Molecular Events Underlying the Enhancement of Conditioned Taste Aversion by D-Cycloserine

Conditioned taste aversion (CTA) is a form of associative learning in which an animal avoids and reacts aversively to a taste (conditioned stimulus, CS) that has been previously paired with a toxin or other malaise-inducing stimulus (unconditioned stimulus, US). CTA is unique among Pavlovian learning paradigms because conditioning is supported across long delays (minutes to hours) between taste and toxin [Garcia et al., 1966; Kalat & Rozin, 1973; Smith & Roll, 1967] and is robust in that an animal can form a strong aversion that can last for months [Houpt et al., 1996; Martin & Timmins, 1980; Steinert et al., 1980] after only a single trial of a taste-toxin pairing [Garcia & Koelling, 1967]. CTA learning is easily manipulated, as the strength or magnitude of the aversion is dependent on the concentration, saliency, and duration of the CS, as well as the amount or strength of the US [Barker, 1976; Dragoin, 1971; Nachman & Ashe, 1973]. The anatomical pathway involved in CTA is well characterized and includes the nucleus of the solitary tract, parabrachial nucleus, amygdala, and gustatory cortex [for a review, see Yamamoto, 2006]. The two forebrain regions, the amygdala and gustatory cortex, are particularly important as lesions of these areas cause deficits in CTA learning [Josselyn et al., 2004; Nerad et al., 1996], and both structures exhibit cellular changes during and after CTA acquisition, such as induction of long-term potentiation [Escobar & Bermudez-Ratoni, 2000], activation of immediate early genes such as c-fos [Lamprecht and Dudai, 1995], phosphorylation of markers such as MAPK [Berman et al., 1998], phosphorylation of NMDAR subunits such as NR2B [Rosenblum et al., 1997], and changes in the activation and expression of genes such as CREB, fra-2, and fen-1 [Desmedt et al., 2003; Kwon et al., 2008; Saavedra-Rodríguez et al., 2009]. As with other forms of associative learning, CTA is N-methyl-D-aspartate receptor (NMDAR)-dependent [Jimenez & Tapia, 2004]. Pharmacological inactivation of NMDARs attenuates or blocks CTA [e.g. Gutierrez et al., 1999] while activation by NMDAR agonists enhances CTA learning [Land & Riccio, 1997]. Data from our lab show that the NMDAR agonist, D-cycloserine (DCS), dose-dependently enhances taste learning, but only under certain parameters [Nunnink et al., 2007].