Abstract
Anxiety disorders may result from an overexpression of aversive memories. Evidence suggests that the hippocampal cholinergic system could be the point of convergence of anxiety and memory. We propose that clinically effective anxiolytics may exert their effect by interfering with this integration mechanism. To assess anxiety and aversive memory, we used the shock-probe burying test. A reduction in anxiety in this test is indicated by decreased burying, whereas impaired cognition is reflected by an increased number of probe-contacts and/or reduced retention latency. Both an aversive stimulus and the memory of that stimulus significantly increased hippocampal acetylcholine (ACh) levels (Experiment 1). In fact, the memory of the event seemed to be more important than the event itself since the aversive memory induced a greater increase in hippocampal ACh. Injections (i.p.) of fluoxetine (Prozac®) reduced burying behavior, while not affecting probe contacts or retention latency (Experiment 2). Although injections of fluoxetine did not affect basal hippocampal ACh efflux (Experiment 3), fluoxetine abolished the increase in ACh induced by the aversive stimulus and the memory of that stimulus (Experiment 4), emphasizing the significance of aversive memories in anxiety disorders. These actions may be mediated by a decrease in the event-related enhancement in cholinergic neurotransmission through M1 cholinergic receptors (Experiment 5). Therefore, anxiety disorders may stem from an unopposed formation of aversive memories and clinically effective anxiolytics hinder the association between emotional and cognitive processing. This reduces the emotional impact of aversive memories, thereby opposing consequent anxiety.
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References
Atack JR (2003). Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site. Curr Drug Target CNS Neurol Disord 2: 213–232.
Bell MA, Wolfe CD (2004). Emotion and cognition: an intricately bound developmental process. Child Dev 75: 366–370.
Bianchi L, Ballini C, Colivicchi MA, Della Corte L, Giovannini MG, Pepeu G (2003). Investigation on acetylcholine, aspartate, glutamate and GABA extracellular levels from ventral hippocampus during repeated exploratory activity in the rat. Neurochem Res 28: 565–573.
Bourin M, Hascoet M (2001). Drug mechanisms in anxiety. Curr Opin Invest Drugs 2: 259–265.
Brocco M, Dekeyne A, Veiga S, Girardon S, Millan MJ (2002). Induction of hyperlocomotion in mice exposed to a novel environment by inhibition of serotonin reuptake. A pharmacological characterization of diverse classes of antidepressant agents. Pharmacol Biochem Behav 71: 667–680.
Bymaster FP, Zhang W, Carter PA, Shaw J, Chernet E, Phebus L et al (2002). Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex. Psychopharmacology 160: 353–361.
Clark DM, McManus F (2002). Information processing in social phobia. Biol Psychiatry 51: 92–100.
Cole SO (1986). Effects of benzodiazepines on acquisition and performance: a critical assessment. Neurosci Biobehav Rev 10: 265–272.
Crestani F, Lorez M, Baer K, Essrich C, Benke D, Laurent JP et al (1999). Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nat Neurosci 2: 833–839.
Damsma G, Westerink BH, de Boer P, de Vries JB, Horn AS (1988). Basal acetylcholine release in freely moving rats detected by on-line trans-striatal dialysis: pharmacological aspects. Life Sci 43: 1161–1168.
Dazzi L, Motzo C, Imperato A, Serra M, Gessa GL, Biggio G (1995a). Modulation of basal and stress-induced release of acetylcholine and dopamine in rat brain by abecarnil and imidazenil, two anxioselective gamma-aminobutyric acidA receptor modulators. J Pharmacol Exp Ther 273: 241–247.
Dazzi L, Motzo C, Maira G, Sanna A, Serra M, Biggio G (1995b). Enhancement of acetylcholine release by flumazenil in the hippocampus of rats chronically treated with diazepam but not with imidazenil or abecarnil. Psychopharmacology 121: 180–185.
De Boer SF, Slangen JL, Van der Gugten J (1990). Plasma catecholamine and corticosterone levels during active and passive shock probe avoidance in rats: effects of chlordiazepoxide. Pharmacol Biochem Behav 47: 1089–1098.
Decker MW, Curzon P, Brioni JD, Americ SP (1994). Effects of ABT-418, a novel cholinergic channel ligand, on place learning in septal-lesioned rats. Eur J Pharmacol 261: 217–222.
