Background
Like fear conditioning, the acquisition phase of extinction involves new learning
that is mediated by the amygdala. During extinction training, the conditioned stimulus
is repeatedly presented in the absence of the unconditioned stimulus, and the expression
of previously learned fear gradually becomes suppressed. Our previous study revealed
that chronic treatment with a selective serotonin reuptake inhibitor (SSRI) impairs
the acquisition of auditory fear conditioning. To gain further insight into how SSRIs
affect fear learning, we tested the effects of chronic SSRI treatment on the acquisition
of extinction.
Methods
Rats were treated chronically (22 days) or subchronically (9 days) with the SSRI citalopram
(10 mg/kg/day) before extinction training. The results were compared with those after
chronic and subchronic treatment with tianeptine (10 mg/kg/day), an antidepressant
with a different method of action. The expression of the NR2B subunit of the N-methyl-D-aspartate receptor in the amygdala was examined after behavioral testing.
Results
Chronic but not subchronic administration of citalopram impaired the acquisition of
extinction and downregulated the NR2B subunit of the N-methyl-D-aspartate receptor in the lateral and basal nuclei of the amygdala. Similar
behavioral and molecular changes were found with tianeptine treatment.
Conclusions
These results provide further evidence that chronic antidepressant treatment can impair
amygdala-dependent learning. Our findings are consistent with a role for glutamatergic
neurotransmission in the final common pathway of antidepressant treatment.
Key Words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Pharmacological treatment of generalized anxiety disorder.Curr Top Behav Neurosci. 2010; 2: 453-467
- Fluvoxamine in the treatment of anxiety disorders.Neuropsychiatr Dis Treat. 2005; 1: 289-299
- Clinical utility of the selective serotonin reuptake inhibitors in the spectrum of anxiety.Biol Psychiatry. 1998; 44: 812-824
- Randomized, double-blind comparison of sertraline and placebo for posttraumatic stress disorder in a Department of Veterans Affairs setting.J Clin Psychiatry. 2007; 68: 711-720
- Treatment of PTSD: An Assessment of the Evidence.National Academies Press, Washington, DC2007
- Case history: The discovery of fluoxetine hydrochloride (Prozac).Nat Rev Drug Discov. 2005; 4: 764-774
- Recent studies on selective serotonergic antidepressants: Trazodone, fluoxetine, and fluvoxamine.J Clin Psychopharmacol. 1987; 7: 44S-49S
- Escitalopram effects on insula and amygdala BOLD activation during emotional processing.Psychopharmacology (Berl). 2008; 196: 661-672
- Neuroimaging abnormalities in the amygdala in mood disorders.Ann N Y Acad Sci. 2003; 985: 420-444
- Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism.Eur Neuropsychopharmacol. 2002; 12: 527-544
- Common changes in cerebral blood flow in patients with social phobia treated with citalopram or cognitive-behavioral therapy.Arch Gen Psychiatry. 2002; 59: 425-433
- Area-specific modulation of neural activation comparing escitalopram and citalopram revealed by pharmaco-fMRI: A randomized cross-over study.Neuroimage. 2010; 49: 1161-1170
- Antidepressant drug treatment modifies the neural processing of nonconscious threat cues.Biol Psychiatry. 2006; 59: 816-820
- The selective serotonin reuptake inhibitor citalopram increases fear after acute treatment but reduces fear with chronic treatment: A comparison with tianeptine.Biol Psychiatry. 2004; 55: 1171-1178
- Emotion circuits in the brain.Annu Rev Neurosci. 2000; 23: 155-184
- Is there savings for Pavlovian fear conditioning after neurotoxic basolateral amygdala lesions in rats?.Neurobiol Learn Mem. 2001; 76: 268-283
- Conditioning, remembering, and forgetting.J Exp Psychol Anim B. 1994; 20: 219-231
- Preservation of Pavlovian associations through extinction.Q J Exp Psychol B. 1996; 49: 245-258
- Context, ambiguity, and unlearning: Sources of relapse after behavioral extinction.Biol Psychiatry. 2002; 52: 976-986
- Intra-amygdala blockade of the NR2B subunit of the NMDA receptor disrupts the acquisition but not the expression of fear conditioning.J Neurosci. 2001; 21: 6889-6896
