Neurosteroids affect spatial/reference, working, and long-term memory of female rats.

Female rats take longer to acquire a spatial task during behavioral estrus, when GABA-active progesterone and metabolites are elevated. Whether neurosteroids and neuroactive steroids (neuro(active) steroids), which can act at GABA receptor complexes (GBRs), have activational effects on spatial/reference, working, and long-term memory was investigated. In Experiment 1, ovariectomized Long-Evans rats (N = 107) received oil vehicle or one of six neuro(active) steroids, with varying GBR efficacy (greatest to least efficacious: 5 alpha-pregnan-3 alpha-ol-20-one (THP), 5 alpha-pregnan-3 alpha-ol-11,20-dione, 4-pregnen-3,20-dione 17 alpha-hydroxyprogesterone, 5-pregnen-3 beta-ol-20-one sulfate, and 5-androstan-3 beta-ol-17-one sulfate (DHEAS). Following neuro(active) steroid (3.2 or 6.4 mg/kg) or vehicle sc, rats were tested in a Morris water maze, the following week in a Y maze, and then in an open field. Neuro(active) steroid, but not vehicle, animals had decreased distances to the hidden water maze platform. THP (3.2 and 6.4 mg/kg) animals were faster to find this platform than vehicle animals. In the Y maze, 3.2 mg/kg THP increased percentage correct, but 6.4 mg/kg THP increased latencies to the goal box. DHEAS had the opposite effect, with 3.2 mg/kg increasing latencies to the goal box, while 6.4 mg/kg increased percentage correct. In Experiment 2, N = 75 ovariectomized rats were icv implanted with one of the neuro(active)steroids or cholesterol vehicle and then tested for spatial/reference memory, working and long-term memory, and motoricity/anxiolysis as in Experiment 1. DHEAS implants decreased, while THP increased, latencies and distances to the hidden platform in the Morris water maze. In the Y maze, THP increased latencies and decreased percentage correct, but DHEAS increased the likelihood of correct choice. Open field behavior of animals administered the various neuro(active) steroids (sc or icv) was not different. Thus, of the neuro(active) steroids examined, the neurosteroids THP and DHEAS had the most pronounced activational affects on spatial/reference, working, and long-term memory, independent of motoricity.