Hippocampus-dependent learning facilitated by a monoclonal antibody or D-cycloserine

Abstract

Persistent neuronal plasticity, including that observed at some hippocampal synapses, requires N-methyl-D-aspartate (NMDA)-mediated transmission. NMDA receptor activation may be necessary for hippocampus-dependent learning as antagonists block acquisition in many such tasks. The behavioural effects of NMDA agonists are less well defined. We have shown that a monoclonal antibody (B6B21) displaced [3H]-glycine that was bound specifically to the NMDA receptor, and enhanced the opening of its integral cation channel in a glycine-like fashion, effects that were competitively antagonized by 7-chlorokynurenic acid. B6B21 also enhanced long-term potentiation in hippocampal slices. We report here that intraventricular infusions of B6B21 significantly enhances acquisition rates in hippocampus-dependent trace eye blink conditioning in rabbits, halving the number of trials required to reach a criterion of 80% conditioned responses. Peripheral injections of D-cycloserine, a partial agonist of the glycine site on the NMDA receptor which crosses the blood-brain barrier, also doubles rabbits' learning rates. Pseudoconditioning control experiments indicated a lack of nonspecific behavioural sensitization effects. Our data suggest that enhanced activation of the glycine coagonist site on the NMDA receptor/channel complex facilitates one form of associative learning and may be used in other learning tasks.

Previous Stress Attenuates the Susceptibility to Midazolam's Disruptive Effect on Fear Memory Reconsolidation: Influence of Pre-Reactivation D-Cycloserine Administration

“…A growing body of data supports the view that DCS facilitates the formation of extinction memory (Ledgerwood et al, 2003;Walker et al, 2002;Yamamoto et al, 2008); moreover, DCS facilitates learning and memory using a variety of learning paradigms in diverse animal species (Land and Riccio, 1999;Matsuoka and Aigner, 1996;Monahan et al, 1989;Pitkänen et al, 1995;Pussinen et al, 1997;Quartermain et al, 1994;Thompson et al, 1992). Our findings showed that DCS administration did not affect freezing during reactivation under the present treatment protocol as comparable levels of fear were observed between DCS-and SAL-treated animals, regardless whether animals were subjected to a threatening event before learning.…”

Trace eyeblink conditioning in rabbits demonstrates heterogeneity of learning ability both between and within age groups

“…Defining these delay paradigms by their interstimulus intervals, they are referred to hereafter as Delay 600 and Delay 250, respectively. For trace conditioning, the 100 ms duration tone CS was followed (after a 500 ms stimulus-free trace interval) by the airpuff US, which we and others (7,23,26,44,49) have referred to by the duration of the trace interval as Trace 500. All training was carried out in sets of three concurrent pairs to control for cohort effects.…”

“…Rabbits of each age group named above (see Table 2) received Trace 500 eyeblink conditioning as described above (49). A 100 ms duration tone CS was followed (after a 500 ms stimulus-free trace interval) by an airpuff US.…”

“…Using linear interpolation algorithms (IgorPro™, WaveMetrics), each curve was normalized to the mean number of trials required to reach criterion for that group, so that qualitative summaries of learning rates for animals requiring different numbers of trials to reach criterion could be made. For additional statistical comparisons of learning rates between groups, the slopes of individual least squares fitted lines for each subject's nonnormalized learning curve (percent CRs per daily session plotted over sessions) were tested with analyses of variance as previously described (49). Data from rabbits that failed to reach the 80% CRs criterion were examined separately, were compared separately to data from those that reached criterion, and are discussed separately below.…”

d-Cycloserine enhances conditioned taste aversion learning in rats

“…D-cycloserine is a high affinity NMDA receptor glycine-binding site agonist that is rapidly transported into the central nervous system after systemic injection (Baran et al, 1995). Systemic administration of D-cycloserine has been shown to enhance learning in several animal models, including trace eye-blink conditioning (Thompson et al, 1992), spatial learning in the water-maze (Temple and Hamm, 1996), inhibitory avoidance (Land and Riccio, 1999), and extinction of fear conditioning as measured with freezing (Richardson et al, 2004) or with fear-potentiated startle (Walker et al, 2002). More recently, D-cycloserine has been shown to accelerate extinction of phobias in humans when administered prior to desensitization exposure sessions (Ressler et al, 2004).…”