title: Effects of pregnanolone and flunitrazepam on the retention of response sequences in rats.
abstract: Neuroactive steroids produce effects similar to other GABA(A) modulators (e.g., benzodiazepines and barbiturates) and have a large therapeutic potential; however, a greater understanding of the effects of these substances on learning and memory is needed. To specifically assess the effects of a neurosteroid on memory, pregnanolone (1-18 mg/kg) was administered to male Long-Evans rats responding under a repeated acquisition and delayed-performance procedure in which different 4-response sequences were acquired and then retested after varying delays. Responding was maintained under a second-order fixed-ratio (FR) 2 schedule of food reinforcement, and incorrect responses (errors) produced a 5-sec timeout. For comparison purposes, both a high (flunitrazepam) and low efficacy agonist/antagonist (flumazenil) of the GABA(A) receptor complex were also administered both alone and in combination. Retention of each sequence was quantified as percent savings in errors-to-criterion and this dependent measure was shown to be sensitive to increases in delay. When administered 15 min prior to the end of either a 30- or 180-minute delay, pregnanolone produced both dose- and delay-dependent decreases in percent savings, response rate and accuracy; this effect was selective in that decreases in retention occurred at doses lower than those that disrupted response rate or accuracy. Flunitrazepam (0.056-1mg/kg) produced similar disruptions in retention and these disruptions were antagonized by 5.6 mg/kg of flumazenil. Both an ineffective (0.056 mg/kg) and an effective (0.18 mg/kg) dose of flunitrazepam also potentiated the dose- and delay-dependent disruptions in retention produced by pregnanolone. These data indicate that the neurosteroid pregnanolone disrupts retention in a manner similar to the benzodiazepine flunitrazepam, and suggests that the interaction of flunitrazepam and pregnanolone on retention may be mediated by the GABA(A) receptor complex.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, 1901 Perdido St., New Orleans, LA 70112, USA. ramato@lsuhsc.edu
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Amato
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Moerschbaecher
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Winsauer
mesh_terms: D000818:Animals; D004338:Drug Combinations; D005445:Flunitrazepam / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D011280:Pregnanolone / Q000008:administration & dosage* / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D011930:Reaction Time / Q000187:drug effects* / Q000502:physiology; D012153:Retention, Psychology / Q000187:drug effects* / Q000502:physiology
chemical_list: D004338:Drug Combinations; D005445:Flunitrazepam; D011280:Pregnanolone