Marcella Pascualy

Sodium lactate and hypertonic sodium chloride induce equivalent panic incidence, panic symptoms, and hypernatremia in panic disorder

BACKGROUND Although experimental induction of panic by infusion of 0.5 mol/L sodium lactate in persons with panic disorder was described three decades ago, the mechanism underlying this observation remains unclear. Here we asked if the rapid administration of the large sodium load contained in the 0.5-mol/L sodium lactate infusion might be involved in panic induction. METHODS We compared in panic disorder and healthy subjects behavioral, electrolyte, endocrine, and acid-base responses to three double-blind randomly ordered equal volume 20-min infusions: 0.5 mol/L sodium lactate, hypertonic saline (3% sodium chloride), and normal saline placebo. RESULTS Sodium lactate (0.5 mol/L) and hypertonic saline produced the same high incidence of panic and equivalent increases in panic symptoms, serum sodium, and plasma vasopressin in the panic disorder subjects. Neither hypertonic infusion increased cortisol or adrenocorticotropin. No normal subject experienced panic in any condition. The 0.5-mol/L sodium lactate infusion induced alkalosis, whereas hypertonic saline and normal saline induced a mild acidosis. CONCLUSIONS Hypertonic sodium solution containing either chloride or lactate anion induces panic in panic disorder. The large sodium loads delivered by hypertonic saline and 0.5 mol/L sodium lactate may be involved in the mechanism of panic induction.

Effect of desipramine on cerebrospinal fluid concentrations of corticotropin-releasing factor in human subjects

To assess the effect of desipramine (DMI) on corticotropin-releasing-factor (CRF) activity in the central nervous system, we measured cerebrospinal fluid (CSF) concentrations of CRF in healthy volunteers following short-term administration of DMI or placebo. DMI administration for 2 days was associated with a significant dose-related reduction in CRF concentrations. There was a nonsignificant 6% reduction in CRF concentrations among the 10 subjects who received 50 mg DMI (delta CRF: -3 +/- 2 pg/ml) and a significant 14% fall in the CRF concentrations of the eight subjects who received 100 mg DMI (delta CRF: -8 +/- 3 pg/ml). The mean CSF concentration of CRF was unchanged in the six subjects randomized to placebo (delta CRF: 1 +/- 5 pg/ml). DMI administration had no effect on CSF norepinephrine concentrations (n = 24) or on plasma cortisol (n = 25). We conclude that short-term administration of DMI in healthy volunteers is associated with a dose-related reduction in CSF concentrations of CRF.

Short-term sertraline treatment suppresses sympathetic nervous system activity in healthy human subjects

Increased sympathetic nervous system (SNS) activity has been associated with stress, major depression, aging, and several medical conditions. This study assessed the effect of the selective serotonin reuptake inhibitor (SSRI), sertraline, on sympathetic nervous system (SNS) activity in healthy subjects. Twelve healthy volunteers participated in a double-blind, placebo-controlled, norepinephrine (NE) kinetic study, in which the effects of sertraline on SNS activity were ascertained by determining NE plasma concentrations and NE plasma appearance rates and clearance rates in sertraline or placebo conditions. Subjects received 50 mg of sertraline or placebo for two days and then one week later underwent the same protocol with the other drug. By single compartmental analysis, plasma NE appearance rates were significantly lower in the sertraline compared to the placebo condition (0.26+/-0.10 vs 0.40+/-0.23 microg/m(2)/min; P=0.04). Our study found that the net effect of short-term SSRI treatment is an apparent suppression of SNS activity as indicated by a decreased plasma NE appearance rate in the sertraline condition. If this preliminary finding can be extended to long-term treatment of patients, this could have significant therapeutic relevance for treating depression in elderly patients or those with cardiac disease, in which elevated SNS activity may exacerbate underlying medical conditions.

Propranolol for disruptive behaviors in nursing home residents with probable or possible alzheimer disease : A placebo-controlled study

Objective:Enhanced behavioral responsiveness to central nervous system (CNS) norepinephrine (NE) in Alzheimer disease (AD) may contribute to the pathophysiology of disruptive behaviors such as aggression, uncooperativeness with necessary care, irritability, and pressured pacing. We evaluated the efficacy of the beta-adrenergic antagonist propranolol for treatment-resistant disruptive behaviors and overall behavioral status in nursing home residents with probable or possible AD. Methods:Thirty-one subjects (age 85 ± 8 [SD]) with probable or possible AD and persistent disruptive behaviors that interfered with necessary care were randomized to propranolol (n = 17) or placebo (n = 14) in a double-blind study. Stable doses of previously prescribed psychotropics were maintained at pre-study dose during the study. Following a propranolol or placebo dose titration period of up to 9 days (per a dosing algorithm), subjects were maintained on maximum achieved dose for 6 weeks. Primary outcome measures were the Neuropsychiatric Inventory (NPI) and the Clinical Global Impression of Change (CGIC). Results:Propranolol augmentation (mean achieved dose 106 ± 38 mg/d) was significantly more effective than placebo for improving overall behavioral status on the total NPI score and CGIC. Improvement in individual NPI items within propranolol subjects was significant only for “agitation/aggression” and “anxiety,” and reached borderline statistical significance favoring propranolol over placebo only for “agitation/aggression.” Pressured pacing and irritability did not appear responsive to propranolol. In propranolol subjects rated “moderately improved” or “markedly improved” on the CGIC at the end of the double-blind study phase, improvement of overall behavioral status had diminished substantially after 6 months of open-label propranolol treatment. Conclusion:Short-term propranolol augmentation treatment appeared modestly effective and well tolerated for overall behavioral status in nursing home residents with probable or possible AD complicated by disruptive behaviors. Propranolol may be helpful specifically for aggression and uncooperativeness (the behaviors assessed by the NPI “agitation/aggressiveness” item). However, the usefulness of propranolol in this very old and frail population was limited by the high frequency of relative contraindications to beta-adrenergic antagonist treatment and diminution of initial behavioral improvements over time.

