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Abstract: A number of studies have reported that d-cycloserine (DCS), a partial agonist of the N-methyl-d-aspartate glutamate receptor, can facilitate the loss of conditioned fear if it is administered during an extinction trial. Here we examine the effects of DCS injected into the hippocampus or amygdala on extinction of context-evoked freezing after contextual fear conditioning in C57BL/6 mice. We find that DCS administered prior to an extinction session decreased freezing from the outset of the session regardless of which brain region was targeted. Retention tests revealed opposite effects on fear expression despite identical behavioral treatments: intra-hippocampal DCS inhibited fear expression while intra-amygdala DCS potentiated fear expression. Following post-extinction session injections of DCS, we found a similar though less pronounced effect. Closer inspection of the data revealed that the effects of DCS interacted with the behavior of the subjects during extinction. Intra-hippocampal injections of DCS enhanced extinction in those mice that showed the greatest amount of within-session extinction, but had less pronounced effects on mice that showed the least within-session extinction. Intra-amygdala injections of DCS impaired extinction in those mice that showed the least within-session extinction, but there was some evidence that the effect in the amygdala did not depend on behavior during extinction. These findings demonstrate that even with identical extinction trial durations, the effects of DCS administered into the hippocampus and amygdala can heavily depend on the organism’s behavior during the extinction session. The broader implication of these findings is that the effects of pharmacological treatments designed to enhance extinction by targeting hippocampal or amygdalar processes may depend on the responsivity of the subject to the behavioral treatment. [Copyright &y& Elsevier]

Abstract: In this study, we investigated how midazolam and d-cycloserine regulate the tonic activity and/or phasic reactivity of brain neurotransmitter systems to fear-evoking stimuli in rats with varying intensities of a fear response. We used a new animal model composed of high (HR) and low (LR) anxiety rats, selected according to their behaviour in the contextual fear test (i.e., the duration of a freezing response was used as a discriminating variable). In these rats, we examined the effects of both drugs on the release of glutamate and GABA in the basolateral amygdala (BLA) during the first extinction trial of a conditioned fear test. The results showed that administration of d-cycloserine (15mg/kg, i.p.) significantly enhanced the inhibition of an aversive context-induced freezing response observed during the extinction session in HR and LR rats. In contrast, midazolam (0.75mg/kg, i.p.) accelerated the attenuation of fear responses only in HR rats. The less anxious behaviour of LR animals given saline was accompanied by elevated basal levels of glutamate in the BLA, in comparison with HR rats, and a stronger elevation of GABA in response to contextual fear. In HR animals, the pretreatment of rats with d-cycloserine and midazolam significantly increased the local concentration of GABA and inhibited the expression of contextual fear. These findings suggest that animals more vulnerable to stress have innate deficits in brain systems that control the activity of the BLA mediating the central effect of stress. These results contribute to our understanding of observed individual differences in the effects of anxiolytic drugs among patients with anxiety disorders. [Copyright &y& Elsevier]