Degroot A, Kashluba S, Treit D (2001). Septal GABAergic and hippocampal cholinergic systems modulate anxiety in the plus-maze and shock-probe tests. Pharmacol Biochem Behav 69: 391–399.
Degroot A, Treit D (2002). Dorsal and ventral hippocampal cholinergic systems modulate anxiety in the plus-maze and shock-probe tests. Brain Res 949: 60–70.
Degroot A, Treit D (2003). Septal GABAergic and hippocampal cholinergic systems interact in the modulation of anxiety. Neuroscience 117: 493–501.
Degroot A, Treit D (2004). Anxiety is functionally segregated within the septo-hippocampal system. Brain Res 1001: 60–71.
Degroot A, Wade M, Davis R, Salhoff C, Nomikos GG (2004). Chlordiazepoxide, but not buspirone blocks the increase in hippocampal cholinergic levels induced by exposure to an elevated platform. Eur J Pharmacol 493: 103–109.
Douglas CL, Baghdoyan HA, Lydic R (2001). M2 muscarinic autoreceptors modulate acetylcholine release in the prefrontal cortex of C57BL/6J mouse. J Pharmacol Exp Ther 299: 960–966.
Egawa T, Mishima K, Egashira N, Fukuzawa M, Abe K, Yae T et al (2002). Impairment of spatial memory in kaolin-induced hydrocephalic rats is associated with changes in the hippocampal cholinergic and noradrenergic contents. Behav Brain Res 129: 31–39.
Fadda F, Cocco S, Stancampiano R (2000). Hippocampal acetylcholine release correlates with spatial learning performance in freely moving rats. Neuroreport 11: 2265–2269.
Fanselow MS (2000). Contextual fear, gestalt memories, and the hippocampus. Behav Brain Res 110: 73–81.
File SE, Gonzalez LE, Andrews N (1998). Endogenous acetylcholine in the dorsal hippocampus reduces anxiety through actions on nicotinic and muscarinic1 receptors. Behav Neourosci 112: 352–359.
Frye CA, Seliga AM (2003). Olanzapine's effects to reduce fear and anxiety and enhance social interactions coincide with increased progestin concentrations of ovariectomized rats. Psychoneuroendocrinology 28: 657–673.
Giovannini MG, Rakovska A, Benton RS, Pazzagli M, Bianchi L, Pepeu G (2001). Effects of novelty and habituation on acetylcholine, GABA, and glutamate release from the frontal cortex and hippocampus of freely moving rats. Neuroscience 106: 43–53.
Hashimoto S, Inoue T, Koyama T (1996). Serotonin reuptake inhibitors reduce conditioned fear stress-induced freezing behavior in rats. Psychopharmacology 123: 182–186.
Imperato A, Dazzi L, Obinu MC, Gessa GL, Biggio G (1994). The benzodiazepine receptor antagonist flumazenil increases acetylcholine release in rat hippocampus. Brain Res 647: 167–171.
Ishigooka J (2003). Benzodiazepine-induced amnesia. Ryoikibetsu Shokogun Shirizu 38: 617–620.
Kawasaki K, Eigyo M, Ikeda M, Kihara T, Koike K, Matsushita A et al (1996). A novel benzodiazepine inverse agonist, S-8510, as a cognitive enhancer. Prog Neuropsychopharmacol Biol Psychiatry 20: 1413–1425.
Kopf SR, Buchholzer ML, Hilgert M, Loffelholz K, Klein J (2001). Glucose plus choline improve passive avoidance behaviour and increase hippocampal acetylcholine release in mice. Neuroscience 103: 365–371.
Lehmann H, Treit D, Parent MB (2000). Amygdala lesions do not impair shock-probe avoidance retention performance. Behav Neurosci 114: 107–116.
Mishima K, Iwasaki K, Tsukikawa H, Matsumoto Y, Egashira N (2000). The scopolamine-induced impairment of spatial cognition parallel acetylcholine release in the ventral hippocampus in rats. Jpn J Pharmacol 84: 163–173.
Monleon S, Urquiza A, Carmen Arenas M, Vinader-Caerols C, Parra A (2002). Chronic administration of fluoxetine impairs inhibitory avoidance in male but not female mice. Behav Brain Res 136: 483–488.