- Acquisition of fear extinction requires activation of NR2B-containing NMDA receptors in the lateral amygdala.Neuropsychopharmacology. 2007; 32: 1929-1940
- Long-term outcome for patients with panic disorder treated with cognitive-behavioral therapy.J Clin Psychiatry. 1990; 51: 17-23
- Exposure therapy for posttraumatic stress disorder.Am J Psychother. 2002; 56: 59-75
- Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats.J Neurosci. 2002; 22: 2343-2351
- A randomized controlled trial of D-cycloserine enhancement of exposure therapy for social anxiety disorder.Biol Psychiatry. 2008; 63: 544-549
- Augmentation of exposure therapy with D-cycloserine for social anxiety disorder.Arch Gen Psychiatry. 2006; 63: 298-304
- D-cycloserine augmented exposure therapy for obsessive-compulsive disorder.Biol Psychiatry. 2007; 62: 835-838
- Efficacy of D-cycloserine for enhancing response to cognitive-behavior therapy for panic disorder.Biol Psychiatry. 2010; 67: 365-370
- Cognitive enhancers as adjuncts to psychotherapy: Use of D-cycloserine in phobic individuals to facilitate extinction of fear.Arch Gen Psychiatry. 2004; 61: 1136-1144
- Augmentation of behavior therapy with D-cycloserine for obsessive-compulsive disorder.Am J Psychiatry. 2008; 165 (quiz 409): 335-341
- Efficacy of exposure versus cognitive therapy in anxiety disorders: Systematic review and meta-analysis.BMC Psychiatry. 2011; 11: 200
- Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: A randomized controlled trial.JAMA. 2000; 283: 2529-2536
- Alprazolam and exposure alone and combined in panic disorder with agoraphobia. A controlled study in London and Toronto.Br J Psychiatry. 1993; 162: 776-787
- A controlled comparison of cognitive-behavior therapy, diazepam, and placebo, alone and in combination, for the treatment of generalized anxiety disorder.J Anxiety Disord. 1990; 4: 267-292
- Is a combined therapy more effective than either CBT or SSRI alone? Results of a multicenter trial on panic disorder with or without agoraphobia.Acta Psychiatr Scand. 2008; 117: 260-270
- Context in the clinic: how well do cognitive-behavioral therapies and medications work in combination?.Biol Psychiatry. 2002; 52: 987-997
- Cognitive-behavioral therapy with and without medication in the treatment of obsessive-compulsive disorder.Prof Psychol-Res Pr. 2002; 33: 162-168
- Cognitive and behavioral therapies alone versus in combination with fluvoxamine in the treatment of obsessive compulsive disorder.J Nerv Ment Dis. 1998; 186: 492-499
- Memory loss in a patient treated with fluoxetine.Ann Pharmacother. 2003; 37: 1800-1803
- Combined pharmacotherapy and cognitive-behavioral therapy for anxiety disorders: Medication effects, glucocorticoids, and attenuated treatment outcomes.Clin Psychol-Sci Pr. 2010; 17: 91-103
- Neurochemical profile of tianeptine, a new antidepressant drug.Clin Neuropharmacol. 1988; 11: S43-S50
- Involvement of AMPA receptor phosphorylation in antidepressant actions with special reference to tianeptine.Eur J Neurosci. 2007; 26: 3509-3517
- Effects of acute and chronic tianeptine administration on serotonin outflow in rats: Comparison with paroxetine by using in vivo microdialysis.Eur J Pharmacol. 2000; 403: 55-65
- The neurobiological properties of tianeptine (Stablon): From monoamine hypothesis to glutamatergic modulation.Mol Psychiatry. 2010; 15: 237-249
- Acute stress-mediated increases in extracellular glutamate levels in the rat amygdala: Differential effects of antidepressant treatment.Eur J Neurosci. 2007; 25: 3109-3114
- In vivo steady-state pharmacokinetic outcome following clinical and toxic doses of racemic citalopram to rats.Br J Pharmacol. 2001; 132: 1683-1690
- Pharmacokinetic and pharmacodynamic responses to chronic administration of the selective serotonin reuptake inhibitor citalopram in rats.Clin Neuropharmacol. 1999; 22: 327-336
- Kinetic profiles of tianeptine and its MC5 metabolite in plasma, blood and brain after single and chronic intraperitoneal administration in the rat.Eur J Drug Metab Pharmacokinet. 1990; 15: 69-74
- Relationship between clinical effects, serum drug concentration and serotonin uptake inhibition in depressed patients treated with citalopram. A double-blind comparison of three dose levels.Eur J Clin Pharmacol. 1985; 28: 553-557
