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.

The alpha1-adrenergic antagonist prazosin ameliorates combat trauma nightmares in veterans with posttraumatic stress disorder: a report of 4 cases.

BACKGROUND: Central nervous system (CNS) adrenergic hyperresponsiveness may be involved in the pathophysiology of posttraumatic stress disorder (PTSD). Two Vietnam combat veterans with PTSD prescribed the centrally active alpha1-adrenergic antagonist prazosin for symptoms of benign prostatic hypertrophy unexpectedly reported elimination of combat trauma nightmares. This observation prompted an open-label feasibility trial of prazosin for combat trauma nightmares in chronic combat-induced PTSD. METHOD: Four consecutively identified combat veterans with chronic DSM-IV PTSD and severe intractable combat trauma nightmares participated in an 8-week open trial of escalating-dose prazosin. Nightmare severity response was rated using the nightmare item of the Clinician Administered PTSD Scale and the Clinical Global Impressions-Change scale. RESULTS: The 2 patients who achieved a daily prazosin dose of at least 5 mg were markedly improved, with complete elimination of trauma nightmares and resumption of normal dreaming. The 2 subjects limited to 2 mg of prazosin to avoid excessive blood pressure reduction were moderately improved with at least 50% reduction in nightmare severity. CONCLUSION: These clinical observations, together with neurobiological evidence for alpha1-adrenergic regulation of CNS neurobiological systems relevant to PTSD, provide rationale for placebo-controlled trials of prazosin for PTSD combat trauma nightmares.

A dendritic GABAA-mediated IPSP regulates facilitation of NMDA-mediated responses to burst stimulation of afferent fibers in piriform cortex.

Studies in a number of cortical systems have shown that the NMDA component of the EPSP is strongly regulated by GABAA-mediated inhibition. The present study explored the possibility that specificity in inhibitory circuitry could allow such regulation to occur during normal function without increasing the propensity for epileptiform bursting, which occurs with indiscriminate GABAA blockade. Specifically, the hypothesis was tested that a dendritic GABAA-mediated IPSP is present which strongly modulates the NMDA component and can be activated independently of the somatic IPSP. The experiments were performed on slices of piriform cortex in which the NMDA component of the EPSP was pharmacologically isolated by bath-applied 6,7-dinitroquinoxaline-2,3-dione. A facilitation of NMDA responses to burst stimulation of afferent fibers is described, which required GABAA blockade and served as an assay for the presence of a functionally significant GABAA input. When bicuculline was applied focally in the somatic region, the feedback IPSP was blocked with little or no increase in the NMDA component of the response to burst stimulation of afferent fibers. In contrast, when bicuculline was applied focally in the dendritic region, the NMDA-mediated response to burst stimulation was facilitated with minimal effect on the somatic IPSP, confirming the hypothesis.

A fluorescein angiographic study of patients with pars planitis and peripheral exudation (snowbanking) before and after cryopexy.

BACKGROUND: Transconjunctival cryopexy of the vitreous base is clinically effective in patients with steroid nonresponsive pars planitis who have peripheral neovascularization. Cryoablation of the region previously has been thought to eliminate the areas of permeable neovascular tissue, thus removing the focus of exudation. The authors report the first study of patients with refractory pars planitis in which fluorescein angiography of the inferior pars plana snowbanks was performed both before and after cryopexy of the vitreous base. METHODS: Twelve consecutive phakic eyes with pars planitis and prominent peripheral snowbanks had fluorescein angiograms of the pars plana. Clinical involvement was graded on the basis of visual acuity, levels of vitreous inflammation and cystoid macular edema, and on the extent of peripheral snowbanking. Transconjunctival cryopexy of the vitreous base was performed. Fluorescein angiography of the pars plana snowbanks was repeated 2 months after the procedure, and clinical involvement again was graded. RESULTS: Early hyperfluorescence with late leakage was present in all eyes and was limited to the area of the pars plana snowbanks. After cryopexy of the vitreous base, all eyes demonstrated hypofluorescence and diminution of late-phase dye leakage in the treated areas. Eighty-three percent of all eyes demonstrated clinical improvement, consistent with previously reported studies. CONCLUSION: Cryopexy of the vitreous base decreases peripheral exudation in patients with refractory pars planitis and snowbanking. This suggests that elimination of peripheral neovascular tissue may be directly related to clinical improvement in these patients.

Associative long-term potentiation in piriform cortex slices requires GABAA blockade.

Previous studies have demonstrated that NMDA-dependent, long-term potentiation (LTP) can be induced in both afferent and intrinsic association fiber systems in the piriform (primary olfactory) cortex. In this report we demonstrate that an associative form of LTP can be induced by coactivation of these two systems, which terminate on adjacent apical dendritic segments of pyramidal cells. Potentiating stimulus trains were delivered to either afferent or association fibers, and weak shocks, which were nonpotentiating when delivered alone, were delivered to the other pathway. Under control recording conditions where homosynaptic (single pathway) LTP is consistently evoked, coincident application of these stimuli failed to induce LTP of the weak shock response. However, after local blockade of the fast, GABAA-mediated IPSP, associative LTP was consistently produced in both directions. Induction was blocked by D-2-amino-5-phosphonovaleric acid, indicating that it is dependent on activation of NMDA receptors. It is speculated that afferent and association fibers are segregated on different dendritic segments of pyramidal cells in piriform cortex to allow regulation of associative LTP by way of centrifugal inputs that modulate the activity of GABAergic interneurons.

NMDA-dependent induction of long-term potentiation in afferent and association fiber systems of piriform cortex in vitro.

Long-term potentiation (LTP) was demonstrated in a slice preparation of piriform (olfactory) cortex. LTP could be reliably induced in both afferent and association fiber pathways. The magnitude of the observed potentiation was greater in the association fiber pathway. 2-Amino-5-phosphonovalerate (APV) blocked induction of LTP in both pathways, indicating that N-methyl-D-aspartate (NMDA) receptor activation is required for induction.

Isolated unilateral hemichoroidal melanosis.

Ocular melanosis is usually diffuse but may be sectoral. An unusual case of isolated unilateral hemispheric choroidal melanosis is presented in a patient with uveitis. Details of the embryologic basis for this condition remain speculative.