Abstract
Introduction
The effects of pre-conditioning administration of anxiolytic benzodiazepines on the acquisition of a conditioned taste aversion (CTA) and on the acquisition of attenuation of neophobia (AN) were investigated in C57BL/6 mice.
Materials and methods
A CTA was induced by injecting lithium chloride (LiCl; 6 mEq.kg−1) 30 min after the animal had imbibed a novel 0.5% saccharin solution. In other animals, neophobia was attenuated by a single access to the novel 0.5% saccharin solution, followed only by injection of saline.
Results and discussion
Pre-conditioning administration of chlordiazepoxide (CDZ; 6–24 mg.kg−1, i.p.) and alprazolam (0.3–1 mg.kg−1, p.o.) resulted in a CTA that did not differ initially from that observed in vehicle-treated controls, but which showed faster extinction. The acquisition of AN was impaired only after the higher doses of CDZ (12–24 mg.kg−1, i.p.) or alprazolam (1 mg.kg−1, i.p.). The results show that in this test, altered acquisition of an aversive CTA memory by anxiolytic benzodiazepines is reflected in more rapid extinction. Moreover, at low doses, these drugs showed selectivity for weakening CTA learning compared to AN learning. Evidence is discussed that selective weakening of aversive memory formation is a clinically relevant effect of anxiolytic benzodiazepines.
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References
Anglade F, Bizot JC, Dodd RH, Baudoin C, Chapouthier G (1994) Opposite effects of cholinergic agents and benzodiazepine receptor ligands in a passive avoidance task in rats. Neurosci Lett 182(2):247–250
Atack JR (2003) Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site. Curr Drug Targets CNS Neurol Disord 2(4):213–232
Baas JM, Grillon C, Bocker KB, Brack AA, Morgan CA 3rd, Kenemans JL, Verbaten MN (2002) Benzodiazepines have no effect on fear-potentiated startle in humans. Psychopharmacology (Berlin) 161(3):233–247
Barad M (2005) Fear extinction in rodents: basic insight to clinical promise. Curr Opin Neurobiol 15(6):710–715
Beck CH, Fibiger HC (1995) Conditioned fear-induced changes in behavior and in the expression of the immediate early gene c-fos: with and without diazepam pretreatment. J Neurosci 15(1 Pt 2):709–720
Berman DE, Dudai Y (2001) Memory extinction, learning anew, and learning the new: dissociations in the molecular machinery of learning in cortex. Science 291(5512):2417–2419
Bermudez-Rattoni F (2004) Molecular mechanisms of taste-recognition memory. Nat Rev Neurosci 5(3):209–217
Berridge KC, Treit D (1986) Chlordiazepoxide directly enhances positive ingestive reactions in rats. Pharmacol Biochem Behav 24(2):217–221
Boomsma DI, van Beijsterveldt CE, Hudziak JJ (2005) Genetic and environmental influences on anxious/depression during childhood: a study from The Netherlands Twin Register. Genes Brain Behav 4(8):466–481
Bourin M, Hascoet M (2003) The mouse light/dark box test. Eur J Pharmacol 463(1–3):55–65
Bouton ME (2002) Context, ambiguity, and unlearning: sources of relapse after behavioral extinction. Biol Psychiatry 52(10):976–986
Bouton ME, Kenney FA, Rosengard C (1990) State-dependent fear extinction with two benzodiazepine tranquilizers. Behav Neurosci 104(1):44–55
Broekkamp CL, Le Pichon M, Lloyd KG (1984) The comparative effects of benzodiazepines, progabide and PK 9084 on acquisition of passive avoidance in mice. Psychopharmacology (Berlin) 83(1):122–125
Bures J, Bermudez Rattoni F, Yamamoto T (1998) Conditioned taste aversion: memory of a special kind. Oxford University Press, Oxford
Buresova O, Bures J (1980) Post-ingestion interference with brain function prevents attenuation of neophobia in rats. Behav Brain Res 1(4):299–312
