Skip to main content

Advertisement

SpringerLink
Log in

Medial prefrontal cortex Transient Receptor Potential Vanilloid Type 1 (TRPV1) in the expression of contextual fear conditioning in Wistar rats

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Contextual fear is evoked by re-exposing an animal to an environment that has been previously paired with an aversive or unpleasant stimulus. It can be assessed by freezing and cardiovascular changes such as increase in mean arterial pressure and heart rate. A marked increase in neuronal activity is associated with contextual fear conditioning, especially in limbic structures involved with defense reactions, such as the ventral portion of medial prefrontal cortex.

Objective

Given the fact that transient receptor potential vanilloid type 1 (TRPV1) receptors could be involved in the expression of defensive behavior, the present work tested the hypothesis that TRPV1 manipulation in the ventromedial prefrontal cortex (vMPFC) modulates the expression of contextual conditioned fear.

Methods

Male Wistar rats received bilateral microinjections into the vMPFC of the TRPV1 receptor antagonists capsazepine (1, 10, and 60 nmol/200 nL) or 6-iodonordihydrocapsaicin (3 nmol/200 nL), and the TRPV1 agonist capsaicin (1 nmol/200 nL) preceded by vehicle or 6-iodonordihydrocapsaicin before re-exposure to the experimental chamber for 10 min, 48 h after conditioning in two different protocols distinct by their aversiveness.

Results

Both antagonists reduced the freezing and cardiovascular responses in the high aversive protocol. Capsaicin caused an increase in fear-associated responses that could be blocked by 6-iodonordihydrocapsaicin.

Conclusions

Our results indicate that TRPV1 receptors located in the vMPFC have a tonic involvement in the modulation of the expression of contextual fear conditioning.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Aguiar DC, Terzian AL, Guimaraes FS, Moreira FA (2009) Anxiolytic-like effects induced by blockade of transient receptor potential vanilloid type 1 (TRPV1) channels in the medial prefrontal cortex of rats. Psychopharmacology (Berl) 205:217–225

    Article  CAS  Google Scholar 

  • Appendino G, Harrison S, De Petrocellis L, Daddario N, Bianchi F, Schiano Moriello A, Trevisani M, Benvenuti F, Geppetti P, Di Marzo V (2003) Halogenation of a capsaicin analogue leads to novel vanilloid TRPV1 receptor antagonists. Br J Pharmacol 139:1417–1424

    Article  CAS  PubMed  Google Scholar 

  • Baldi E, Lorenzini CA, Bucherelli C (2004) Footshock intensity and generalization in contextual and auditory-cued fear conditioning in the rat. Neurobiol Learn Mem 81:162–166

    Article  PubMed  Google Scholar 

  • 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 15:709–720

    CAS  PubMed  Google Scholar 

  • Blanchard RJ, Blanchard DC (1969) Passive and active reactions to fear-eliciting stimuli. J Comp Physiol Psychol 68:129–135

    Article  CAS  PubMed  Google Scholar 

  • Casarotto PC, Terzian AL, Aguiar DC, Zangrossi H, Guimaraes FS, Wotjak CT, Moreira FA (2011) Opposing roles for cannabinoid receptor type-1 (CB) and transient receptor potential vanilloid type-1 channel (TRPV1) on the modulation of panic-like responses in rats. Neuropsychopharmacology 37:478–486

    Article  PubMed  Google Scholar 

  • Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heatactivated ion channel in the pain pathway. Nature 389:816–824

    Article  CAS  PubMed  Google Scholar 

  • Corcoran KA, Quirk GJ (2007) Activity in prelimbic cortex is necessary for the expression of learned, but not innate, fears. J Neurosci 27(4):840–844

    Article  CAS  PubMed  Google Scholar 

  • Di Marzo V (2010) Anandamide serves two masters in the brain. Nat Neurosci 13:1446–1448

    Article  PubMed  Google Scholar 

  • Di Marzo V, Bisogno T, De Petrocellis L (2001) Anandamide: some like it hot. Trends Pharmacol Sci 22:346–349

