A NEUROPHARMACOLOGICAL ANALYSIS OF LEARNED HELPLESSNESS IN RAT (GENETICS).

Abstract

The purpose of this research project was to look for a neuropharmacological correlate to the behavioral deficits seen in learned helplessness (LH). The fact that antidepressant drugs reverse the deficits seen in a helpless rat, strongly suggests that the deficit is due to some neurochemical imbalance. This imbalance could be due to either the uncontrollable stressor or genetically induced. The three experiments suggest that there are fundamental differences in the way the CNS of helpless-prone rats and helpless-resistant rats cope with unpredictable and inescapable footshock. The goal of Experiment I was to search for a correlation between LH and receptor changes in the frontal cortex. The results did not support the hypothesis. The use of a heterogeneous stock of rat may have masked any basic differences between helpless-prone and helpless-resistant rats with regard to the 5-HT₂ and β-adrenergic receptors in the frontal cortex. Based on previous studies and the results from Experiment I, one could argue that there exists a genetic component in LH. The results from Experiment II suggest a strong genetic component to LH, not unlike that found in certain forms of human depressive disorders. Accordingly, rats from eight different stocks were tested for susceptibility to LH training. Of the eight stocks tested, Kyoto and Charles River Holtzman rats were the most susceptible at 53% and 55%, respectively. Overall, the variability ranged from 0% to 50%. These results indicate that wide differences in susceptibility to LH training exist in rats from different stocks or suppliers. The results of Experiment II suggested that the Kyoto Wistar rat would be a reliable inbred strain in which to study LH. With regards to the original goal of this research, it was decided that an evaluation of different neuro-transmitter systems during the LH paradigm would yield a potential for success in finding a biochemical marker that would differentiate LH-prone from LH-resistant rats. The results of Experiment III suggest, at least in hippocampus, that the serotonin (5-HT) and norepinephrine (NE) systems are differentially affected in the LH-prone and LH-resistant rat. In particular 5-HT levels are not affected by stress alone, but are increased in LH-prone rats following a frustrating test session. Also, the NE metabolite MHPG, is not affected by stress, but does increase in the LH-prone rat following testing. Both of these results differentiate the LH-prone and LH-resistant rat. In conclusion, the three experiments suggest that there is a genetic component in LH and that the NE and 5-HT systems are differentially affected by uncontrollable and inescapable shock in LH-prone and LH-resistant rats.