d-Cycloserine enhances conditioned taste aversion learning in rats

Conditioned taste aversion (CTA) is a form of associative learning in which the pairing of a taste with a toxin causes an animal to avoid the taste. NMDA receptor mediated neurotransmission has been implicated in CTA, but the role of the NMDA receptor glycine-binding site has not been examined. To examine the effects on CTA of the glycinergic NMDA receptor agonist d-cycloserine, rats received d-cycloserine (15 mg/kg, i.p.) or vehicle 15 min before 10-min access to 0.125% saccharin, followed by a low dose of LiCl (19 mg/kg, i.p.). CTA was measured with 24-h, 2-bottle preference tests between water and saccharin. Vehicle-treated rats formed a mild CTA that rapidly extinguished, while d-cycloserine-treated rats formed a stronger CTA that extinguished slowly. The effect of d-cycloserine was specific to the NMDA receptor glycine-binding site, because pretreatment with HA-966 (6 mg/kg), a partial glycinergic agonist, blocked enhancement by d-cycloserine. Three follow-up experiments suggest that the enhancement of CTA was not due to an aversive effect of d-cycloserine. First, saccharin paired with d-cycloserine (15 mg/kg) alone did not induce a CTA, although a higher dose (30 mg/kg) did significantly lower saccharin preference. Second, pretreatment with d-cycloserine did not increase the duration of “lying-on-belly” behavior induced by LiCl. Third, pretreatment with d-cycloserine did not increase c-Fos induction by either LiCl or vehicle injection in central visceral relays (the nucleus of the solitary tract, the parabrachial nucleus, the central nucleus of the amygdala, the supraoptic nucleus, and the paraventricular nucleus). These results confirm the participation of NMDA receptor, and specifically the glycine-binding site of NMDA receptor, in CTA learning.