5-HT2A Receptor Activation Normalizes Exaggerated Fear Behavior in p-Chlorophenylalanine (PCPA)-Treated Rats

Full-Text HTML Download Download as PDF (Size:463KB) PP. 454-462
DOI: 10.4236/jbbs.2012.24053    3,014 Downloads   5,826 Views   Citations


Deficits in serotonin (5-hydroxytryptamine, 5-HT) neurotransmission are implicated in abnormal emotional behaviors such as aggression, anxiety, and depression. However, the specific 5-HT receptor mechanisms involved are not well understood. The role of 5-HT2 receptors in fear potentiated startle, (FPS) was examined in rats chronically treated with pchlorophenylalanine (PCPA) to reduce brain 5-HT. PCPA-treated rats show an enhanced magnitude of FPS. Systemic administration of the 5-HT2 receptor agonist (±)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride (DOI) reduced FPS in both PCPA-treated and saline (SAL)-treated control animals, normalizing the exaggerated fear response in PCPA-treated rats. In both SAL- and PCPA-treated animals, the DOI-induced reduction of learned fear was reversed by the 5-HT2 antagonist ketanserin, but not by the 5-HT2B/2C antagonist SB 206553. Together, these findings suggest 5-HT2A receptors are critical regulators of learned fear, and that 5-HT2A receptors may be an important pharmacological target to normalize exaggerated learned fear resulting from chronic 5-HT-ergic disruption.

Cite this paper

C. Hughes, L. Tran and N. Keele, "5-HT2A Receptor Activation Normalizes Exaggerated Fear Behavior in p-Chlorophenylalanine (PCPA)-Treated Rats," Journal of Behavioral and Brain Science, Vol. 2 No. 4, 2012, pp. 454-462. doi: 10.4236/jbbs.2012.24053.


