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

Nature volume 388, pages 471–474 (1997)Cite this article

Abstract

Antagonists of NMDA (N-methyl-D-aspartate)-type glutamate receptors disrupt several forms of learning1,2,3,4,5,6,7,8. 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 neurons15,16. In second-order fear conditioning17,18, the reinforcer is a fear-eliciting conditioned stimulus rather than an unconditioned stimulus. Expression of conditioned fear is amygdala-dependent19,20 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.

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Figure 1: Fear-potentiated startle to the second-order CS in ACSF (top) and AP5 (bottom) groups tested before second-order conditioning training, and after two (post-training 1), and three (post-training 2) sessions of second-order conditioning training.
Figure 2: Figure 2 a, Fear-potentiated startle to the first-order auditory CS when rats were tested with no drug infused at the time of test (post-tra.ining 2), and when AP5 or ACSF vehicle were infused into the amygdala immediately before the test (post-training 3).

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Acknowledgements

We thank Bill Falls, whose pilot studies suggested a role for NMDA receptors in acquisition of second-order conditioning and stimulated this investigation. This research was supported by grants from AFPSR and NIMH (to M.D.) and by an NIH individual NRSA from NIMH (to J.C.G.)

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

    Jonathan C. Gewirtz & Michael Davis

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Correspondence to Jonathan C. Gewirtz.

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Gewirtz, J., Davis, M. Second-order fear conditioning prevented by blocking NMDA receptors in amygdala. Nature 388, 471–474 (1997). https://doi.org/10.1038/41325

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