Modulation of ethanol state-dependent learning by dorsal hippocampal NMDA receptors in mice

Abstract 

The possible role of N-methyl-d-aspartate (NMDA) receptors of dorsal hippocampus on ethanol state-dependent learning was studied in adult male mice (Pasteur Institute, Iran). As a model of memory, a single-trial step-down passive avoidance task was used. All animals were bilaterally implanted with cannulae into the CA1 regions of dorsal hippocampi. Results show that intraperitoneal (i.p.) administration of ethanol (0.5 and 1g/kg) 30min before training impaired memory performance in animals when tested 24h later. Pretest administration of the same doses of ethanol-induced state-dependent retrieval of the memory acquired under pretraining ethanol (1g/kg, i.p.) influence. Pretest intra-CA1 microinjection of NMDA (0.001, 0.01, and 0.1μg/mouse) by itself had no effect on memory retrieval and ethanol-induced amnesia. However, pretest intra-CA1 administration of the same doses of NMDA with an ineffective dose of ethanol (0.25g/kg, i.p.) significantly restored the retrieval and potentiated ethanol state-dependent learning. On the other hand, pretest administration of a competitive NMDA receptor antagonist d-AP5 (d-(−)-2-Amino-5-phosphonopentanoic acid) (0.01, 0.1, and 1μg/mouse, intra-CA1) or a noncompetitive NMDA receptor antagonist MK-801 maleate [(5S, 10R)-(+)-5-Methyl-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5, 10-imine maleate] (0.25, 0.5, and 1g/mouse, intra-CA1) 5min before the administration of ethanol (1g/kg, i.p.) significantly inhibited ethanol state-dependent learning. Intra-CA1 pretest administration of d-AP5 (0.01, 0.1, and 1μg/mouse) or MK-801 maleate [5S, 10R)-(+)-5-Methyl-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5, 10-imine maleate] (0.25, 0.5, and 1μg/mouse) alone did not affect memory retention. It may be concluded that dorsal hippocampal NMDA receptors are involved in mediating ethanol state-dependent learning.

Keywords: Ethanol, NMDA, d-AP5, MK-801, State-dependent learning, Passive avoidance, Mouse