Neuroactive steroids and the constraint of memory.
Different normo- and pathophysiological conditions are associated with large variations in plasma and brain concentrations of neuroactive steroids. In an attempt to specify the possible role of these steroids in memory processes, we examined the ability of pregnanolone, a positive modulator of the gamma-aminobutyric acid type A (GABAA) receptor complex, to sustain state dependence in rats. Animals treated with either saline or different doses of pregnanolone were trained to complete a fixed ratio 10 (FR10) schedule of lever presses for milk reward within 120 s, and were tested for the retention of this response 48 h later while treated with the same or a different treatment. The data indicate that saline-to-drug as well as drug-to-saline state changes produced robust failures to recall the response. Furthermore, animals trained with pregnanolone showed transfer of the response when tested with the benzodiazepine chlordiazepoxide and vice versa. The partial benzodiazepine 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 endogenously; the release of neuroactive steroids in response to various physiological conditions may act to contain but also to constrain memories associated with these events, rendering these memories inaccessible on other occasions. The apparent memory impairment that can so be produced may render the effects of past experience available in a manner that is appropriately selective.
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D000818:Animals; D002243:Carbolines / Q000494:pharmacology; D002707:Chlordiazepoxide / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D011280:Pregnanolone / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time; D011963:Receptors, GABA-A / Q000502:physiology*; D012201:Reward
D002243:Carbolines; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; C035874:FG 7142; D002707:Chlordiazepoxide; D011280:Pregnanolone