Second-order fear conditioning prevented by blocking NMDA receptors in amygdala

Antagonists of NMDA (N-methyl-D-aspartate)-type glutamate receptors disrupt several forms of learning(1-8). Although this might indicate that NMDA-receptor-mediated processes are critical for synaptic plasticity, there may be other mechanisms by which NMDA-receptor antagonism could interfere with learning(1,9-12). For instance, fear conditioning would be blocked by microinfusion of the NMDA-receptor antagonist AP5 (D,L-2-amino-5-phosphonovalerate) into the basolateral amygdala(6,13,14) if AP5 inhibited routine synaptic transmission, thereby reducing the ability of stimuli to activate amygdala neurons(15,16). In second-order fear conditioning(17,18), the reinforcer is a fear-eliciting conditioned stimulus rather than an unconditioned stimulus. Expression of conditioned fear is amygdala-dependent(19,20) and so provides a behavioural assessment of the ability of the reinforcer to activate amygdala neurons in the presence of AP5. We report here that intra-amygdala AP5 actually enhances expression of conditioned fear to the conditioned stimulus that provides the reinforcement signal for second-order conditioning. Nevertheless, acquisition of second-order fear conditioning is completely blocked. Our findings strongly support the view that NMDA receptors are critically involved in synaptic plasticity.