Neurosteroids are concentrated within and are known to produce effects that modulate central nervous system function. Among the effects associated with the administration of the excitatory neurosteroid dehydroepiandrosterone sulfate (DHEAS), is the enhancement of memory. The mechanism for this enhancement is not well understood, however, DHEAS can increase the release of acetylcholine (ACh) in the hippocampus of rats and also facilitate neurotransmission mediated by NMDA receptors. Moreover, some cognitive effects of DHEAS are potentiated by the co-administration of steroid sulfatase inhibitors (SSI). The SSI (P-o-Sulfamoyl)-N-tetradeconoyl tyramine (DU-14) can enhance hippocamal ACh as well as block scopolamine induced amnesia. Cholinergic neurons emanating from basal forebrain structures play an important role in memory function. However, it is possible that DHEAS may facilitate cognitive function by other mechanisms as well. The questions to be determined by this investigation are whether acute and/or chronic peripheral administration of DHEAS or the steroid sulfatase inhibitor can facilitate hippocampal neurotransmission and cognitive function following cholinergic lesioning of the medial septum with either a nonselective or selective cholinergic neurotoxin. In particular, this study will seek to determine the effects of DHEAS and/or DU-14 administration on the performance of rats following either ibotenate or 192IgG-saporin immunotoxin induced basal forebrain cholinergic lesions in passive avoidance and the delayed matching to position T-maze cognitive tests. Hippocampal levels of the neurotransmitters, ACh, glutamate and GABA as well as acetylcholinesterase activity in the basal forebrain will be determined.
