EFFECTS OF SINGLE-DOSE KETAMINE INFUSION ON BEHAVIORAL PARAMETERS AND NEURONAL ACTIVATION IN THE MEDIAL PREFRONTAL CORTEX OF JUVENILE RATS EXPOSED TO PRENATAL STRESS

Abstract

Objectives: Subanesthetic dose of ketamine administration produces antidepressant-like response especially in treatmentresistant depression patients. Ketamine’s rapid and sustained actions have also been demonstrated in normal or chronically stressed animals, but no experimental studies have examined its effects in prenatally stressed rodents. Therefore, aim of the
present study was to investigate the behavioral and structural consequences of single-dose ketamine application in juvenile rats exposed to prenatal stress.
Methods: Prenatal stress protocol was applied by immobilization of pregnant rats during the last week of their gestation for 3 hours a day. While treatment group received a single-dose (10 mg/kg) of intraperitoneal ketamine injection, control and stress groups received same amount of saline injections at P38. After completion of behavioral tests (sucrose preference, modified grip and forced swim), animals were sacrificed via intracardiac perfusion. Then, immediate gene expression in the medial prefrontal cortex was evaluated by c-Fos immunohistochemistry.
Results: Although the active coping and depressive-like behavior of juvenile animals exposed to prenatal stress did not significantly change, ketamine application caused alterations in the sucrose preference pattern of animals and immobility time in the forced swim test. Two-way ANOVA test results showed significant differences among groups and a group X gender interaction in the density of c-Fos expressing neurons present in the medial prefrontal cortex.
Conclusion: A single-dose ketamine treatment might differentially affect the depressive-like behaviors of juvenile animals exposed to prenatal stress and activate neurons in the medial prefrontal cortical region in a gender-dependent manner.

Keywords

• c-Fos
• depression
• ketamine
• prefrontal cortex
• prenatal stress

References

1. World Health Organization. The world health report 2001 – Mental
2. Health: new understanding, new hope. Geneva: WHO; 2001.
3. Andrade L, Caraveo-A. Epidemiology of major depressive episodes: Results from the international consortium of psychiatric epidemiology (ICPE) surveys. Int J Methods Psychiatr Res 2003; 12:3–21.
4. Gray AL, Hyde TM, Deep-Soboslay A, Kleinman JE, Sodhi MS. Sex differences in glutamate receptor gene expression in major depression and suicide. MS Mol Psychiatry 2015;20:1057–68.
5. Katz MM, Tekell JL, Bowden CL, Brannan S. Houston JP, Bermann N, Frazer A. Onset and early behavioral effects of pharmacologically different antidepressants and placebo in depression. Neuropsychopharmacology 2004;29:566–79.
6. Gagné GG Jr, Furman MJ, Carpenter LL, Price LH. Efficacy of
7. continuation ECT and antidepressant drugs compared to longterm
8. antidepressants alone in depressed patients. Am J Psychiatry

