Effects of pregnanolone and flunitrazepam on the retention of response sequences in rats

Pharmacol Biochem Behav. 2011 Sep;99(3):391-8. doi: 10.1016/j.pbb.2011.05.023. Epub 2011 May 27.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Drug Combinations
  • Flunitrazepam / administration & dosage*
  • Flunitrazepam / pharmacology
  • Male
  • Pregnanolone / administration & dosage*
  • Pregnanolone / pharmacology
  • Psychomotor Performance / drug effects*
  • Psychomotor Performance / physiology
  • Rats
  • Rats, Long-Evans
  • Reaction Time / drug effects*
  • Reaction Time / physiology
  • Retention, Psychology / drug effects*
  • Retention, Psychology / physiology


  • Drug Combinations
  • Flunitrazepam
  • Pregnanolone