Latent inhibition of cued fear conditioning: an NMDA receptor‐dependent process that can be established in the presence of anisomycin

Abstract

Much of the research examining the biological basis for long-term memories has focused on mechanisms that support the formation of conditioned associations. Less information is available on biological mechanisms which underlie processes that modify the strength of conditioned associations. Latent inhibition is a phenomenon by which pre-exposure to a to-be-conditioned stimulus (CS) weakens subsequent conditioning of that CS to an unconditioned stimulus (US). Here we report that latent inhibition of cued fear conditioning is dependent on NMDA receptor activation. MK-801 (1 mg/kg), an NMDA receptor antagonist, abolished latent inhibition of cued fear conditioning. This dose of MK-801 administered before training did not disrupt cued fear conditioning. Conversely, anisomycin (150 mg/kg), a protein synthesis inhibitor, had no effect on latent inhibition of cued fear conditioning when administered 20 min before, immediately after, or 2, 4, 6, or 8 h after CS pre-exposure. Furthermore, continuous anisomycin administration (50 mg/kg, administered every 2 h for 6 h starting 20 min prior to pre-exposure) did not disrupt latent inhibition of cued fear conditioning. In addition, anisomycin had no effect on a long-lasting version of latent inhibition of cued fear conditioning that was maintained over a 7-day interval. Anisomycin administered before training, however, disrupted learning of the CS-US association. These findings suggest that latent inhibition of cued fear conditioning is a long-lasting NMDA receptor-dependent process that can develop during the inhibition of protein synthesis.

Interactive effects of ethanol and nicotine on learning in C57BL/6J mice depend on both dose and duration of treatment

“…In support, ethanol enhances NMDA-receptor-mediated activity at low doses and inhibits it at high doses (Lima-Landman and Albuquerque 1989); the ability of ethanol to dose-dependently potentiate or depress NMDA-receptor-mediated activity suggests that the action of ethanol on these receptors may underlie both the enhancing and impairing effects of ethanol on learning. Furthermore, research suggests that the cognitive enhancing effects of nicotine may involve interactions with NMDA receptors (Lewis and Gould 2005). Thus, if higher doses of ethanol disrupt learning by inhibiting NMDA receptor function, nicotine could reverse this by facilitating NMDA receptor function.…”

9YExtinction: Does It or Doesn’t It? The Requirement of Altered Gene Activity and New Protein Synthesis

“…Adding to the complexity of this analysis are behavioral studies showing that extinction can occur normally when protein synthesis is inhibited (Lattal and Abel 2001;, as can latent inhibition (Lewis and Gould, 2004). Latent inhibition is similar to extinction in that both involve stimulus exposure in the absence of reinforcement and both may share a dependence on L-type voltage-gated calcium channels (Barad et al 2004) and NMDA receptors (Lewis and Gould 2004).…”

Coantagonism of glutamate receptors and nicotinic acetylcholinergic receptors disrupts fear conditioning and latent inhibition of fear conditioning

“…These findings suggest that nAChRs may mediate processes that support contextual fear conditioning and latent inhibition of cued fear conditioning that are similar or parallel to processes mediated by AMPARs and NMDARs. It is clear that NMDARs are involved in both contextual fear conditioning and latent inhibition of cued fear conditioning (Kim et al 1991;Stiedl et al 2000;Gould et al 2002;Lewis and Gould 2004). One possible mechanism through which AMPARs and nAChRs could contribute to acquisition of these tasks is by contributing to the membrane depolarization necessary for activating NMDAR-mediated processes.…”

“…The mice were placed on water restriction, as lick suppression was the dependent variable. The procedure consisted of five phases conducted over an 8-d period and is based on previous research examining latent inhibition of cued fear conditioning (Gould and Wehner 1999b;Gould et al 2001;Lewis and Gould 2004).…”

“…Contextual fear conditioning and latent inhibition of cued fear conditioning have been shown to be dependent on NMDAR activation Gould et al 2002;Lewis and Gould 2004;Davis and Gould 2005). The NMDAR is unique from other receptors in the central nervous system, in that it is both ligand and voltage gated (Nowak et al 1984).…”