- Tianeptine: A review of its use in depressive disorders.CNS Drugs. 2001; 15: 231-259
- Acute selective serotonin reuptake inhibitors increase conditioned fear expression: Blockade with a 5-HT(2C) receptor antagonist.Biol Psychiatry. 2007; 62: 1111-1118
- Memory consolidation for contextual and auditory fear conditioning is dependent on protein synthesis, PKA, and MAP kinase.Learn Mem. 1999; 6: 97-110
- Behavioral measurement of conditioned fear.in: Brush F.R. Black A.H. Aversive Conditioning and Learning. Academic Press, New York1971: 105-179
- Switching on and off fear by distinct neuronal circuits.Nature. 2008; 454: 600-606
- Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala.J Neurosci. 1992; 12: 854-863
- Amygdalar NMDA receptors are critical for new fear learning in previously fear-conditioned rats.J Neurosci. 1998; 18: 8444-8454
- The similarities and diversities of signal pathways leading to consolidation of conditioning and consolidation of extinction of fear memory.J Neurosci. 2003; 23: 8310-8317
- The basolateral amygdala is critical for the acquisition and extinction of associations between a neutral stimulus and a learned danger signal but not between two neutral stimuli.J Neurosci. 2010; 30: 12608-12618
- Cloned glutamate receptors.Annu Rev Neurosci. 1994; 17: 31-108
- Molecular diversity of glutamate receptors and implications for brain function.Science. 1992; 258: 597-603
- Developmental and regional expression in the rat-brain and functional-properties of 4 NMDA receptors.Neuron. 1994; 12: 529-540
- Role of distinct NMDA receptor subtypes at central synapses.Sci STKE. 2004; re16: 2004
- Impairment of conditioned freezing to tone, but not to context, in Fyn-transgenic mice: Relationship to NMDA receptor subunit 2B function.Eur J Neurosci. 2005; 21: 1359-1369
- Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity.Science. 2004; 304: 1021-1024
- Overexpression of motor protein KIF17 enhances spatial and working memory in transgenic mice.Proc Natl Acad Sci U S A. 2002; 99: 14500-14505
- Two forms of synaptic plasticity with distinct dependence on age, experience, and NMDA receptor subtype in rat visual cortex.J Neurosci. 2003; 23: 6557-6566
- Roles of NMDA NR2B subtype receptor in prefrontal long-term potentiation and contextual fear memory.Neuron. 2005; 47: 859-872
- NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII.Neuron. 2005; 48: 289-301
- Chronic treatment with fluoxetine prevents the return of extinguished auditory-cued conditioned fear.Psychopharmacology (Berl). 2011; 215: 231-237
- Synapse regression in depression: The role of 5-HT receptors in modulating NMDA receptor function and synaptic plasticity.Aust N Z J Psychiatry. 2010; 44: 301-308
- Serotonin 5-HT1A receptors regulate NMDA receptor channels through a microtubule-dependent mechanism.J Neurosci. 2005; 25: 5488-5501
- Chronic administration of imipramine and citalopram alters the expression of NMDA receptor subunit mRNAs in mouse brain. A quantitative in situ hybridization study.J Mol Neurosci. 1998; 10: 219-233
- Adaptive-changes in the N-methyl-D-aspartate receptor complex after chronic treatment with imipramine and 1-aminocyclopropanecarboxylic acid.J Pharmacol Exp Ther. 1993; 265: 1380-1386
- Adaptation of the N-methyl-D-aspartate receptor complex following chronic antidepressant treatments.J Pharmacol Exp Ther. 1994; 269: 95-102
- Antidepressant effects of ketamine in depressed patients.Biol Psychiatry. 2000; 47: 351-354
- An open-label trial of riluzole in patients with treatment-resistant major depression.Am J Psychiatry. 2004; 161: 171-174
- A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.Arch Gen Psychiatry. 2006; 63: 856-864
- Anxiolytic- and antidepressant-like properties of ketamine in behavioral and neurophysiological animal models.Neuroscience. 2009; 161: 359-369
- Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure.Biol Psychiatry. 2011; 69: 754-761
- Open-label trial of riluzole in generalized anxiety disorder.Am J Psychiatry. 2005; 162: 2379-2381
- Cellular mechanisms underlying the antidepressant effects of ketamine: Role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors.Biol Psychiatry. 2008; 63: 349-352
