Journal
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
Volume 99, Issue 3, Pages 391-398Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pbb.2011.05.023
Keywords
Memory; Pregnanolone; Flunitrazepam; Flumazenil; GABAA receptor; Rats
Funding
- National Institute on Alcohol and Alcoholism [USPHS AA09803]
- National Institute on Drug Abuse [DA019625]
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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 GABAA 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 (0.056-1 mg/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 GABAA receptor complex. (C) 2011 Elsevier Inc. All rights reserved.
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