Muraki I (2001). Behavioral and neurochemical study on the mechanism of the anxiolytic effect of a selective serotonin reuptake inhibitor, a selective serotonin1A agonist and lithium carbonate. Hokkaido Igaku Zasshi 76: 57–70.
Olariu A, Tran MH, Yamada K, Mizuno M, Hefco V, Nabeshima T (2001). Memory deficits and increased emotionality induced by beta-amyloid (25–35) are correlated with the reduced acetylcholine release and altered phorbol dibutyrate binding in the hippocampus. J Neural Transm 108: 1065–1079.
Pain L, Launoy A, Fouquet N, Oberling P (2002). Mechanisms of action of midazolam on expression of contextual fear in rats. Br J Anaesth 89: 614–621.
Pare WP (1996). Enhanced retrieval of unpleasant memories influenced by shock controllability, shock sequence, and rat strain. Biol Psychiatry 39: 808–813.
Pesold C, Treit D (1992). Excitotoxic lesions of the septum produce anxiolytic effects in the elevated plus-maze and shock-probe burying tests. Physiol Behav 52: 37–47.
Pinel JPJ, Treit D (1978). Burying as a defensive response in rats. Comp Physiol Psychol 92: 708–712.
Sanchez C, Meier E (1997). Behavioral profiles of SSRIs in animal models of depression, anxiety and aggression. Are they all alike? Psychopharmacology 129: 197–205.
Shah AA, Treit D (2003). Excitotoxic lesions of the medial prefrontal cortex attenuate fear responses in the elevated-plus maze, social interaction and shock probe burying tests. Brain Res 969: 183–194.
Sienkiewicz-Jarosz H, Czlonkowska AI, Siemiatkowski M, Maciejak P, Szyndler J, Plaznik A (2000). The effects of physostigmine and cholinergic receptor ligands on novelty-induced neophobia. J Neural Transm 107: 1403–1412.
Skelton MR, Ponniah S, Wang DZ, Doetschman T, Vorhees CV, Pallen CJ (2003). Protein tyrosine phosphatase alpha (PTP alpha) knockout mice show deficits in Morris water maze learning, decreased locomotor activity, and decreases in anxiety. Brain Res 984: 1–10.
Smythe JW, Bhatnagar S, Murphy D, Timothy C, Costall B (1998). The effects of intrahippocampal scopolamine infusions on anxiety in rats as measured by the black-white box test. Brain Res Bull 45: 89–93.
Stancampiano R, Cocco S, Cugusi C, Sarais L, Fadda F (1999). Serotonin and acetylcholine release response in the rat hippocampus during a spatial memory task. Neuroscience 89: 1135–1143.
Thiel CM, Huston JP, Schwarting RK (1998). Hippocampal acetylcholine and habituation learning. Neuroscience 85: 1253–1262.
Treit D, Menard J (1997). Dissociations among the anxiolytic effects of septal, hippocampal, and amygdaloid lesions. Behav Neurosci 111: 653–658.
Treit D, Menard J, Pesold C (1994). The shock probe burying test. Neurosci Protoc Module 3: 9–17.
Treit D, Pesold C, Rotzinger S (1993). Noninteractive effects of diazepam and amygdaloid lesions in two animal models of anxiety. Behav Neurosci 107: 1099–1105.
Treit D, Pinel JPJ, Fibiger HC (1981). Conditioned defensive burying: a new paradigm for the study of anxiolytic agents. Pharmacol Biochem Behav 15: 619–626.
Tsuda A, Yoshishige I, Tanaka M (1988). The contrasting effects of diazepam and yohimbine on conditioned defensive burying in rats. Psychobiology 16: 213–217.
Tzavara ET, Wade M, Nomikos GG (2003). Biphasic effects of cannabinoids on acetylcholine release in the hippocampus: site and mechanism of action. J Neurosci 23: 9374–9384.
Worms P, Guedet C, Perio A, Soubrie P (1989). Systemic injection of pirenzepine induces a deficit in passive avoidance learning in rats. Psychopharmacology 98: 286–288.
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Degroot, A., Nomikos, G. Fluoxetine Disrupts the Integration of Anxiety and Aversive Memories. Neuropsychopharmacol 30, 391–400 (2005). https://doi.org/10.1038/sj.npp.1300624
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DOI: https://doi.org/10.1038/sj.npp.1300624