Burriss L, Ayers E, Powell DA (2007) Combat veterans show normal discrimination during differential trace eyeblink conditioning, but increased responsivity to the conditioned and unconditioned stimulus. J Psychiatr Res 41(9):785–794
Chapouthier G, Bondoux D, Martin B, Desforges C, Launay JM (1991) Genetic difference in sensitivity to beta-carboline: evidence for the involvement of brain benzodiazepine receptors. Brain Res 553(2):342–346
Concannon JT, Freda J (1980) Modulation of conditioned taste aversion by sodium pentobarbital. Pharmacol Biochem Behav 13(6):761–764
Cooper SJ (1989) Benzodiazepine receptor-mediated enhancement and inhibition of taste reactivity, food choice, and intake. Ann N Y Acad Sci 575:321–336 discussion 336–337
Crabbe JC, Gallaher EJ, Cross SJ, Belknap JK (1998) Genetic determinants of sensitivity to diazepam in inbred mice. Behav Neurosci 112(3):668–677
Crawley JN (1985) Exploratory behavior models of anxiety in mice. Neurosci Biobehav Rev 9(1):37–44
Crawley JN, Belknap JK, Collins A, Crabbe JC, Frankel W, Henderson N, Hitzemann RJ, Maxson SC, Miner LL, Silva AJ, Wehner JM, Wynshaw-Boris A, Paylor R (1997) Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology (Berlin) 132(2):107–124
Cryan JF, Kelly PH, Chaperon F, Gentsch C, Mombereau C, Lingenhoehl K, Froestl W, Bettler B, Kaupmann K, Spooren WP (2004) Behavioral characterization of the novel GABAB receptor-positive modulator GS39783 (N,N′-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4, 6-diamine): anxiolytic-like activity without side effects associated with baclofen or benzodiazepines. J Pharmacol Exp Ther 310(3):952–963
D′Adamo P, Wolfer DP, Kopp C, Tobler I, Toniolo D, Lipp HP (2004) Mice deficient for the synaptic vesicle protein Rab3a show impaired spatial reversal learning and increased explorative activity but none of the behavioral changes shown by mice deficient for the Rab3a regulator Gdi1. Eur J Neurosci 19(7):1895–1905
Davidson JR (2004) Use of benzodiazepines in social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. J Clin Psychiatry 65(Suppl 5):29–33
Davis M (1990) Animal models of anxiety based on classical conditioning: the conditioned emotional response (CER) and the fear-potentiated startle effect. Pharmacol Ther 47(2):147–165
Davis M (2002) Role of NMDA receptors and MAP kinase in the amygdala in extinction of fear: clinical implications for exposure therapy. Eur J Neurosci 16(3):395–398
de Jongh R, Groenink L, van Der Gugten J, Olivier B (2002) The light-enhanced startle paradigm as a putative animal model for anxiety: effects of chlordiazepoxide, flesinoxan and fluvoxamine. Psychopharmacology (Berlin) 159(2):176–180
Delgado MR, Olsson A, Phelps EA (2006) Extending animal models of fear conditioning to humans. Biol Psychol 73(1):39–48
Dickinson-Anson H, McGaugh JL (1993) Midazolam administered into the amygdala impairs retention of an inhibitory avoidance task. Behav Neural Biol 60(1):84–87
Domjan M, Gillan D (1976) Role of novelty in the aversion for increasingly concentrated saccharin solutions. Physiol Behav 16(5):537–542
Fanselow MS, Helmstetter FJ (1988) Conditional analgesia, defensive freezing, and benzodiazepines. Behav Neurosci 102(2):233–243
Gafford GM, Parsons RG, Helmstetter FJ (2005) Effects of post-training hippocampal injections of midazolam on fear conditioning. Learn Mem 12(6):573–578
Gelpin E, Bonne O, Peri T, Brandes D, Shalev AY (1996) Treatment of recent trauma survivors with benzodiazepines: a prospective study. J Clin Psychiatry 57(9):390–394
Griebel G, Belzung C, Perrault G, Sanger DJ (2000) Differences in anxiety-related behaviours and in sensitivity to diazepam in inbred and outbred strains of mice. Psychopharmacology (Berlin) 148(2):164–170
Grillon C, Baas JM, Pine DS, Lissek S, Lawley M, Ellis V, Levine J (2006) The benzodiazepine alprazolam dissociates contextual fear from cued fear in humans as assessed by fear-potentiated startle. Biol Psychiatry 60(7):760–766
