Facilitation of Conditioned Fear Extinction by D-Cycloserine Is Mediated by Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinasecascades and Requires de Novo Protein Synthesis in Basolateral Nucleus of Amygdala

Neuroscience 134 (2005) 247–260

FACILITATION OF CONDITIONED FEAR EXTINCTION BY D-CYCLOSERINE IS MEDIATED BY MITOGEN-ACTIVATED PROTEIN KINASE AND PHOSPHATIDYLINOSITOL 3-KINASE CASCADES AND REQUIRES DE NOVO PROTEIN SYNTHESIS IN BASOLATERAL NUCLEUS OF AMYGDALA
Y. L. YANGa AND K. T. LUb*
Institute of Biotechnology, Department of Molecular Biology and Biochemistry, National Chia-Yi University, 300 University Road, Chia-Yi, Taiwan b Department of Life Science, National Taiwan Normal University, 88 Ming-Chow Road, Sec 4, Taipei, Taiwan a

Key words: extinction, D-cycloserine, MAPK, PI-3 kinase, amygdala.

Abstract—Recent results showed that either systemic or intra-amygdala administration of D-cycloserine, a partial agonist at the glycine modulatory site on the glutamate N-methylD-aspartate receptor facilitates the extinction of conditioned fear. Here we evaluated the role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase in the basolateral nucleus of amygdala on the effect of D-cycloserine. The facilitation effect of D-cycloserine on fear extinction and mitogen-activated protein kinase activation was completely blocked by intra-amygdala administration of mitogen-activated protein kinase inhibitor PD98059 (500 ng/side, bilaterally) or U0-126 (20 M/side, bilaterally). Furthermore, phosphatidylinositol 3-kinase inhibitor (wortmannin, 5.0 g/side, bilaterally) infused into the basolateral nucleus of amygdala significantly reduced both facilitation effect of D-cycloserine and phosphatidylinositol 3-kinase activation. Intra-amygdala administration of a transcription inhibitor (actinomycin D, 10 g dissolved in 1.6 l vehicle; 0.8 l per side) and a translation inhibitor (anisomycin, 125 g dissolved in 1.6 l vehicle; 0.8 l per side) completely blocked the facilitation effect of D-cycloserine. Control experiments indicated the blockage by actinomycin D or anisomycin were not due to lasting damage to the basolateral nucleus of amygdala or state

