Neuroactive steroids and the constraint of memory

Different normo- and pathophysiological conditions are associated with larg e variations in plasma and brain concentrations of neuroactive steroids. In an attempt to specify the possible role of these steroids in memory proces ses, we examined the ability of pregnanolone, a positive modulator of the g amma-aminobutyric acid type A (GABAA) receptor complex, to sustain state de pendence in rats. Animals treated with either saline or different doses of pregnanolone were trained to complete a fixed ratio 10 (FR10) schedule of l ever presses for milk reward within 120 s, and were tested for the retentio n of this response 48 h later while treated with the same or a different tr eatment. The data indicate that saline-to-drug as well as drug-to-saline st ate changes produced robust failures to recall the response. Furthermore, a nimals trained with pregnanolone showed transfer of the response when teste d with the benzodiazepine chlordiazepoxide and vice versa. The partial benz odiazepine inverse agonist N-methyl-beta-carboline-3-carboxamide (FG-7142) antagonized the states produced by both pregnanolone and chlordiazepoxide. State changes constitute a mechanism of action that may operate endogenousl y; the release of neuroactive steroids in response to various physiological conditions may act to contain but also to constrain memories associated wi th these events, rendering these memories inaccessible on other occasions. The apparent memory impairment that can so be produced may render the effec ts of past experience available in a manner that is appropriately selective .