Gutierrez R, Rodriguez-Ortiz CJ, De La Cruz V, Nunez-Jaramillo L, Bermudez-Rattoni F (2003) Cholinergic dependence of taste memory formation: evidence of two distinct processes. Neurobiol Learn Mem 80(3):323–331
Hode Y, Ratomponirina C, Gobaille S, Maitre M, Kopp C, Misslin R (2000) Hypoexpression of benzodiazepine receptors in the amygdala of neophobic BALB/c mice compared to C57BL/6 mice. Pharmacol Biochem Behav 65(1):35–8
Hogg S (1996) A review of the validity and variability of the elevated plus-maze as an animal model of anxiety. Pharmacol Biochem Behav 54(1):21–30
Iwamoto Y, Morinobu S, Takahashi T, Yamawaki S (2007) Single prolonged stress increases contextual freezing and the expression of glycine transporter 1 and vesicle-associated membrane protein 2 mRNA in the hippocampus of rats. Prog Neuropsychopharmacol Biol Psychiatry 31(3):642–651
Jensen RA, Martinez JL Jr, Vasquez BJ, McGaugh JL (1979) Benzodiazepines alter acquisition and retention of an inhibitory avoidance response in mice. Psychopharmacology (Berlin) 64(1):125–126
Kelly P, Callaerts-Vegh Z, Hoyer D (2005) Contrasting actions of chlordiazepoxide and scopolamine on conditioned taste aversion: implication for anxiolytic action. Prog. No. 416.10. Society of Neuroscience, Washington
Lissek S, Powers AS, McClure EB, Phelps EA, Woldehawariat G, Grillon C, Pine DS (2005) Classical fear conditioning in the anxiety disorders: a meta-analysis. Behav Res Ther 43(11):1391–1424
Mathiasen L, Mirza NR (2005) A comparison of chlordiazepoxide, bretazenil, L838, 417 and zolpidem in a validated mouse Vogel conflict test. Psychopharmacology (Berlin) 182(4):475–484
Mellman TA, Bustamante V, David D, Fins AI (2002) Hypnotic medication in the aftermath of trauma. J Clin Psychiatry 63(12):1183–1184
Merikangas KR, Low NC (2005) Genetic epidemiology of anxiety disorders. Handb Exp Pharmacol 169:163–179
Myers KM, Davis M (2002) Behavioral and neural analysis of extinction. Neuron 36(4):567–584
Nagatani T, Yamamoto T (1991) Antagonism by propyl-beta-carboline-3-carboxylate of passive avoidance impairment induced by diazepam. Eur J Pharmacol 198(1):109–112
Oishi H, Iwahara S, Yang KM, Yogi A (1972) Effects of chlordiazepoxide on passive avoidance responses in rats. Psychopharmacologia 23(4):375–385
Patel JB, Ciofalo VB, Iorio LC (1979) Benzodiazepine blockade of passive-avoidance task in mice: a state-dependent phenomenon. Psychopharmacology (Berlin) 61(1):25–28
Phelps EA, Delgado MR, Nearing KI, LeDoux JE (2004) Extinction learning in humans: role of the amygdala and vmPFC. Neuron 43(6):897–905
Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463(1-3):3–33
Ramirez-Lugo L, Zavala-Vega S, Bermudez-Rattoni F (2006) NMDA and muscarinic receptors of the nucleus accumbens have differential effects on taste memory formation. Learn Mem 13(1):45–51
Rau V, DeCola JP, Fanselow MS (2005) Stress-induced enhancement of fear learning: an animal model of posttraumatic stress disorder. Neurosci Biobehav Rev 29(8):1207–1223
Reilly S, Bornovalova MA (2005) Conditioned taste aversion and amygdala lesions in the rat: a critical review. Neurosci Biobehav Rev 29(7):1067–1088
Rescorla RA (1996) Preservation of pavlovian associations through extinction. The Q J Exp Psychol 49:245
Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, Hodges L, Davis M (2004) Cognitive enhancers as adjuncts to psychotherapy: use of d-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry 61(11):1136–1144
Rickels K, Downing R, Schweizer E, Hassman H (1993) Antidepressants for the treatment of generalized anxiety disorder. A placebo-controlled comparison of imipramine, trazodone, and diazepam. Arch Gen Psychiatry 50(11):884–895
