Effects of D-Cycloserine, an Nmda Receptor Agonist, on Conditioned Taste Aversion Learning

Conditioned taste aversion (CTA) learning occurs as a result of the pairing of a novel taste with a malaise-inducing substance. This is a robust associative learning paradigm that has been shown to be N-methyl-D-Aspartic acid (NMDA) receptor-mediated, as NMDA receptor antagonists attenuate CTA learning. This work presents four experiments that examine the role of an NMDA receptor agonist, d-Cycloserine (DCS), in CTA learning. The first experiment showed that DCS enhanced CTA learning but only under certain constraints. Namely, DCS enhanced CTA when there was a short delay between the taste and toxin pairing (10 minutes), but not when there was a longer delay (45 minutes). We next tried to explain this phenomenon by probing three possibilities: (1) DCS fails to enhance CTA after a long delay because its activity is short-lived, (2) during the long delay, DCS enhances learned safety towards the taste that would counteract CTA acquisition or (3) enhancement of CTA by DCS depends upon the temporal proximity of taste and toxin. Our data showed that DCS was effective at enhancing short-delay CTA for at least one hour after administration; thus a short half-life is not sufficient to explain why DCS fails to enhance long-delay CTA. DCS did not enhance learned safety, even though learned safety is NMDA receptor-mediated; therefore it is unlikely that learned safety during the long delay masked enhancement of CTA learning. DCS enhanced CTA only when there was a short period of taste processing; longer temporal delays between initial taste processing and LiCl, even with an immediate taste-toxin pairing, did not support DCS enhancement. Thus the lack of an effect of DCS on long-delay CTA is not due to a short half-life of DCS nor a build-up of learned safety during the long-delay, nor the temporal distance between the taste and toxin stimuli. The duration of time since initiation of the taste stimuli appears critical, however. There are a few potential neural mechanisms that may explain this short- vs. long-delay phenomenon. The most relevant finding in recent literature suggests that NMDA receptors can become internalized after activation. It is possible that NMDA receptors become activated after the initial taste and may internalize during the delay between taste and toxin causing less enhancement of DCS on long-delay CTA.