1. Departments of Psychology & Psychiatry, Yale University, Ribicoff Research Facilities of the Connecticut Mental Health Center, 34 Park Street, New Haven, Connecticut 06508, USA

Correspondence to: Jonathan C. Gewirtz¹ Correspondence and requests for materials should be addressed to J.C.G. (e-mail: Email: jonathan.gewirtz@yale.edu).

Abstract

Antagonists of NMDA (N-methyl-D-aspartate)-type glutamate receptors disrupt several forms of learning^{1, 2, 3, 4, 5, 6, 7, 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 learning¹,^{9, 10, 11, 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 amygdala⁶,^{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.