary and arginine vasopressin mRNA expression in the PVN were unchanged by chronic cortisol administration. Sustained elevation of circulating glucocorticoids results in suppression of HPA peptide and peptide receptor expression in the PVN and anterior pituitary similar to those found in rodents. Chronic therapeutic administration of glucocorticoids in humans may have unintended consequences for hypothalamic and pituitary function.

Effects of repetitive hypoglycemia on neuroendocrine response and brain tyrosine hydroxylase activity in the rat.

Hypoglycemia-associated autonomic failure (HAAF) is a syndrome of acute adaptation to a metabolic stressor, in which neuroendocrine responses to repetitive hypoglycemic bouts are blunted. The CNS mechanisms that contribute to HAAF are unknown. In the present study, we modeled HAAF in the rat and measured the activity of tyrosine hydroxylase (TH) as an index of acute noradrenergic activation, to test the hypothesis that noradrenergic activation of the hypothalamus might be impaired. In association with a significant counter-regulatory response to a single bout of hypoglycemia (elevated corticosterone, catecholamines, and glucagon), TH activity was elevated overall in brainstem NE cell body areas and hypothalamus. With multiple hypoglycemic episodes in a 24 h period, the counter-regulatory response was blunted, and hypothalamic TH activity was comparable to that of saline-infused controls. In a similar paradigm, multiple bouts of CNS neuroglucopenia did not blunt the hyperglycemic or corticosterone responses, and were required for elevation of TH activity. This alternate response pattern suggests that insulin-induced hypoglycemia and cerebral neuroglucopenia represent somewhat different metabolic stressors at the CNS.

Acute modulation of aged human memory by pharmacological manipulation of glucocorticoids.

In a previous longitudinal study of basal cortisol levels and cognitive function in humans, we showed that elderly humans with 4- to 7-yr cumulative exposure to high levels of cortisol present memory impairments, compared with elderly humans with moderate cortisol levels over years. Here, we measured whether memory performance in two groups of elderly humans separated on the basis of their cortisol history over a 5-yr period could be modulated by a hormone-replacement protocol in which we inhibited cortisol secretion by the administration of metyrapone and then restored baseline cortisol levels by infusion of hydrocortisone. We showed that in elderly subjects with a 5-yr history of moderate cortisol levels (n = 8), metyrapone treatment significantly impaired memory performance, a deficit that was reversed following hydrocortisone replacement. In the elderly subjects with a 5-yr history of high cortisol levels and current memory deficits (n = 9), metyrapone treatment did not have any significant effect on memory performance, but hydrocortisone treatment significantly decreased delayed memory. These results suggest that memory function in elderly humans can be intensely modulated by pharmacological manipulation of glucocorticoids, although the direction of these effects depends on the cortisol history of each individual.

PVN activation is suppressed by repeated hypoglycemia but not antecedent corticosterone in the rat.

The mechanism(s) underlying hypoglycemia-associated autonomic failure (HAAF) are unknown. To test the hypothesis that the activation of brain regions involved in the counterregulatory response to hypoglycemia is blunted with HAAF, rats were studied in a 2-day protocol. Neuroendocrine responses and brain activation (c-Fos immunoreactivity) were measured during day 2 insulin-induced hypoglycemia (0.5 U insulin x 100 g body x wt(-1) x h(-1) iv for 2 h) after day 1 hypoglycemia (Hypo-Hypo) or vehicle. Hypo-Hypo animals demonstrated HAAF with blunted epinephrine, glucagon, and corticosterone (Cort) responses and decreased activation of the medial hypothalamus [the paraventricular (PVN), dorsomedial (DMH), and arcuate (Arc) nuclei]. To evaluate whether increases in day 1 Cort were responsible for the decreased hypothalamic activation, Cort was infused intracerebroventricularly (72 microg) on day 1 and the response to day 2 hypoglycemia was measured. Intracerebroventricular Cort infusion failed to alter the neuroendocrine response to day 2 hypoglycemia, despite elevating both central nervous system and peripheral Cort levels. However, day 1 Cort blunted responses in two of the same hypothalamic regions as Hypo-Hypo (the DMH and Arc) but not in the PVN. These results suggest that decreased activation of the PVN may be important in the development of HAAF and that antecedent exposure to elevated levels of Cort is not always sufficient to produce HAAF.