9. ;157:1960–5.
10. Duman RS, Li N, Liu RJ, Duric V, Aghajanian G. Signaling pathways
11. underlying the rapid antidepressant actions of ketamine. Neuropharmacology 2012;62:35–41.
12. M aan het Rot, CA Zarate Jr, DS Charney, SJ. Ketamine for depression: where do we go from here? Biol Psychiatry 2012;72: 537–47.
13. Murrough JW, Losifescu VD, Chang LC. antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013; 170:1134-42.
14. Price BR , Losifescu VD, Murrough JW. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depress Anxiety 2014;31: 335–43.
15. Romeo B, Choucha W, Fossati P, Rotge JY. Meta-analysis of short- and mid-term efficacy of ketamine in unipolar and bipolar depression. Psychiatry Res 2015;230:682–88.
16. Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY, Aghajanian G, Duman RS. Glutamate NMDA receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 2011;69:754–61.
17. Heller AS, Johnstone T, Peterson MJ, Kolden GG, Kalin NH, Davidson RJ. Increased prefrontal cortex activity during negative emotion regulation as a predictor of depression symptom severity trajectory over 6 months. JAMA Psychiatry 2013;70:1181–9.
18. Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA,
19. Licznerski P, Lepack A, Majik MS, Jeong LS, Banasr M, Son H, Duman RS. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med 2012;18:1413–7.
20. Grimm S, Luborzewski A, Schubert F, Merkl A, Kronenberg G, Colla M, Heuser I, Bajbouj M. Region-specific glutamate changes in patients with unipolar depression. J Psychiatr Res 2012;46: 1059–65.
21. Muhammad A, Kolb B. Mild prenatal stress-modulated behavior
22. and neuronal spine density without affecting amphetamine sensitization.
23. Dev Neurosci 2011;33:85–98.
24. Soztutar E, Colak E, Ulupinar E. Gender- and anxiety leveldependent
25. effects of perinatal stress exposure on medial prefrontal cortex. Exp Neurol 2015;2:274–84.
26. Li N, Liu RJ, Dwyer JM, Duman RS. Glutamate NMDA receptor antagonists rapidly reverse behavioral and synaptic deficits caused
27. by chronic stress exposure. Biol Psychiatry 2011;69:754–61.
28. Långsjö JW, Salmi E, Kaisti KK, Aalto S, Hinkka S, Aantaa R, Oikonen V, Viljanen T, Kurki T, Silvanto M, Scheinin H. Effects of subanesthetic ketamine on regional cerebral glucose metabolism in humans. Anesthesiology 2004;100:1065–71.
29. Murrough JW. Ketamine as a novel antidepressant: from synapse
30. to behavior. Clin Pharmacol Ther 2012;91:303–9.
31. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010;329:959–64.
32. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011;475:91–5.
33. Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY,
34. Aghajanian G, Duman RS. Glutamate N-methyl-D-aspartate receptor
35. antagonists rapidly reverse behavioral and synaptic deficits caused
36. by chronic stress exposure. Biol Psychiatry 2011;69:754–61.
37. Willner P. Validity, reliability and utility of the chronic mild stress
38. model of depression: a 10-year review and evaluation.
39. Psychopharmacology (Berl) 1997;134:319–29.
40. Ulupinar E, Erol K, Ay H, Yucel F. Rearing conditions differently
41. affect the motor performance and cerebellar morphology of prenatally
42. stressed juvenile rats. Behav Brain Res 2015;278:235–43.
43. Carrier N, Kabbaj M. Sex differences in the antidepressant like
44. effects of ketamine. Neuropharmacology 2013;70:27–34.
45. Paxinos G, Watson C. The rat brain in stereotaxic coordinates.
46. San Diego (CA): Academic Press; 1986.
47. Weinstock M. The long-term behavioural consequences of prenatal
48. stress. Neurosci Biobehav Rev 2008;32:1073–86.
49. Porsolt RD, Anton G, Blavet N, Jalfre M. Behavioural despair in
50. rats: a new model sensitive to antidepressant treatments. Eur J
51. Pharmacol 1978;47:379–91.
52. Morley-Fletcher S, Darnaudery M, Koehl M, Casolini P, Van