References: Baker J, Azorlosa J (1996) The NMDA antagonist MK-801 blocks the extinction of Pavlovian fear conditioning. Behav Neurosci 110:618–620. Campeau S, Davis M (1995) Involvement of the central nucleus and basolateral complex of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli. J Neurosci 15:2301–2311. Cassella J, Davis M (1986) The design and calibration of a startle measurement system. Physiol Behav 36:377–383. Collinridge G, Bliss T (1995) Memories of NMDA receptors and LTP. Trends Neurosci 18:54 –56. Cox J, Westbrook R (1994) The NMDA receptor antagonist MK-801 blocks acquisition and extinction of conditioned hypoalgesia responses in the rat. Q J Exp Psychol 47B:187–210. Davis M (1997) Neurobiology of fear responses: The role of the amygdala. J Neuropsychol Clin Neurosci 9:382– 402. Davis M (2000) The role of the amygdala in conditioned and unconditioned fear and anxiety. In: The amygdala, Vol. 2 (Aggleton JP, ed), pp 213–287. Oxford, UK: Oxford University Press. 260 Y. L. Yang and K. T. Lu / Neuroscience 134 (2005) 247–260 visual recognition memory in rhesus monkeys. J Pharmacol Exp Ther 278:891– 897. McAllister WR, McAllister DE (1971) Behavioral measurements of conditioned fear. In: Aversive conditioning and learning (Brush FR, ed), pp 105–179. New York: Academic Press. Miserendino MJD, Sananes CB, Melia KR, Davis M (1990) Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala. Nature 345:716–718. Monahan J, Handelmann G, Hood W, Cordi A (1989) D-cycloserine, a positive modulator of the N-methyl-D-aspartate receptor, enhances performance of learning tasks in rats. Pharmacol Biochem Behav 34:649 – 653. Morris R (1989) Synaptic plasticity and learning: selective impairment of learning in rats and blockade of long-term potentiation in vivo by the N-methyl-D-aspartate antagonist AP5. J Neurosci 9:3040–3057. Olney JW (1994) New mechanisms of excitatory transmitter neurotoxicity. J Neural Transm Suppl 43:47–51. Pavlov I (1927) Conditioned reflexes. Oxford: Oxford University Press. Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, 3rd ed. New York: Academic. Pussinen R, Niememinen S, Koivisto E, Haapalinna A, Riekkinen S, Sirvio J (1997) Enhancement of intermediate-term memory by an alpha-1 agonist or a partial agonist at the glycine site of the NMDA receptor. Neurobiol Learn Mem 67:69 –74. Quartermain D, Mower J, Rafferty M, Herting R, Lanthorn T (1994) Acute but not chronic activation of the NMDA-coupled glycine receptor with D-Cycloserine facilitates learning and retention. Eur J Pharmacol 257:7–12. Ressler KJ, Rothbaum BO, Tannebaum L, Anderson P, Graap K, Zimand E, Hodges L, Davis M (2004) Cognitive enhancers as adjuncts to psychotherapy: Use of D-Cycloserine in phobics to facilitate extinction of fear. Arch Gen Psychiatry 61:1136 –1144. Richardson R, Ledgerwood L, Cranney J (2004) Facilitation of fear extinction by D-cycloserine: Theoretical and clinical implications. Learn Mem 11:510 –516. Rogan MT, Staubli UV, LeDoux JE (1997) Fear conditioning induces associative long-term potentiation in the amygdala. Nature 390:604–607. Schafe GE, LeDoux JE (2000) Memory consolidation of auditory Pavlovian fear conditioning requires protein synthesis and protein kinase A in the amygdala. J Neurosci 20:8177– 8187. Schwartz B, Hashtroudi S, Herting R, Schwartz P, Deutsch S (1996) D-Cycloserine enhances implicit memory in Alzheimer patients. Neurology 46:420 – 424. Staubli U, Thibaoult O, DiLorenzo M, Lynch G (1989) Antagonism of NMDA receptors impairs acquisition but not retention of olfactory memory. Behav Neurosci 103:54 – 60. Thompson L, Disterhoft J (1997) Age- and dose-dependent facilitation of associative eyeblink conditioning by D-cycloserine in rabbits. Behav Neurosci 111:1303–1312. Tsai G, Falk W, Gunther J (1998) A preliminary study of D-cycloserine treatment in Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 10:224–226. Tsai G, Falk W, Gunther J, Coyle J (1999) Improved cognition in Alzheimer’s disease with short-term D-cycloserine treatment. Am J Psychiatry 156:467– 469. van Berckel B, Evenblij C, van Loon B, Maas M, van der Geld M, Wynne J, van Ree J, Kahn R (1999) D-cycloserine increases positive symptoms in chronic schizophrenic patients when administered in addition to antipsychotics: a double-blind, parallel, placebo-controlled study. Neuropsychopharmacology 21:203–210. Walker DL, Ressler KJ, Lu KT, Davis M (2002) Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusion of D-cycloserine as assessed with fear-potentiated startle. J Neurosci 22:2343–2351. Davis M, Falls WA, Gewirtz J (2000) Neural systems involved in fear inhibition: Extinction and conditioned inhibition. In: Contemporary issues in modeling psychopathology (Myslobodsky M, Weiner I, eds), pp 113–142. Boston: Kluwer Academic Publishers. Falls W, Davis M (1992) Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala. J Neurosci 12:854 – 863. Falls W, Davis M (1995) Behavioral and physiological analysis of fear inhibition: extinction and conditioned inhibition. In: Neurobiological and clinical consequences of stress: From normal adaptation to PTSD (Friedman MJ, Charney DS, Deutch AY, eds), pp 177–202. Philadelphia: Lippincott-Raven. Fanselow MS, LeDoux JE (1999) Why we think plasticity underlying pavlovian fear conditioning occurs in the basolateral amygdala. Neuron 23:229 –232. Flood J, Baker M, Davis J (1990) Modulation of memory processing by glutamic acid receptor antagonists. Brain Res 521:197–202. Flood J, Morley J, Lanthorn T (1992) Effect on memory processing by D-cycloserine, an agonist of the NMDA/glycine receptor. Neurosci Lett 146:215–218. Gewirtz JC, Davis M (1997) Second-order fear conditioning prevented by blocking NMDA receptors in amygdala. Nature 388:471– 474. Goff D, Tsai G, Levitt J, Amico E, Manoach D, Schoenfeld D, Hayden D, McCarley R, Coyle J (1999) A placebo-control trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia. Arch Gen Psychiatry 56:21–27. Javitt D, Aylberman I, Zukin S, Heresco L, Lindenmayer J (1994) Amelioration of negative symptoms in schizophrenia by glycine. Am J Psychiatry 151:1234 –1236. Kehoe E, Macrae M, Hutchinson C (1996) MK-801 protects conditioned response from extinction in the rabbit nictitating membrane preparation. Psychobiology 24:127–135. Kim J, DeCola J, Landeira-Fernandez J, Fanselow M (1991) N-methylD-aspartate receptor antagonist APV blocks acquisition but not expression of fear conditioning. Behav Neurosci 105:126 –133. Konorski J (1948) Conditioned reflexes and neuronal organization. London: Cambridge University Press. Land C, Riccio D (1999) D-cycloserine: Effects on long-term retention of a conditioned response and on memory for contextual attributes. Neurobiol Learn Mem 72:158 –168. Lawler BA, Davis KL (1992) Does modulation of glutamatergic function represent a viable therapeutic strategy in Alzheimer’s disease? Biol Psychiatry 31:337–350. Ledgerwood L, Richardson R, Cranney J (2003) Effects of D-cycloserine on extinction of conditioned freezing. Behav Neurosci 117:341–349. Ledgerwood L, Richardson R, Cranney J (2004) D-cycloserine and the facilitation of extinction of conditioned fear. Consequences for reinstatement. Behav Neurosci 118:505–513. Lee H, Kim J (1998) Amygdalar NMDA receptors are critical for new fear learning in previously fear-conditioned rats. J Neurosci 18:8444–8454. Lin CH, Yeh SH, Lin CH, Lu KT, Leu TH, Cheung WC, Gean PW (2001) A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala. Neuron 31:845–851. Lin CH, Yeh SH, Lu HY, Gean PW (2003) The similarities and diversities of signal pathways leading to consolidation of conditioning and consolidation of extinction of fear memory. J Neurosci 23:8310–8317. Lu KT, Walker DL, Davis M (2001) Mitogen-activated protein kinase cascade in the basolateral nucleus of amygdala is involved in extinction of fear-potentiated startle. J Neurosci 21(RC162):1–5. Maren S, Aharonov G, Stote D, Fanselow M (1996) N-methyl-Daspartate receptors in the basolateral amygdala are required for both acquisition and expression of conditional fear in rats. Behav Neurosci 110:1365–1374. Matsuoka N, Aigner T (1996) D-cycloserine, a partial agonist at the glycine site coupled to N-methyl-D-aspartate receptors, improves (Accepted 1 April 2005)