Characterization of the behavioral effects of the neuroactive steroid pregnanolone on schedule-controlled behavior in DBA/2J and C57BL/6J inbred mice.

摘要

Neurosteroids represent a class of endogenous compounds that exhibit rapid, nongenomic effects. The progesterone derived pregnane steroids, allopregnanolone and pregnanolone, are potent modulators of the GABAA receptor system. These compounds appear to be involved in regulating homeostasis during times of physiological stress by altering CNS tone. Also, the pregnane steroids appear to modulate many of the behavioral effects of ethanol and individual variability in endogenous levels of these steroids may influence one's response to ethanol. The present research employed the use of inbred mouse strains to examine the role of genetic factors in the behavioral effects of the neuroactive steroid pregnanolone to examine individual differences in response to this steroid.; Recent evidence suggests an interaction between neurosteroids and ethanol, specifically at the GABAA receptor. Experiments 1 and 2 aimed to characterize shared receptor mechanisms between ethanol and the neuroactive steroid pregnanolone through drug discrimination. Two inbred mouse strains, DBA/2J and C57BL/6J, were used to also examine the role of genetic factors on the discriminative stimulus effects of pregnanolone. Overall, the discriminative stimulus effects of pregnanolone were mediated through GABAA receptor positive modulation in both strains of mice. The main strain effect observed was an increased sensitivity to the shared receptor mechanisms between pregnanolone and a benzodiazepine and barbiturate in the DBA/2J strain.; Given that strain differences were not observed in response to pregnanolone in Experiments 1 and 2, Experiment 3 used an additional measure of behavior to assess genetic factors in the behavioral effects of pregnanolone. The rate-altering effects of pregnanolone and additional GABAA receptor positive modulators were tested in DBA/2J and C57BL/6J mice responding under a multiple schedule. Overall, there were differential effects of several neurosteroids and GABAA receptor positive modulators between the DBA/2J and C57BL/6J mice suggesting that there may be genetic factors influencing the behavioral effects of these compounds.; Together, the results of these experiments suggest GABAA receptor positive modulation as the main receptor mechanism mediating the discriminative stimulus effects of pregnanolone. Though there did not appear to be genetic factors influencing the behavioral effects of pregnanolone, genetic influences on the behavioral effects of other GABAA receptor positive modulators were suggested.