Orotate improves memory and enhances synaptic long-term potentiation in active avoidance behaviour in rats with perforant path stimulation as the conditioned stimulus

Abstract

Male Wistar rats were trained in an active avoidance task with stimulation of the perforant path with impulse trains of 15 Hz as the conditioning stimulus. Immediately after the first training session, methylglucamine orotate (225 μg), a memory improving drug, was injected intraventricularly. The retention of the learned behaviour was determined on the following day in a relearning session. Field potentials evoked in the dentate area by test stimuli from the perforant path electrode were recorded at different times after learning and relearning sessions determine whether there were functional changes in the perforant path-granular cell synapses, which are involved in the conditioning pathway. Untreated control animals exhibited a so-called ‘postconditioning potentiation’, expressed as a long-lasting increase of both the excitatory postsynaptic potential (EPSP) and the population spike of the granular cells of the evoked test potentials. This finding reproduces previously published results. Methylglucamine orotate-treated rats showed significantly more conditioned reactions in the relearning sessions compared with untreated controls and a significantly more pronounced potentiation of the population spike, whereas the postconditioning potentiation of the field EPSP remained unaffected by the treatment. When both the control animals and the metylglucamine orotate-treated rats were divided into subgroups of good and poor learners according to their learning scores from the first training session, differences between the effect of the drug became evident. In good learners, the treatment with methylglucamine orotate after the learning session slightly, but significantly, improved retention compared with that of untreated good learners. The corresponding postconditioning potentiation of the population spike exhibited a slight, but significant, increase and that of the field EPSP remained unchanged. In poor learners, retention was considerably enhanced by the treatment, the response nearly reaching that of untreated good learners. This significant improvement of memory was accompanied by a significant potentiation of the population spike of the test potentials. The population spike was not potentiated in untreated poor learners after learning. However, the field EPSP, which was not potentiated in untreated poor learners, was not influenced by the orotate treatment. The results confirm the memory-improving effect of orotate, demonstrating at the same time that the action was much more pronounced in individuals with weak retention. The correlation between memory improvement and enhanced potentiation of the population spike without changes of the field EPSP after orotate treatment suggests a postsynaptic site of drug action during consolidation of the long-term memory trace, probably strengthening or accelerating underlying macromolecular changes.