Altered responsiveness to glutamatergic modulation by MK-801 and to repeated stress of immune challenge in female dopamine transporter knockout rats.

Chronic stress is a key factor in psychiatric and neurological disorders often worsening disease symptoms. In this study, a unique animal model, the dopamine transporter knockout (DAT-KO) rat exhibiting behavioral signs resembling those occurring in mania, schizophrenia, attention deficit hyperactivity disorder, and obsessive-compulsive disorder was used. We have tested the hypothesis that the hyperdopaminergic state in DAT-KO rats (i) modulates behavioral response to the NMDA antagonist MK-801 (dizocilpine) and (ii) leads to abnormal endocrine and immune activation under subchronic stress induced by an immune challenge. Glutamatergic modulation with MK-801 induced a different behavioral pattern. While the WT rats responded to MK-801 injection with a robust rise in their locomotor activity, the hyperactive DAT-KO rats exhibited reduced locomotion. Signs of chronic stress including increased basal corticosterone and aldosterone but blunted anxiety were demonstrated in rats lacking the DAT. Repeated injections of increasing doses of lipopolysaccharide (LPS, 5 days) did not modify plasma prolactin concentrations which were however significantly lower in DAT-KO than in WT rats. Concentrations of plasma high mobility group box 1 (HMGB1) protein were significantly higher in LPS-treated DAT-KO than in WT rats. The gene expression of interleukin-6 in the anterior pituitary increased under the stress induced by the immune challenge in the WT but not the DAT-KO rats. The most evident differences between the genotypes were revealed in the spleen. The splenic gene expression of interleukin-1ß, interleukin-6, and HMGB1 was lower and that of ferritin was higher in DAT-KO compared to WT rats. Obtained results emphasize the functional interaction of the endocrine and immune systems with monoamine and glutamatergic neurotransmission in the mechanisms leading to behavioral alterations and psychiatric disorders associated with dopamine dysfunction.

Exposure to chronic stressor upsurges the excitability of serotoninergic neurons and diminishes concentrations of circulating corticosteroids in rats two weeks thereafter.

BACKGROUND: Exposure to predator scent (PS) has been used as a model of stress associated with danger to life and body integrity. Under stress conditions, the brain serotoninergic (5-HT) system plays an important role. METHODS: We tested the hypothesis that repeated PS exposure alters the excitability of 5-HT neurons of the dorsal raphe nucleus. To study the mechanisms involved, we approached serum and adrenal corticosterone and aldosterone concentrations, as well as brain-derived neurotrophic factor (BDNF) expression. Adult male Sprague-Dawley rats were exposed to PS for 10 min daily for 10 consecutive days. Two weeks after the last exposure, electrophysiological and biochemical assessments were performed. RESULTS: Measurements by in vivo electrophysiology showed increased firing activity of 5-HT neurons in rats exposed to PS. Exposure to PS resulted in reduced serum corticosterone and aldosterone concentrations. Concentrations of both corticosteroids in the adrenal glands and the relative weight of the adrenals were unaffected. The gene expression of hippocampal BDNF of rats exposed to PS remained unaltered. PS exposure failed to induce changes in the gene expression of selected adrenal steroidogenic factors. CONCLUSION: Reduced corticosteroid concentrations in the blood appear to be the result of increased metabolism and/or tissue uptake rather than altered steroidogenesis. The decrease in circulating corticosterone in rats who experienced repeated PS may represent part of the mechanisms leading to increased excitability of 5-HT neurons. The increase in 5-HT neuronal activity might be an important compensatory mechanism designated to diminish the harmful effects of the repeated PS exposure on the brain.