Classical fear conditioning occurs when an affectively neutral stimulus is paired with a noxious aversive stimulus (unconditioned stimulus [US]) such as footshock. Afterward, the previously neutral stimulus (i.e., now the conditioned stimulus [CS]) is able to elicit a variety of autonomic, hormonal, and skeletal responses that accompany the conscious experience of fear in humans and which are used to operationally define fear in laboratory animals. The fear-eliciting properties of the CS can be extinguished by repeatedly presenting the CS in the absence of the US. It is generally believed that extinction does not reflect unlearning of the original association but involves instead the formation of new associations that compete with the previously conditioned response (see Bouton and Bolles (1985) Context, Event Memories, and Extinction (Lawrence Erlbaum Associates, Hillsdale, N.J.); Falls and Davis (1995) “Behavioral and Physiological Analysis of Fear Inhibition,” in Neurobiological and Clinical Consequences of Stress: From Normal Adaptation to PTSD, eds. Friedman et al. (Lippincott-Raven Publishers, Philadelphia, Pa.); Davis et al. (2000) “Neural Systems Involved in Fear Inhibition: Extinction and Conditioned Inhibition,” in Contemporary Issues in Modeling Psychopathology, eds. Myslobodsky and Weiner (Kluwer Academic Publishers, Boston, Mass.); Rescorla (2001) “Experimental Extinction,” in Handbook of Contemporary Learning Theories, eds. Mowrer and Klein (Erlbaurm, Mahwah, N.J.)).
As with fear conditioning itself, fear extinction can be blocked by N-methyl-D-aspartate (NMDA) receptor antagonists administered either systemically (Cox and Westbrook (1994) Quarterly J. Exp. Psych. 47B:187-210; Baker and Azorlosa (1996) Behav. Neuroscience 110:618-620) or infused directly into the amygdala (Falls et al. (1992) J. Neuroscience 12:854-863; 1992; Lee and Kim (1998) J. Neuroscience 18:8444-8454). The involvement of the amygdala is of particular interest given the well known involvement of this structure in excitatory fear conditioning (Kapp et al. (1990) “A Neuroanatomical Systems Analysis of Conditioned Bradycardia in the Rabbit,” in Neurocomputation and Learning: Foundations of Adaptive Networks, eds. Gabriel and Moore (Bradford Books, New York); Fanselow and LeDoux (1999) Neuron 23:229-232; Davis (2000) “The Role of the Amygdala in Conditioned and Unconditioned Fear and Anxiety,” in The Amygdala, Volume 2, ed. Aggleton (Oxford University Press, Oxford, United Kingdom)).
Because NMDA receptor antagonists block extinction, it is possible that NMDA receptor agonists would facilitate extinction. However, the well-documented neurotoxic effects of NMDA receptor agonists argue against their use in humans. For example, increasing attention has focused on partial agonists that might facilitate NMDA receptor activity in a more limited fashion (Lawlor and Davis (1992) Biological Psychiatry 31:337-350; Olney (1994) J. Neural Transmission Suppl. 43:47-51). In fact, partial agonists such as D-Cycloserine (DCS), a compound that acts at the strychnine-insensitive glycine recognition site of the NMDA receptor complex, have been shown to enhance learning and memory in several animal paradigms including visual recognition tasks in primates (Matsuoka and Aigner (1996) J. Pharmacol. Exp. Ther. 278:891-897), eyeblink conditioning in rabbits (Thompson et al. (1992) Nature 359:638-641), avoidance learning in rats and mice (Monahan et al. (1989) Pharmacol., Biochem. Behav. 34:649-653; Flood et al. (1992) Eur. J. Pharmacol. 221:249-254; Land and Riccio (1999) Neurobiol. Learn. Mem. 72:158-168), and maze learning in rats and mice (Monahan et al. (1989) Pharmacol., Biochem. Behav. 34:649-653; Quartermain et al. (1994) Eur. J. Pharmacol. 257:7-12; Pitkanen et al. (1995) Eur. Neuropsychopharmacol. 5:457-463; Pussinen et al. (1997) Neurobiol. Learn. Mem. 67:69-74), without producing obvious neurotoxicity. DCS has also been found, in some studies, to modestly improve cognition in clinical populations (Javitt et al. (1994) Am. J. Psychiatry 151:1234-1236; Schwartz et al. (1996) Neurology 46:420-424; Goff et al. (1999) Arch. General Psychiatry 56:21-27; Tsai et al. (1999) Am. J. Psychiatry 156:467-469), and has been used for many years to treat tuberculosis, again without obvious neurotoxicity.
A reduced ability to extinguish intense fear memories is a significant clinical problem for a wide range of psychiatric disorders including specific phobias, panic disorder, and post-traumatic stress disorder (see Morgan et al. (1995) Biol. Psychiatry 38:378-385; Fyer (1998) Biol. Psychiatry 44:1295-1304; Gorman et al. (2000) Am. J. Psychiatry 157:493-505). Because treatment for these disorders often relies upon the progressive extinction of fear memories (Zarate and Agras (1994) Psychiatry 57:133-141; Dadds et al. (1997) Psychological Bull. 122:89-103; Foa (2000) J. Clin. Psychiatry 61:43-48), pharmacological enhancement of extinction could be of considerable clinical benefit in these conditions.