Effects of learned helplessness on brain GABA receptors.

GABA is involved in both clinical depression and in animal models of depression; however, the roles of GABA(A) and GABA(B) receptors in specific brain regions are not clear. Changes in densities of both GABA(A) and GABA(B) receptors have been reported with the learned helplessness animal model of depression and with chronic antidepressant drug treatment. However, some of these findings are discrepant. Thus, we used quantitative autoradiography to study the GABA(A) and GABA(B) receptors in learned helplessness and we used an experimental paradigm that allows non-specific effects of stress to be differentiated from learned helplessness. Densities of GABA binding were measured in prefrontal cortex, septum, hippocampus, hypothalamus and amygdala. In the septum, learned helpless rats had increased densities of GABA(A) receptors and rats that did not become helpless after inescapable stress had decreased GABA(B) receptor densities. No significant group differences of GABA(A) or GABA(B) receptor densities were observed in any other brain region studied. These results suggest a unique role for the septum in modulating GABA in the learned helplessness animal model of depression.

Increased septal 5-HIAA efflux in rats that do not develop learned helplessness after inescapable stress.

Learned helplessness is a behavioral deficit that can be induced by exposure to inescapable stress. Previous studies have implicated the lateral septum in mediating this phenomenon, and in this brain region, serotonin plays an important role in the development, maintenance, prevention, and reversal of learned helplessness behavior. Using the technique of in vivo microdialysis, we measured the efflux of serotonin (5-HT), dopamine (DA), and their respective metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and 3, 4-dihydroxyphenylacetic acid (DOPAC), from the lateral septum of rats that either developed or did not develop learned helplessness. During the microdialysis session all rats were subjected to restraint stress. Control groups included naïve, home cage rats as well as tested control rats that were subjected to the identical handling, restraint, and shuttlebox testing as the rats that received inescapable shock. Overall, levels of 5-HIAA were significantly higher in non-helpless rats. There were no significant effects of restraint or differences in levels of 5-HT, DA, or DOPAC. We propose that this increase in 5-HIAA is indicative of an overall increase in serotonin metabolism in the lateral septum of rats that do not become helpless after inescapable stress. This increased serotonin metabolism in the lateral septum may protect the animal from adverse behavioral consequences of inescapable stress. J. Neurosci. Res. 61:101-106, 2000. Published 2000 Wiley-Liss, Inc.

Acute stress does not alter 5-HT1A receptor density.

Previous research suggests that 5-HT1A receptors are altered with exposure to chronic stress. No previous studies have examined the effect of acute stress on 5-HT1A. Using receptor autoradiography it was observed that there were no differences in [3H]-8-OH-DPAT binding between control rats and rats that received 20 minutes of restraint stress 2 hours prior to sacrifice. This study suggests that the changes in 5-HT1A receptor density associated with chronic stress develop over the course of repeated stress.

Serotonin and learned helplessness: a regional study of 5-HT1A, 5-HT2A receptors and the serotonin transport site in rat brain.

Serotonin (5-HT) plays a central role in the neurochemistry of the learned helplessness animal model of depression. Using quantitative autoradiography, we measured the density of 5-HT1A and 5-HT2A receptors and of 5-HT transport sites in medial prefrontal cortex, dorsal hippocampus, septum, hypothalamus, and amygdala in learned helpless rats, and in rats that were nonhelpless after inescapable stress, as well as in shuttlebox-tested and nonhandled controls. We found no changes in 5-HT1A receptor density among the groups in any region studied. In dorsal hippocampus, 5-HT2A receptor density was decreased in nonhelpless rats, while in amygdala 5-HT2A receptor density was decreased in both groups of stressed rats, whether helpless or nonhelpless. In the hypothalamus 5-HT2A receptor density, was decreased in helpless rats as compared to controls. In medial prefrontal cortex, the serotonin transport sites showed decreased density in helpless rats as compared to controls but not to nonhelpless rats. These findings further highlight the complexity of regional 5-HT effects in the learned helplessness animal model.

Decrease in stress-induced c-Fos-like immunoreactivity in the lateral septal nucleus of learned helpless rats.

Inescapable stress can induce learned helplessness in many species of animals. Learned helplessness is a phenomenon which has some behavioral and neurotransmitter analogies with human clinical depression. Stress can also induce the expression of immediate early genes, including c-fos in many areas of the central nervous system. We examined stress-induced c-Fos-like immunoreactivity (FLI) using the learned helplessness paradigm. Naive rats showed significantly higher FLI than the tested groups in all the amygdaloid regions and in the hypothalamic paraventricular nucleus. However, in the lateral septal nucleus, helpless animals showed significantly reduced FLI in response to stress, compared to the other groups. These, and other previous data, highlight the importance of the septal area in mediating behavioral responses to inescapable stress.