Neurochemical and electrophysiological events underlying stress-induced depression in an animal model.

This paper has described an animal (rodent) model of depression in which depression-like characteristics are produced by exposure of animals to stressful events that they cannot control. This model, called "stress-induced depression," appears to be mediated by stress-induced changes in brain norepinephrine (NE), and evidence now indicates that a large depletion of NE in the Locus Coeruleus region of the brain stem (LC) is critical for producing the behavioral disturbance seen in this model. To explain the functional significance of NE depletion in the LC, it has been suggested that this change results in decreased stimulation, (i.e., functional blockade) of alpha-2 receptors that normally inhibit firing of LC neurons. Consequently, LC neurons should be disinhibited in stress-induced depression. The final part of this paper describes findings from electrophysiological measurement of LC activity. Prior to measuring changes occurring in stress-induced depression, studies examined the basic role played by alpha-2 receptors in LC activity. These receptors were found to regulate the responsivity of LC neurons to excitatory stimuli, so that pharmacological blockade of these receptors increased the firing of LC neurons to excitatory input. When LC activity was then measured in stressed animals showing behavioral depression, responsivity of LC neurons to excitatory input was elevated in comparison to animals not exposed to stress. Also, administration of an alpha-2 blocking drug could not increase responsivity of LC neurons in stressed animals, which further indicated that alpha-2 receptors in the LC region were functionally blocked in these animals. Finally, the amount that LC neurons increased their firing to an excitatory stimulus (i.e., an index of alpha-2 receptor blockade) was highly correlated with the amount of behavioral depression seen in an activity test conducted just prior to electrophysiological measurement. These electrophysiological findings indicate that LC neurons are disinhibited in stress-induced depression, and that this disinhibition is particularly characterized by increased responsivity of LC neurons to excitatory input, which is indicative of alpha-2 receptor blockade. These findings further support the view that the LC is involved in stress-induced depression, and are consistent with a proposed mechanism that attributes behavioral disturbance in the model to disinhibition of LC neurons arising from subnormal activation of inhibitory alpha-2 receptors.

Studies of biological factors associated with the inheritance of schizophrenia: a selective review.

Although a familial component to schizophrenia has been established through several family, twin and adoption studies, an inherited biological factor has yet to be established. Efforts to define clinical familial subtypes of schizophrenia have generally been unsuccessful, although recent data from our study population of pairs of siblings with schizophrenia suggests that schizophrenia with recurrent episodes of major depression may define one such group. There have only been a few biological traits consistently found to be associated with schizophrenia and also found to be heritable. These findings (e.g. measures of monoamine metabolism, brain structural morphology, neurophysiological markers, and protein polymorphisms) are reviewed in the present chapter. The proportion of patients with any of the noted abnormalities never approaches 100%, nor have any been found to be specific to schizophrenia. Research into the biogenetics of schizophrenia is clearly just beginning.

Ultrastructure and biochemistry of sympathetic ganglia in idiopathic orthostatic hypotension.

The role of transsynaptic dysfunction in the pathogenesis of idiopathic orthostatic hypotension (IOH, or idiopathic autonomic insufficiency) was examined microscopically and biochemically in autopsy specimens. Light microscopy of the sympathetic ganglia showed abnormalities in all 4 IOH patients, including focal phagocytosis of neurons, increased numbers of satellite cells, and perivascular lymphocytic infiltrates. Electron microscopy revealed proliferation and hypertrophy of satellite cells and abnormalities in the unmyelinated axons. In contrast, the spinal cord intermediolateral columns, containing the presynaptic neurons, were unremarkable in 1 patient, exhibited only mild gliosis in another, and showed neuron loss and fibrillary gliosis in 2 patients. Postsynaptic dopamine-beta-hydroxylase (DBH) activity was decreased at least fourfold (p less than 0.02) in sympathetic ganglia of patients with IOH, while tyrosine hydroxylase (T-OH) was normal. Ganglion choline acetyltransferase (ChAc) activity, an index of presynaptic function and integrity, was normal in the IOH group. A number of our observations suggest that presynaptic disease is not an absolute requirement for adrenergic abnormalities in IOH. The intermediolateral columns of the spinal cord were histologically normal in 2 of the patients with IOH, and ultrastructural abnormalities in sympathetic ganglia were consistent with primary adrenergic degeneration. In addition, presynaptic ChAc activity was normal in IOH ganglia, whereas postsynaptic DBH activity was depressed. Finally, postsynaptic T-OH activity, which is regulated by transsynaptic mechanisms, was normal in IOH ganglia.