Ripoll N, Nic Dhonnchadha BA, Sebille V, Bourin M, Hascoet M (2005) The four-plates test–retest paradigm to discriminate anxiolytic effects. Psychopharmacology (Berlin) 180(1):73–83
Robertson HA (1979) Benzodiazepine receptors in “emotional” and “non-emotional” mice; comparison of four strains. Eur J Pharmacol 56(1–2):163–166
Sanger DJ, Joly D (1985) Anxiolytic drugs and the acquisition of conditioned fear in mice. Psychopharmacology (Berlin) 85(3):284–288
Scaife JC, Langley RW, Bradshaw CM, Szabadi E (2005) Diazepam suppresses the acquisition but not the expression of ‘fear-potentiation’ of the acoustic startle response in man. J Psychopharmacol 19(4):347–356
Scaife JC, Hou RH, Samuels ER, Baqui F, Langley RW, Bradshaw CM, Szabadi E (2007) Diazepam-induced disruption of classically-conditioned fear-potentiation of late-latency auditory evoked potentials is prevented by flumazenil given before, but not after, CS/US pairing. J Psychopharmacol 21(1):93–101
Siegmund A, Wotjak CT (2006) Toward an animal model of posttraumatic stress disorder. Ann N Y Acad Sci 1071:324–334
Sotres-Bayon F, Cain CK, LeDoux JE (2006) Brain mechanisms of fear extinction: historical perspectives on the contribution of prefrontal cortex. Biol Psychiatry 60(4):329–336
Stanhope KJ, Dourish CT (1996) Effects of 5-HT1A receptor agonists, partial agonists and a silent antagonist on the performance of the conditioned emotional response test in the rat. Psychopharmacology (Berlin) 128(3):293–303
Stein L, Berger BD (1969) Paradoxical fear-increasing effects of tranquilizers: evidence of repression of memory in the rat. Science 166(902):253–256
Stone ME, Grimes BS, Katz DB (2005) Hippocampal inactivation enhances taste learning. Learn Mem 12(6):579–586
Sullivan GM, Apergis J, Bush DE, Johnson LR, Hou M, Ledoux JE (2004) Lesions in the bed nucleus of the stria terminalis disrupt corticosterone and freezing responses elicited by a contextual but not by a specific cue-conditioned fear stimulus. Neuroscience 128(1):7–14
Villarreal G, Hamilton DA, Petropoulos H, Driscoll I, Rowland LM, Griego JA, Kodituwakku PW, Hart BL, Escalona R, Brooks WM (2002) Reduced hippocampal volume and total white matter volume in posttraumatic stress disorder. Biol Psychiatry 52(2):119–125
Welzl H, D'Adamo P, Lipp HP (2001) Conditioned taste aversion as a learning and memory paradigm. Behav Brain Res 125(1–2):205–213
Wigger A, Sanchez MM, Mathys KC, Ebner K, Frank E, Liu D, Kresse A, Neumann ID, Holsboer F, Plotsky PM, Landgraf R (2004) Alterations in central neuropeptide expression, release, and receptor binding in rats bred for high anxiety: critical role of vasopressin. Neuropsychopharmacology 29(1):1–14
Wignall EL, Dickson JM, Vaughan P, Farrow TF, Wilkinson ID, Hunter MD, Woodruff PW (2004) Smaller hippocampal volume in patients with recent-onset posttraumatic stress disorder. Biol Psychiatry 56(11):832–836
Yamamoto T (2007) Brain regions responsible for the expression of conditioned taste aversion in rats. Chem Senses 32(1):105–109
Yamamoto T, Fujimoto Y (1991) Brain mechanisms of taste aversion learning in the rat. Brain Res Bull 27(3–4):403–406
Yamamoto T, Shimura T, Sako N, Yasoshima Y, Sakai N (1994) Neural substrates for conditioned taste aversion in the rat. Behav Brain Res 65(2):123–137
Acknowledgment
The authors wish to thank Eric Mueller for excellent technical assistance.
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Callaerts-Vegh, Z., Hoyer, D. & Kelly, P.H. Selective effects of benzodiazepines on the acquisition of conditioned taste aversion compared to attenuation of neophobia in C57BL/6 mice. Psychopharmacology 206, 389–401 (2009). https://doi.org/10.1007/s00213-009-1614-4
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DOI: https://doi.org/10.1007/s00213-009-1614-4