Glucocorticoid feedback sensitivity and adrenocortical responsiveness in posttraumatic stress disorder.

BACKGROUND: Decreased basal cortisol levels have been reported in individuals with posttraumatic stress disorder (PTSD). There is evidence for enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis in PTSD, which could account for this, but other possible mechanisms have not been ruled out. We examined the HPA axis employing a metyrapone-cortisol infusion protocol designed to study negative feedback sensitivity. METHODS: Vietnam combat trauma-exposed subjects met DSM-IV criteria for PTSD. Exclusion criteria included substance abuse and most medications. Endogenous feedback inhibition was removed by blocking cortisol synthesis with oral metyrapone and reintroduced by intravenous infusion of cortisol. In a placebo condition, subjects received oral placebo and normal saline infusion. Serial blood samples drawn over 4 hours were assayed for adrenocorticotrophic hormone (ACTH), cortisol, and 11-deoxycortisol. Selected samples were assayed for cortisol binding globulin (CBG) and dehydroepiandrosterone (DHEA). RESULTS: Basal plasma cortisol was significantly decreased in PTSD subjects (n = 13) compared with control subjects (n = 16). No significant difference in the ACTH response to cortisol infusion following metyrapone was observed; however 11-deoxycortisol was significantly decreased in PTSD subjects. In addition, CBG was significantly increased in PTSD subjects, and DHEA was significantly decreased in both PTSD and combat-exposed control subjects. CONCLUSIONS: These observations suggest decreased adrenocortical responsiveness may be an additional or alternative mechanism accounting for low cortisol in PTSD.

Glucocorticoid induction of the glaucoma gene MYOC in human and monkey trabecular meshwork cells and tissues.

PURPOSE: To examine the intracellular and extracellular expression of myocilin in the human and primate trabecular meshwork (TM) in the presence and absence of glucocorticoids. METHODS: Myocilin expression was examined in cultured human TM cells by Northern blot analysis and myocilin antibody-mediated immunoprecipitation. Myocilin expression was quantified using high-resolution two-dimensional polyacrylamide gel electrophoresis of radiolabeled proteins from human TM cells, TM tissue explants, and perfused human anterior segments cultured with and without dexamethasone (DEX) for 14 to 21 days, as well as TM tissue from pigtailed monkeys treated orally for 1 year with cortisone acetate. Immunofluorescence with anti-myocilin antibodies was used to localize cellular and extracellular expression of myocilin in cultured human TM cells. RESULTS: Glucocorticoid treatment caused a significant induction of myocilin mRNA, a tetrad of cell-associated proteins, and 8 to 20 secreted proteins (molecular mass [M(r)] 56 and 59 kDa and isoelectric point [pI] 5.2 and 5.3) in some, but not all the cultured human TM cells and explanted tissues. Western immunoblot analysis using anti-myocilin peptide antibodies identified these proteins as encoded by the MYOC gene. There was significant induction of the myocilin proteins in three perfusion-cultured human eyes, in which DEX-induced elevated intraocular pressure developed. Monkeys treated 1 year with cortisol acetate showed steroid glaucoma-like morphologic changes in the TM that correlated with the induction of myocilin in the TM. Immunofluorescence analysis of cultured TM cells localized myocilin intracellularly in discrete perinuclear and cytoplasmic vesicular deposits as well as extracellularly on the cell surface associated with the extracellular matrix. In several DEX-treated TM cell lines, there were significant levels of myocilin secreted into the media. Enzymatic deglycosylation of proteins in the TM media converted the higher molecular weight isoforms of myocilin (approximately 57 kDa) to the lower molecular weight isoforms ( approximately 55 kDa). CONCLUSIONS: Although the function of myocilin is unknown, induction of these TM proteins was found in eyes in which glucocorticoid-induced ocular hypertension developed. Therefore, myocilin may play an important pathogenic role in ocular hypertension in addition to its role in certain forms of POAG.