[1] M. J. Owens and C. B. Nemeroff, “The Serotonin Transporter and Depression,” Depress Anxiety, Vol. 8, Suppl. 1, 1998, pp. 5-12. doi:10.1002/(SICI)1520-6394(1998)8:1+<5::AID-DA2>3.0.CO;2-I
[2] G. J. Marek, L. L. Carpenter, C. J. McDougle, and L. H. Price, “Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsy-Chiatric Disorders,” Neuropsychopharmacology, Vol. 28, No. 2, 2003, pp. 402-412. doi:10.1038/sj.npp.1300057
[3] J. E. LeDoux, “Emotion Circuits in the Brain,” Annual Review of Neuroscience, Vol. 23, No. 1, 2000, pp. 155- 184. doi:10.1146/annurev.neuro.23.1.155
[4] J. F. Lopez-Gimenez, G. Mengod, J. M. Palacios and M. T. Vilaro, “Selective Visualization of Rat Brain 5-HT2A Receptors by Autoradiography With [3H]MDL 100,907,” Naunyn Schmiedebergs Arch Pharmacol, Vol. 356, No. 4, 1997, pp. 446-454. doi:10.1007/PL00005075
[5] D. A. Morilak, S. J. Garlow and R. D. Ciaranello, “Immunocytochemical Localization and Description of Neurons Expressing Serotonin 2 Receptors in the Rat Brain,” Neuroscience, Vol. 54, No. 3, 1993, pp. 701-717. doi:10.1016/0306-4522(93)90241-7
[6] A. Pazos, R. Cortes and J. M. Palacios, “Quantitative Autoradiographic Mapping of Serotonin Receptors in the Rat Brain. II. Serotonin-2 Receptors,” Brain Research, Vol. 346, No. 2, 1985, pp. 231-249. doi:10.1016/0006-8993(85)90857-1
[7] M. Pompeiano, J. M. Palacios and G. Mengod, “Distribution of the Serotonin 5-HT2 Receptor Family mRNAs: Comparison between 5-HT2A and 5-HT2C Receptors,” Molecular Brain Research, Vol. 23, No. 1-2, 1994, pp. 163-178. doi:10.1016/0169-328X(94)90223-2
[8] C. R. Hughes and N. B. Keele, “Phenytoin Normalizes Exaggerated Fear Behavior in P-Chlorophenylalanine (PCPA)- Treated Rats,” Epilepsy & Behavior, Vol. 9, No. 4, 2006, pp. 557-563. doi:10.1016/j.yebeh.2006.09.002
[9] T. Inoue, X. B. Li, T. Abekawa, Y. Kitaichi, T. Izumi, S. Nakagawa and T. Koyama, “Selective Serotonin Reuptake Inhibitor Reduces Conditioned Fear through Its Effect in the Amygdala,” European Journal of Pharmacology, Vol. 497, No. 3, 2004, pp. 311-316. doi:10.1016/j.ejphar.2004.06.061
[10] X. L. Jiang, G. Q. Xing, C. H. Yang, A. Verma, L. Zhang and H. Li, “Stress Impairs 5-HT2A Receptor-Mediated Serotonergic Facilitation of GABA Release in Juvenile Rat Basolateral Amygdala,” Neuropsychopharmacology, Vol. 34, No. 2, 2009, pp. 410-423. doi:10.1038/npp.2008.71
[11] D. G. Rainnie, “Serotonergic Modulation of Neurotransmission in the Rat Basolateral Amygdala,” Journal of Neurophysiology, Vol. 82, No. 1, 1999, pp. 69-85.
[12] G. E. Stutzmann and J. E. LeDoux, “GABAergic Antagonists Block the Inhibitory Effects of Serotonin in the Lateral Amygdala: A Mechanism for Modulation of Sensory Inputs Related to Fear Conditioning,” Journal of Neurophysiology, Vol. 19, No. 11, 1999, pp. RC8.
[13] N. B. Keele, “The Role of Serotonin in Impulsive and Aggressive Behaviors Associated with Epilepsy-Like Neuronal Hyperexcitability in the Amygdala,” Epilepsy & Behavior, Vol. 7, No. 3, 2005, pp. 325-335. doi:10.1016/j.yebeh.2005.06.014
[14] N. B. Keele and D. R. Randall, “Altered Modulation of Excitatory Neurotransmission in the Amygdala by Serotonin in an Animal Model of Impulsive Aggression,” Annals of the New York Academy of Sciences, Vol. 985, 2003, pp. 528-532. doi:10.1111/j.1749-6632.2003.tb07119.x
[15] L. Valzelli, S. Bernasconi and M. Dalessandro, “Time-Courses of P-CPA-Induced Depletion of Brain Serotonin and Muricidal Aggression in the Rat,” Pharmacological Research Communications, Vol. 15, No. 4, 1983, pp. 387- 395. doi:10.1016/S0031-6989(83)80048-4
[16] J. Hannon and D. Hoyer, “Molecular Biology of 5-HT Receptors,” Behavioural Brain Research, Vol. 195, No. 1, 2008, pp. 198-213. doi:10.1016/j.bbr.2008.03.020
[17] D. Fiorella, R. A. Rabin and J. C. Winter, “Role of 5-HT2A and 5-HT2C Receptors in the Stimulus Effects of Hallucinogenic Drugs. II: Reassessment of LSD False Positives,” Psychopharmacology (Berl), Vol. 121, No. 3, 1995, pp. 357-363. doi:10.1007/BF02246075
[18] F. M. Shen, J. Wang, C. R. Ni, J. G. Yu, W. Z. Wang and D. F. Su, “Ketanserin-Induced Baroreflex Enhancement in Spontaneously Hypertensive Rats Depends on Central 5-HT(2A) Receptors,” Clinical and Experimental Pharmacology and Physiology, Vol. 34, No. 8, 2007, pp. 702- 707. doi:10.1111/j.1440-1681.2007.04626.x
[19] C. Korstanje, R. Sprenkels, H. N. Doods, J. G. Hugtenburg, E. Boddeke, H. D. Batink, M. J. Thoolen and P. A. Van Zwieten, “Characterization of Flufylline, Fluprofylline, Ritanserin, Butanserin and R 56413 With Respect to in-Vivo Alpha1-,Alpha2- and 5-HT2-Receptor Antagonism and in-Vitro Affinity for Alpha1-, Alpha2- and 5-HT2-Receptors: Comparison With Ketanserin,” Journal of Pharmacy and Pharmacology, Vol. 38, No. 5, 1986, pp. 374-379. doi:10.1111/j.2042-7158.1986.tb04590.x