53. Reeth O, Maccari S. Prenatal stress in rats predicts immobility
54. behavior in the forced swim test. Effects of a chronic treatment
55. with tianeptine. Brain Res 2003;989:246–51.
56. Weinstock M. Sex-dependent changes induced by prenatal stress
57. in cortical and hippocampal morphology and behaviour in rats: an
58. update. Stress 2011;14:604–13.
59. Willner P. Chronic mild stress (CMS) revisited: consistency and
60. behavioural-neurobiological concordance in the effects of CMS.
61. Neuropsychobiology 2005;52:90–110.
62. Garcia LSB, Comim CM, Valvassori SS, Réus GZ, Stertz L,
63. Kapczinski F, Gavioli EC, Quevedo J. Ketamine treatment reverses
64. behavioral and physiological alterations induced by chronic mild
65. stress in rats. Prog Neuropsychopharmacol Biol Psychiatry
66. ;33:450–55.
67. Rezin GT, Goncalves CL, Daufenbach JF, Fraga DB, Santos PM,
68. Ferreira GK, Hermani FV, Comim CM, Quevedo J, Streck EL.
69. Acute administration of ketamine reverses the inhibition of mitochondrial
70. respiratory chain induced by chronic mild stress. Brain
71. Res Bull 2009;79:418–21.
72. Browne CA, Lucki I. Antidepressant effects of ketamine: mechanisms
73. underlying fast-acting novel antidepressants. Front
74. Pharmacol 2013;4:161.
75. Akinfiresoye L, Tizabi Y. Antidepressant effects of AMPA and ketamine
76. combination: role of hippocampal BDNF, synapsin, and
77. mTOR. Psychopharmacology 2013;230:291–8.
78. Ma XC, Dang YH, Jia M, Ma R, Wang F, Wu J, Gao CG,
79. Hashimoto K. Long-lasting antidepressant action of ketamine, but
80. not glycogen synthase kinase-3 inhibitor SB216763, in the chronic
81. mild stress model of mice. PLoS ONE 2013;8:e56053.
82. Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen
83. G, Manji HK. Cellular mechanisms underlying the antidepressant
84. effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-
85. -propionic acid receptors. Biol Psychiatry 2008;63:349–52.
86. Popik P, Kos T, Sowa-Kucma M, Nowak G. Lack of persistent
87. effects of ketamine in rodent models of depression. Psychopharmacology
88. ;198:421–30.
89. Engin E, Treit D, Dickson CT, Anxiolytic- and antidepressantlike
90. properties of ketamine in behavioral and neurophysiological
91. animal models. Neuroscience 2009;161:359–69.
92. Bourin, M. Animal models of anxiety: are they suitable for predicting
93. drug action in humans? Polish J Pharmacol1997;49:79–84.
94. Can ÖD, Ulup›nar E, Özkay ÜD, Yegin B, Öztürk Y. The effect
95. of simvastatin treatment on behavioral parameters, cognitive performance,
96. and hippocampal morphology in rats fed a standard or a
97. high-fat diet. Behav Pharmacol 2012;23:582–92.
98. Cryan JF, Valentino RJ, Lucki I. Assessing substrates underlying
99. the behavioral effects of antidepressants using the modified rat
100. forced swimming test. Neurosci Biobehav Rev 2005;29:547–69.
101. Hoshaw BA, Hill TI, Crowley JJ, Malberg JE, Khawaja X,
102. Rosenzweig LS, Schechter LE, Lucki I. Antidepressant-like behavioral
103. effects of IGF-I produced by enhanced serotonin transmission.
104. Eur J Pharmacol 2008;594:109–16.
105. Burgdorf J, Zhang XL, Nicholson KL, Balster RL, Leander JD,
106. Stanton PK, Gross AL, Kroes RA, Moskal JR. GLYX-13, a
107. NMDA receptor glycine-site functional partial agonist, induces
108. antidepressant-like effects without ketamine-like side effects.
109. Neuropsychopharmacology 2013;38:729–42.
110. Carrier N, Kabbaj M. Sex differences in the antidepressant like
111. effects of ketamine. Neuropharmacology 2013;70:27–34.
112. Gigliucci V, O’Dowd G, Casey S, Egan D, Gibney S, Harkin A.
113. Ketamine elicits sustained antidepressant-like activity via a serotonin-
114. Koike H, Iijima M, Chaki S. Effects of ketamine and LY341495 on
115. the depressive-like behavior of repeated corticosterone-injected