Increased CSF cortisol in AD is a function of APOE genotype.

BACKGROUND: Increased hypothalamic-pituitary-adrenal (HPA) axis activity manifested by elevated cortisol levels is observed in AD and may contribute to AD by lowering the threshold for neuronal degeneration. Presence of the APOE-epsilon4 allele increases risk for AD. Increased cortisol concentrations in apoE-deficient mice suggest that APOE genotype may influence cortisol concentrations in AD. METHODS: The authors measured cortisol levels in CSF and determined APOE genotypes for 64 subjects with AD and 34 nondemented older control subjects. RESULTS: CSF cortisol was significantly higher in AD than in control subjects. CSF cortisol concentrations differed with respect to APOE genotype in both subjects with AD (epsilon4/epsilon4 > epsilon3/4epsilon > epsilon3/epsilon3) and normal older control subjects (epsilon3/epsilon4 > epsilon3/epsilon3 > epsilon2/epsilon3). Comparison of CSF cortisol concentrations within the epsilon3/epsilon4 and epsilon3/epsilon3 genotypes revealed no differences between AD and control subject groups. CONCLUSIONS: Higher CSF cortisol concentrations were associated with increased frequency of the APOE-epsilon4 allele and decreased frequency of the APOE-epsilon2 allele in AD subjects relative to control subjects. This effect of APOE genotype on HPA axis activity may be related to the increased risk for AD in persons carrying the APOE-epsilon4 allele and decreased risk for AD in persons carrying the APOE-epsilon2 allele.

Human glucocorticoid feedback inhibition is reduced in older individuals: evening study.

We have previously shown that when tested in the morning, older men and women, pretreated with metyrapone to block endogenous cortisol synthesis, exhibit delayed suppression of plasma ACTH in response to cortisol infusion. To confirm this finding and to determine whether aging-related changes in feedback responsiveness are exaggerated near the time of the circadian nadir in adrenocortical secretion, we performed a similar study in the evening. Healthy young (20-35 yr, n = 22) and old (>65 yr, n = 21) men and women were administered metyrapone orally (750 mg) at 1600 and 1900 h, followed by a cortisol infusion of 0.06 mg/kg/h for 150 min. Blood samples were taken at 15-min intervals for 4 h following infusion onset for measurement of plasma ACTH, cortisol, 11-deoxycortisol, and corticosteroid binding globulin. When corrections were made for differences in circulating cortisol concentrations achieved among age and gender subgroups, feedback inhibition of ACTH was found to be significantly greater in young than in old subjects of both genders. Our studies support the hypothesis that glucocorticoid responses to stress in aging individuals are likely to be prolonged due to blunted and delayed inhibition of ACTH secretion, thus increasing the total exposure to glucocorticoids.

Gender differences in age-related changes in HPA axis reactivity.

Possible differences between men and women in age-related patterns of hypothalamic-pituitary-adrenal (HPA) axis response to challenge were examined to test the hypothesis that women show greater age-related increase in HPA axis reactivity to challenge. Twenty-six younger subjects, 9 men and 17 women, ages 22-26 and 14 older subjects, 7 men and 7 women, ages 67-88 participated in the study. Patterns of change in salivary "free" cortisol were measured in response to a standardized, 30-minute cognitive challenge, administered individually to each subject beginning at 1600 h. Consistent with previous research, there was a significant main effect for age with respect to baseline cortisol: older age was associated with higher baseline cortisol (P = <0.001). Results also provide support for the hypothesized age-by-gender interaction with respect to patterns of response to challenge. There was a significant interaction with respect to maximum percentage increase over baseline (P < 0.002): among younger adults, the men exhibited greater increases whereas among the older adults, the women exhibited greater increases. A similar, though only marginally significant pattern was seen for total area under the response curve (P = 0.07). Repeated measures ANOVA confirmed the gender-by-age differences in the patterns of response (P = 0.01 for time*age*gender interaction).

Violence prevention at work. A business perspective.