- An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder.J Clin Psychopharmacol. 2008; 28: 631-637
- Involvement of striatal and extrastriatal DARPP-32 in biochemical and behavioral effects of fluoxetine (Prozac).Proc Natl Acad Sci U S A. 2002; 99: 3182-3187
- New perspectives in glutamate and anxiety.Pharmacol Biochem Behav. 2012; 100: 752-774
- Towards a glutamate hypothesis of depression: An emerging frontier of neuropsychopharmacology for mood disorders.Neuropharmacology. 2012; 62: 63-77
- Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: Implications for the pharmacotherapy of depression.Pharmacopsychiatry. 1996; 29: 23-26
- Effects of D-cycloserine on extinction: Consequences of prior exposure to imipramine.Biol Psychiatry. 2007; 62: 1195-1197
- Fear erasure in mice requires synergy between antidepressant drugs and extinction training.Science. 2011; 334: 1731-1734
- Effects of amygdala, hippocampus, and periaqueductal gray lesions on short- and long-term contextual fear.Behav Neurosci. 1993; 107: 1093-1098
- The lateral amygdaloid nucleus: Sensory interface of the amygdala in fear conditioning.J Neurosci. 1990; 10: 1062-1069
- Neurotoxic basolateral amygdala lesions impair learning and memory but not the performance of conditional fear in rats.J Neurosci. 1999; 19: 8696-8703
- Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala.Nature. 1990; 345: 716-718
- Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning.Behav Neurosci. 1992; 106: 274-285
- Is the forced swimming test a suitable model for revealing antidepressant activity?.Psychopharmacology (Berl). 1988; 94: 147-160
- A behavioural and biochemical study in mice and rats of putative selective agonists and antagonists for 5-HT1 and 5-HT2 receptors.Br J Pharmacol. 1985; 84: 743-753
- MDMA-induced neurotoxicity: Parameters of degeneration and recovery of brain serotonin neurons.Pharmacol Biochem Behav. 1988; 29: 269-274
- Corticosterone response to the plus-maze: High correlation with risk assessment in rats and mice.Physiol Behav. 1999; 68: 47-53
- Differences in the central nervous system distribution and pharmacology of the mouse 5-hydroxytryptamine-6 receptor compared with rat and human receptors investigated by radioligand binding, site-directed mutagenesis, and molecular modeling.Mol Pharmacol. 2003; 64: 1295-1308
- Postnatal ontogeny of expression of the corticosteroid receptor genes in mammalian brains: Inter-species and intra-species differences.Brain Res Rev. 2008; 57: 596-605
- Expression of estrogen receptors (alpha, beta) and androgen receptor in serotonin neurons of the rat and mouse dorsal raphe nuclei; sex and species differences.Neurosci Res. 2004; 49: 185-196
- Mouse defensive behaviors: Pharmacological and behavioral assays for anxiety and panic.Neurosci Biobehav Rev. 2001; 25: 205-218
- Laboratory routines cause animal stress.Contemp Top Lab Anim Sci. 2004; 43: 42-51
- Handling history of rats modifies behavioural effects of drugs in the elevated plus-maze test of anxiety.Eur J Pharmacol. 1993; 235: 109-112
- D-cycloserine deters reacquisition of cocaine self-administration by augmenting extinction learning.Neuropsychopharmacology. 2010; 35: 357-367
- A history of corticosterone exposure regulates fear extinction and cortical NR2B, GluR2/3, and BDNF.Neuropsychopharmacology. 2009; 34: 707-716
- Fluoxetine, comprehensive cognitive behavioral therapy, and placebo in generalized social phobia.Arch Gen Psychiatry. 2004; 61: 1005-1013
- Randomized, placebo-controlled trial of exposure and ritual prevention, clomipramine, and their combination in the treatment of obsessive-compulsive disorder.Am J Psychiatry. 2005; 162: 151-161
- Exposure therapy and sertraline in social phobia: 1-year follow-up of a randomised controlled trial.Br J Psychiatry. 2003; 182: 312-318
- Contextual control of the extinction of conditioned fear.Learn Motiv. 1979; 10: 445-466
- State-dependent fear extinction with two benzodiazepine tranquilizers.Behav Neurosci. 1990; 104: 44-55
Article info
Publication history
Published online: December 20, 2012
Accepted:
October 15,
2012
Received in revised form:
October 15,
2012
Received:
February 13,
2012
Identification
Copyright
© 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