[20] D. Hoyer, G. Engel and H. O. Kalkman, “Molecular Pharmacology of 5-HT1 and 5-HT2 Recognition Sites in Rat and Pig Brain Membranes: Radioligand Binding Studies With [3H]5-HT, [3H]8-OH-DPAT, (-)[125I]Iodocyanopin-dolol, [3H]Mesulergine and [3H]Ketanserin,” European Journal of Pharmacology, Vol. 118, No. 1-2, 1985, pp. 13-23. doi:10.1016/0014-2999(85)90658-2
[21] O. M. Ghoneim, J. A. Legere, A. Golbraikh, A. Tropsha and R. G. Booth, “Novel Ligands for the Human Histamine H1 Receptor: Synthesis, Pharmacology, and Comparative Molecular Field Analysis Studies of 2-Dimethylamino-5-(6)-phenyl-1,2,3,4-tetrahydronaphthalenes,” Bioorganic & Medicinal Chemistry, Vol. 14, No. 19, 2006, pp. 6640-6658. doi:10.1016/j.bmc.2006.05.077
[22] J. S. Bonini, W. C. Da Silva, C. K. Da Silveira, C. A. Kohler, I. Izquierdo and M. Cammarota, “Histamine Facilitates Consolidation of Fear Extinction,” International Journal of Neuropsychopharmacology, Vol. 14, No. 9, 2011, pp. 1209-1217. doi:10.1017/S1461145710001501
[23] A. Zlomuzica, L. A. Ruocco, A. G. Sadile, J. P. Huston and E. Dere, “Histamine H1 Receptor Knockout Mice Exhibit Impaired Spatial Memory in the Eight-Arm Radial Maze,” British Journal of Pharmacology, Vol. 157, No. 1, 2009, pp. 86-91. doi:10.1111/j.1476-5381.2009.00225.x
[24] T. Izumi, T. Inoue, Y. Kitaichi, S. Nakagawa and T. Koyama, “Target Brain Sites of the Anxiolytic Effect of Citalopram, a Selective Serotonin Reuptake Inhibitor,” European Journal of Pharmacology, Vol. 534, No. 1-3, 2006, pp. 129-132. doi:10.1016/j.ejphar.2005.12.073
[25] I. G. McKeith, E. F. Marshall, I. N. Ferrier, M. M. Armstrong, W. N. Kennedy, R. H. Perry, E. K. Perry and D. Eccleston, “5-HT Receptor Binding in Post-Mortem Brain From Patients With Affective Disorder,” Journal of Affective Disorders, Vol. 13, No. 1, 1987, pp. 67-74. doi:10.1016/0165-0327(87)90075-9
[26] J. Neuger, B. Wistedt, B. Sinner, A. Aberg-Wistedt and R. Stain-Malmgren, “The Effect of Citalopram Treatment on Platelet Serotonin Function in Panic Disorders,” International Clinical Psychopharmacology, Vol. 15, No. 2, 2000, pp. 83-91. doi:10.1097/00004850-200015020-00004
[27] B. A. Nic Dhonnchadha, M. Hascoet, P. Jolliet and M. Bourin, “Evidence for a 5-HT2A Receptor Mode of Action in the Anxiolytic-Like Properties of DOI in Mice,” Behavioural Brain Research, Vol. 147, No. 1-2, 2003, pp. 175-184. doi:10.1016/S0166-4328(03)00179-7
[28] N. Ripoll, M. Hascoet and M. Bourin, “Implication of 5-HT2A Subtype Receptors in DOI Activity in the Four- Plates Test-Retest Paradigm in Mice,” Behavioural Brain Research, Vol. 166, No. 1, 2006, pp. 131-139. doi:10.1016/j.bbr.2005.07.013
[29] B. A. Nic Dhonnchadha, M. Bourin and M. Hascoet, “Anxiolytic-Like Effects of 5-HT2 Ligands on Three Mouse Models of Anxiety,” Behavioural Brain Research, Vol. 140, No. 1-2, 2003, pp. 203-214. doi:10.1016/S0166-4328(02)00311-X
[30] D. Pare, G. J. Quirk and J. E. LeDoux, “New Vistas on Amygdala Networks in Conditioned Fear,” Journal of Neurophysiology, Vol. 92, No. 1, 2004, pp. 1-9. doi:10.1152/jn.00153.2004
[31] M. G. McKernan and P. Shinnick-Gallagher, “Fear Conditioning Induces a Lasting Potentiation of Synaptic Currents in Vitro,” Nature, Vol. 390, No. 6660, 1997, pp. 607- 611. doi:10.1038/37605
[32] M. T. Rogan, U. V. Staubli and J. E. LeDoux, “Fear Conditioning Induces Associative Long-Term Potentiation in the Amygdala,” Nature, Vol. 390, No. 6660, 1997, pp. 604- 607. doi:10.1038/37601
[33] S. Rumpel, J. LeDoux, A. Zador and R. Malinow, “Postsynaptic Receptor Trafficking Underlying a Form of Associative Learning,” Science, Vol. 308, No. 5718, 2005, pp. 83-88. doi:10.1126/science.1103944
[34] J. J. Kim and M. S. Fanselow, “Modality-Specific Retrograde Amnesia of Fear,” Science, Vol. 256, No. 5057, 1992, pp. 675-677. doi:10.1126/science.1585183
[35] R. G. Phillips and J. E. LeDoux, “Differential Contribution of Amygdala and Hippocampus to Cued and Contextual Fear Conditioning,” Behavioral Neuroscience, Vol. 106, No. 2, 1992, pp. 274-285. doi:10.1037/0735-7044.106.2.274
[36] A. F. Sadikot and A. Parent, “The Monoaminergic Innervation of the Amygdala in the Squirrel Monkey: An Immunohistochemical Study,” Neuroscience, Vol. 36, No. 2, 1990, pp. 431-447. doi:10.1016/0306-4522(90)90439-B
[37] R. P. Vertes, “A PHA-L Analysis of Ascending Projections of the Dorsal Raphe Nucleus in the Rat,” The Journal of Comparative Neurology, Vol. 313, No. 4, 1991, pp. 643-668. doi:10.1002/cne.903130409
[38] N. R. Hanley and J. G. Hensler, “Mechanisms of LigandInduced Desensitization of the 5-Hydroxytrypta-mine(2A) Receptor,” Journal of Pharmacology and Experimental Therapeutics, Vol. 300, No. 2, 2002, pp. 468-477. doi:10.1124/jpet.300.2.468
[39] J. B. Rosen and J. Schulkin, “From Normal Fear to Pathological Anxiety,” Psychological Review, Vol. 105, No. 2, 1998, pp. 325-350. doi:10.1037/0033-295X.105.2.325

comments powered by Disqus

Copyright © 2017 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.