116. rats. Pharmacol Biochem Behav 2013;107:20–3.
117. Koike H, Fukumoto K, Iijima M, Chaki S. Role of BDNF/TrkB
118. signaling in antidepressant-like effects of a group II metabotropic
119. glutamate receptor antagonist in animal models of depression.
120. Behav Brain Res 2013;238:48–52.
121. Muller HK, Wegener G, Liebenberg N, Zarate, CA Jr, Popoli M,
122. Elfving B. Ketamine regulates the presynaptic release machinery in
123. the hippocampus. J Psychiatr Res 2013;47:892–9.
124. Walker AK, Budac DP, Bisulco S, Lee AW, Smith RA, Beenders
125. B, Kelley KW, Dantzer R. NMDA receptor blockade by ketamine
126. abrogates lipopolysaccharide-induced depressive-like behavior in
127. C57BL/6J Mice. Neuropsychopharmacology 2013;38:1609–16.
128. Yilmaz A, Schulz D, Aksoy A, Canbeyli R. Prolonged effect of an
129. anesthetic dose of ketamine on behavioral despair. Pharmacol
130. Biochem Behav 2002;71:341–4.
131. Garcia LS, Comim CM, Valvassori SS, Reus GZ, Barbosa LM,
132. Andreazza AC, Stertz L, Fries GR, Gavioli EC, Kapczinski F,
133. Quevedo J. Acute administration of ketamine induces antidepressant-
134. like effects in the forced swimming test a decreases BDNF
135. levels in the rat hippocampus. Prog Neuropsychopharmacol Biol
136. Psychiatry 2008;32:140–4.
137. Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen
138. G, Manji HK. Cellular mechanisms underlying the antidepressant
139. effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-
140. -propionic acid receptors. Biol Psychiatry 2008;63:349–52.
141. Parise EM, Alcantara LF, Warren BL, Wright KN, Hadad R, Sial
142. OK, Kroeck KG, Iñiguez SD, Bolaños-Guzmán CA. Repeated
143. ketamine exposure induces an enduring resilient phenotype in adolescent
144. and adult rats. Biol Psychiatry 2013;74:750–9.
145. Tizabi Y, Bhatti BH, Manaye KF, Das JR, Akinfiresoye L.
146. Antidepressant-like effects of low ketamine dose is associated with
147. increased hippocampal AMPA/NMDA receptor density ratio in
148. female Wistar-Kyoto rats. Neuroscience 2012;213:72–80.
149. Franceschelli A, Sens J, Herchick S, Thelen C, Pitychoutis PM.
150. Sex differences in the rapid and the sustained antidepressant-like
151. effects of ketamine in stress-naïve and “depressed” mice exposed to
152. chronic mild stress. Neuroscience 2015;290:49–60.
153. Ulupinar E, Yucel F, Ortug G. The effects of prenatal stress on the
154. Purkinje cell neurogenesis. Neurotoxicol Teratol 2006;28:86–94.
155. Bock J, Riedel A, Braun K. Differential changes of metabolic brain
156. activity and interregional functional coupling in prefronto-limbic
157. pathways during different stress conditions: functional imaging in
158. freely behaving rodent pups. Front Cell Neurosci 2012;10:6–19.
159. Kolb B, Mychasiuk R, Muhammad A, Li Y, Frost DO, Gibb R.
160. Experience and the developing prefrontal cortex. Proc Natl Acad
161. Sci U S A 2012;109:S17186–93.
162. Chang CH, Chen MC, Lu J. Effect of antidepressant drugs on the
163. vmPFC-limbic circuitry. Neuropharmacology 2015;92:116–24.
164. Långsjö JW, Kaisti KK, Aalto S, Hinkka S, Aantaa R, Oikonen V,
165. Sipilä H, Kurki T, Silvanto M, Scheinin H. Effects of subanesthetic
166. doses of ketamine on regional cerebral blood flow, oxygen
167. consumption, and blood volume in humans. Anesthesiology
168. ;99:614–23.
169. Holcomb HH, Lahti AC, Medoff DR, Cullen T, Tamminga CA.
170. Effects of noncompetitive NMDA receptor blockade on anterior
171. cingulate cerebral blood flow in volunteers with schizophrenia.
172. Neuropsychopharmacology 2005;30:2275–82.
173. Fuchikami M, Thomas A, Liu R, Wohleb ES, Land BB, DiLeone
174. RJ, Aghajanian GK, Duman RS. Optogenetic stimulation of infralimbic
175. PFC reproduces ketamine’s rapid and sustained antidepressant
176. actions. Proc Natl Acad Sci U S A 2015;112:8106–11.