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 Alzheimers 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.

Cerebrospinal Fluid Epinephrine in Alzheimer’s Disease and Normal Aging

Central nervous system (CNS) adrenergic systems are involved in regulation of behavior and blood pressure. The effects of Alzheimers disease (AD) and normal aging on resting CNS adrenergic activity were estimated by measuring cerebrospinal fluid (CSF) epinephrine (EPI) concentrations in 74 persons with AD, 42 cognitively normal healthy older persons, and 54 healthy young persons. The responsiveness of CSF EPI to the alpha-2 adrenergic antagonist yohimbine and the alpha-2 adrenergic agonist clonidine was measured in smaller subject groups. Resting CSF EPI was higher in AD than in older or young subjects, and increased with dementia severity in AD subjects. There was no relationship between resting CSF EPI and blood pressure. CSF EPI increased following yohimbine in AD and older subjects but not in young subjects. CSF EPI was unaffected by clonidine in all subject groups. The agitation increase following yohimbine was substantially greater in AD subjects than in older or young subjects. CNS adrenergic activity seems increased in AD, may further increase as AD progresses, and may be involved in the pathophysiology of agitation.

Localization of 3H-Prazosin Binding Sites in the Supraoptic and Paraventricular Nuclei of the Human Hypothalamus

Using 3H-prazosin, we have examined the distribution of alpha 1-adrenergic receptors in the supraoptic and paraventricular nuclei of the human hypothalamus. Our studies show that binding sites for 3H-prazosin in human hypothalamus possess pharmacological characteristics similar to those of rat brain. Autoradiographic studies revealed discrete localization of 3H-prazosin to the paraventricular and supraoptic nuclei.

The effects of normal aging on cortisol and adrenocorticotropin responses to hypertonic saline infusion

To assess the effects of aging on hypothalamic-pituitary-adrenal (HPA) axis responsivity, we compared the plasma cortisol and adrenocorticotropin (ACTH) responses to hypertonic saline infusion between normal older and young human volunteers. We administered a 90 min hypertonic saline infusion (5% sodium chloride at 0.06 ml/kg/min) and a 90 min placebo infusion (0.9% sodium chloride at 0.06 ml/kg/min) to normal young subjects (n = 13, age = 29 +/- 2 years) and normal older subjects (n = 8, age = 63 +/- 3 years). Plasma cortisol, ACTH, osmolality and arginine vasopressin (AVP) were measured before and at 30 min intervals during the infusions. The rate of increase in plasma osmolality and AVP induced by hypertonic saline infusion was similar between groups. The plasma cortisol increase during hypertonic saline infusion was greater in normal older subjects than in young subjects (p = .03), but a stimulatory effect of hypertonic saline infusion on plasma ACTH was not apparent in either older or young subjects. These results suggest increased sensitivity with human aging to stimulation of cortisol release by hypertonic saline infusion at the adrenocortical level of the HPA axis.

Oral physostigmine in alzheimer's disease: Effects on norepinephrine and vasopressin in cerebrospinal fluid and plasma

Physostigmine is a cholinesterase inhibitor which enhances central and peripheral cholinergic activity. In this study, we explored in persons with Alzheimers disease (AD) the effects of an acute dose of physostigmine in patients receiving chronic physostigmine treatment on the activity of the cholinergically regulated noradrenergic and arginine vasopressin (AVP) systems. Specifically, we estimated the effects of sustained release oral physostigmine on central and peripheral noradrenergic and AVP systems by measuring norepinephrine (NE) and AVP in cerebrospinal fluid (CSF) and plasma. Lumbar punctures were performed in both physostigmine and no drug treatment conditions. In some subjects the effects of physostigmine on the plasma AVP response to the osmolar stimulus of a hypertonic saline infusion also were measured. NE concentrations in both CSF and plasma were significantly lower in the physostigmine than in the no drug condition. AVP concentrations did not differ between conditions in either compartment, nor did physostigmine affect the AVP response to hypertonic saline. Physostigmine appears to decrease both central and peripheral noradrenergic activity in AD.

Lack of cholinergic regulation of vasopressin and norepinephrine responses to hypertonic saline in humans

In vitro studies in hypothalamic-pituitary explants in the rat have suggested cholinergic mediation of arginine vasopressin (AVP) osmoregulation. In this study we attempted to demonstrate, in humans, cholinergic mediation of AVP osmoregulation. Specifically, we tested the hypothesis that the plasma AVP response to an osmolar stimulus would be attenuated by pharmacologic blockade of central nervous system muscarinic or nicotinic receptors in humans. We also evaluated the effects of cholinergic blockade on the norepinephrine (NE) response to an osmolar stimulus. Young normal males underwent hypertonic saline infusion following administration of the centrally active muscarinic antagonist scopolamine or the centrally active nicotinic antagonist mecamylamine. Neither mecamylamine nor scopolamine affected the AVP response to hypertonic saline infusion. Mecamylamine reduced NE concentrations in a dose-dependent manner, but did not affect the slope of the NE increase during hypertonic saline infusion. In a second experiment, we evaluated the effects of scopolamine and mecamylamine on the AVP and NE responses to physostigmine, a cholinesterase inhibitor which stimulates AVP release into plasma through a non-osmolar central nervous system cholinergic mechanism. Scopolamine eliminated the AVP response to physostigmine. Mecamylamine reduced NE concentrations both before and after scopolamine administration but did not affect the slope of the AVP response. These results fail to support cholinergic regulation of the AVP response to osmolar stimulation in humans.