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

Abstract

With increasing interest in using neuroactive steroids therapeutically, greater understanding of the effects of these substances on learning and memory is needed. Neuroactive steroids have effects at both the NMDA and GABAA receptor complexes, and therefore, may have the capacity to alter memory processes. To specifically assess the effects of a neurosteroid on memory, male Long‐Evans rats responding under a retention procedure were administered pregnanolone (1 ‐ 18 mg/kg). During the procedure, a tandem response sequence was acquired and then retested after delays of 30 (n=12) or 180 (n=12) minutes. Responding during both sequence acquisition and retest was maintained under a second‐order fixed‐ratio (FR) 2 schedule of food reinforcement and incorrect responding (errors) produced a 5‐sec timeout. Retention of the sequence was quantified as percent savings in errors to criterion and the 180‐min delay interval alone produced a time‐dependent decrease in retention. Pregnanolone produced a dose‐dependent decrease in the response rate, accuracy, and percent savings. However, decreases in retention occured at doses lower than those that disrupted response rate and accuracy. These data indicate that the neurosteroid pregnanolone potently disrupts retention and that this effect may be an important consideration in the evaluation of neuroactive steroids as therapeutics. Supported by DA 019625

Neurosteroid Actions in Memory and Neurologic/Neuropsychiatric Disorders

“…Whether or not the cognitive enhancing effects are due to PregS or PREG remains to be determined. However, the cognitive enhancing effects of PregS in healthy subjects are unlikely to be due to the PREG metabolite ALLO since acute administration of this and other GABAergic modulating neurosteroids to healthy subjects inhibits learning and memory function in a manner similar to benzodiazepines (187–191). On the contrary, ALLO may play a role in the effects of PREG seen in patients with schizophrenia and other neuropsychiatric and neurologic disorders in which neural network activity is dysregulated (51).…”