A hypothesis accounting for the inconsistent benefit of glucocorticoid therapy in closed head trauma.

Because of disagreement between clinical studies, the American College of Neurological Surgeons (ACNS) most recent recommendation (1996) is that glucocorticoids should not be used in the treatment of closed head trauma (CHT). The current paper reviews clinical studies of glucocorticoids and CHT in order to examine what factors might have accounted for the inconsistent results leading to the ACNS's recommendation. A careful analysIs of these studies reveals that, contrary to the ACNS's sweeping conclusion, the available data support the use of glucocorticoids for patients with CHT, but only in specific cases. Glucocorticoids may be beneficial in the treatment of CHT uncomplicated by intracranial hemorrhage; in situations where intracranial hemorrhage accompanies CHT, glucocorticoid treatment appears detrimental. The second part of this paper examines possible mechanisms accounting for the differential effectiveness of glucocorticoids in CHT patients with and without intracranial hemorrhage. These mechanisms include vasospasm, free radical damage, blood-borne factors, and glutamate neurotoxicity.

Selective activation of mesoamygdaloid dopamine neurons by conditioned stress: attenuation by diazepam.

Populations of dopamine (DA) neurons in the rat brain are selectively activated by stress, and the response is attenuated by the administration of anxiolytics. Given the role of the component nuclei of the amygdaloid complex in conditioned associations, stress responses and the anxiolytic effects of benzodiazepines, we hypothesized that particular mesoamygdaloid DA projections might be especially sensitive to the effects of conditioned stress and to diazepam (DZ). We mapped the effect of a conditioned stressor on the concentration of the DA metabolite homovanillic acid (HVA) in distinct amygdaloid nuclei and other brain nuclei and areas and the effect of DZ (1 or 3 mg/kg) on the conditioned response in drug-experienced subjects. The conditioned stress paradigm resulted in significant elevations in classical indices of stress, including serum corticosterone and plasma epinephrine. Conditioned stress-induced increases in the estimated activity of DA neurons were specific for DA neurons projecting to the central, basolateral and lateral amygdaloid nuclei, and for DA projections to the dorsal septal nucleus. Conditioned stress-induced increases in the HVA concentration of responsive amygdaloid nuclei were antagonized by low, anxiolytic doses of DZ. These results indicate a role for a subset of mesoamygdaloid DA projections in transducing the impact of perceived stressors on the output of the amygdaloid complex. A role for particular amygdaloid DA projections in the formation of conditioned fear or anticipatory anxiety and its modulation by anxiolytics is also suggested.

Differential effects of conditioned and unconditioned stress on the neurotensin content of dopamine cell body groups of the ventral mesencephalon.

The findings of this study extend the observations of Deutch et al. who suggested that NT in the ventral mesencephalon may be involved in the environmentally elicited activation of selectively responsive populations of mesotelencephalic dopamine neurons. The unconditioned response of NT-LI to electric footshock was observed only at an intensity of 500 microA and only in the lateral subdivision of the VTA. The selective effect of footshock stress on the NT content of a specific cell body group of the ventral mesencephalon suggests that NT mechanisms in the lateral VTA may, in part, underlie the stress-induced activation of dopamine neurons that originate in the lateral VTA. However, it should be noted that populations of dopamine neurons are activated by footshock intensities less than 500 microA, while NT concentrations of mesencephalic dopamine cell body groups are not altered by these shock intensities. The disparity weakens the possibility of a role for NT in the stress-induced activation of brain dopamine neurons unless NT mechanisms may be involved in transducing the effects of higher intensity stressors versus low intensity stressors. However, it should be noted that changes in the concentration of NT-LI represent an endpoint of unknown sensitivity and functional significance and best serve as an initial approximation of the effects of a manipulation on NT-containing neurons. It is plausible that NT mechanisms in the ventral mesencephalon may act in concert with other neuropeptides such as substance P and Met-enkephalin to transduce the effects of stressors on alterations in the activity of mesotelencephalic dopamine neurons that originate in the ventral mesencephalon. An examination of the effects of footshock stress on the content of prepro-NT mRNA in the dopamine cell body groups of the ventral mesencephalon would be of interest in assessing whether stress enhances NT gene expression or alters the characteristics of release of this neuropeptide in the ventral mesencephalon. Lacking NT receptor antagonists, it would also be of interest to determine the effects of the passive immunoneutralization of NT in the ventral mesencephalon on footshock-induced increases in the biochemically estimated activity of mesotelencephalic dopamine neurons to better understand the involvement of NT as a transducer of the effects of stress on dopamine neuronal activity. The distinct topography of conditioned versus unconditioned stress on the concentration of NT-LI in the dopamine cell body groups of the ventral mesencephalon suggests that NT may be involved in the differential activation of distinct dopamine neuronal populations by these different stressors.(ABSTRACT TRUNCATED AT 400 WORDS)