INTRODUCTION: The risk of workplace violence varies depending on the type and location of the business. Business managers should assess violence risk and develop a program based on the level of risk faced by their employees. DISCUSSION: This assessment should include: (1) a review of workplace security and identification of positions with increased risk of exposure to violence, (2) risk reduction through environmental design and employee training, (3) development of a plan and identification of professional resources to respond to incidents should they occur, and (4) communication of the employer's commitment to providing a safe work environment for employees. CONCLUSIONS: For most businesses, threat assessment and management comprise the cornerstone of a workplace violence-prevention program. Planning and preparation are key to workplace violence prevention.

Hypothalamic melanin-concentrating hormone and estrogen-induced weight loss.

Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide produced by neurons of the lateral hypothalamic area (LHA). Because genetic MCH deficiency induces hypophagia and loss of body fat, we hypothesized that MCH neurons may represent a specific LHA pathway that, when inhibited, contributes to the pathogenesis of certain anorexia syndromes. To test this hypothesis, we measured behavioral, hormonal, and hypothalamic neuropeptide responses in two models of hyperestrogenemia in male rats, a highly reproducible anorexia paradigm. Whereas estrogen-induced weight loss engaged multiple systems that normally favor recovery of lost weight, the expected increase of MCH mRNA expression induced by energy restriction was selectively and completely abolished. These findings identify MCH neurons as specific targets of estrogen action and suggest that inhibition of these neurons may contribute to the hypophagic effect of estrogen.

Hypothalamic pituitary adrenocortical and sympathetic nervous system responses to the cold pressor test in Alzheimer's disease.

BACKGROUND: Increased basal activity of the hypothalamic-pituitary-adrenocortical (HPA) axis has been repeatedly demonstrated in Alzheimer's disease (AD), and some studies suggest increased basal activity of the sympathetic nervous system (SNS) in this disorder; however, the effects of AD on HPA axis or SNS responses to a standardized aversive stressor have not been examined. The neuroendocrine response to aversive stress may be relevant to the pathophysiology of AD. METHODS: Plasma adrenocorticotropic hormone (ACTH), cortisol, norepinephrine (NE), and epinephrine responses to a 1-min cold pressor test (CPT) were measured in nine medically healthy AD outpatients (age 76 +/- 2 years) and nine age- and gender-matched medically healthy cognitively normal older subjects (age 76 +/- 1 year). RESULTS: The cortisol response to CPT was increased in the AD group but the ACTH response did not differ between groups. Basal NE concentrations were higher in the AD group. Although NE responses to CPT did not differ between groups, the blood pressure response to CPT was higher in the AD subjects. CONCLUSIONS: These results suggest increased HPA axis responsiveness to CPT at the level of the adrenal cortex in AD. The results also suggest increased basal sympathoneural activity and increased cardiovascular responsiveness to sympathoneural stimulation in AD under the conditions of this experimental protocol. Increased SNS stimulatory modulation of the adrenal cortex is a possible mechanism contributing to the observed enhanced cortisol response to CPT in these AD subjects.

Effect of intracerebroventricular alpha-MSH on food intake, adiposity, c-Fos induction, and neuropeptide expression.

alpha-Melanocyte-stimulating hormone (alpha-MSH) is a hypothalamic neuropeptide proposed to play a key role in energy homeostasis. To investigate the behavioral, metabolic, and hypothalamic responses to chronic central alpha-MSH administration, alpha-MSH was infused continuously into the third cerebral ventricle of rats for 6 days. Chronic alpha-MSH infusion reduced cumulative food intake by 10.7% (P < 0.05 vs. saline) and body weight by 4.3% (P < 0.01 vs. saline), which in turn lowered plasma insulin levels by 29.3% (P < 0.05 vs. saline). However, alpha-MSH did not cause adipose-specific wasting nor did it alter hypothalamic neuropeptide mRNA levels. Central alpha-MSH infusion acutely activated neurons in forebrain areas such as the hypothalamic paraventricular nucleus, as measured by a 254% increase in c-Fos-like immunoreactivity (P < 0.01 vs. saline), as well as satiety pathways in the hindbrain. Our findings suggest that, although an increase of central melanocortin receptor signaling acutely reduces food intake and body weight, its anorectic potency wanes during chronic infusion and causes only a modest decrease of body weight.