    Article  PubMed  Google Scholar 

  • de Novellis V, Vita D, Gatta L, Luongo L, Bellini G, De Chiaro M, Marabese I, Siniscalco D, Boccella S, Piscitelli F, Di Marzo V, Palazzo E, Rossi F, Maione S (2011) The blockade of the transient receptor potential vanilloid type 1 and fatty acid amide hydrolase decreases symptoms and central sequelae in the medial prefrontal cortex of neuropathic rats. Mol Pain 7:7

    Article  PubMed Central  PubMed  Google Scholar 

  • Docherty RJ, Yeats JC, Piper AS (1997) Capsazepine block of voltage-activated calcium channels in adult rat dorsal root ganglion neurones in culture. Br J Pharmacol 121:1461–1467

    Article  CAS  PubMed  Google Scholar 

  • Fanselow MS (1980) Conditioned and unconditional components of post-shock freezing. Pavlov J Biol Sci 15:177–182

    CAS  PubMed  Google Scholar 

  • Ferreira-Junior NC, Fedoce AG, Alves FH, Corrêa FM, Resstel LB (2012) Medial prefrontal cortex endocannabinoid system modulates baroreflex activity through CB(1) receptors. Am J Physiol Regul Integr Comp Physiol 302(7):R876–R885

    Article  CAS  PubMed  Google Scholar 

  • Fogaça MV, Aguiar DC, Moreira FA, Guimarães FS (2012) The endocannabinoid and endovanilloid systems interact in the rat prelimbic medial prefrontal cortex to control anxiety-like behavior. Neuropharmacology 63(2):202–210

    Article  PubMed  Google Scholar 

  • Frysztak RJ, Neafsey EJ (1991) The effect of medial frontal cortex lesions on respiration, “freezing,” and ultrasonic vocalizations during conditioned emotional responses in rats. Cereb Cortex 1:418–425

    Article  CAS  PubMed  Google Scholar 

  • Frysztak RJ, Neafsey EJ (1994) The effect of medial frontal cortex lesions on cardiovascular conditioned emotional responses in the rat. Brain Res 643:181–193

    Article  CAS  PubMed  Google Scholar 

  • Giordano C, Cristino L, Luongo L, Siniscalco D, Petrosino S, Piscitelli F, Marabese I, Gatta L, Rossi F, Imperatore R, Palazzo E, de Novellis V, Di Marzo V, Maione S (2012) TRPV1-dependent and -independent alterations in the limbic cortex of neuropathic mice: impact on glial caspases and pain perception. Cereb Cortex 22(11):2495–2518

    Article  PubMed  Google Scholar 

  • Jaskiw GE, Weinberger DR (1990) Ibotenic acid lesions of the medial prefrontal cortex potentiate FG-7142-induced attenuation of exploratory activity in the rat. Pharmacol Biochem Behav 36:695–697

    Google Scholar 

  • Jinks AL, McGregor IS (1997) Modulation of anxiety-related behaviours following lesions of the prelimbic or infralimbic cortex in the rat. Brain Res 772(1–2):181–190

    Article  CAS  PubMed  Google Scholar 

  • Karlsson U, Sundgren-Andersson AK, Johansson S, Krupp JJ (2005) Capsaicin augments synaptic transmission in the rat medial preoptic nucleus. Brain Res 1043:1–11

    Article  CAS  PubMed  Google Scholar 

  • Kasckow JW, Mulchahey JJ, Geracioti TD Jr (2004) Effects of the vanilloid agonist olvanil and antagonist capsazepine on rat behaviors. Prog Neuropsychopharmacol Biol Psychiatry 28:291–295

    Article  CAS  PubMed  Google Scholar 

  • Kawahara H, Drew GM, Christie MJ, Vaughan CW (2011) Inhibition of fatty acid amide hydrolase unmasks CB1 receptor and TRPV1 channel-mediated modulation of glutamatergic synaptic transmission in midbrain periaqueductal grey. Br J Pharmacol 163:1214–1222

    Article  CAS  PubMed  Google Scholar 

  • Ledoux JE, Iwata J, Cicchetti P, Reis DJ (1988) Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J Neurosci 8:2517–2529

    CAS  PubMed  Google Scholar 

  • Lisboa SF, Reis DG, Da Silva AL, Correa FM, Guimaraes FS, Resstel LB (2010) Cannabinoid CB1 receptors in the medial prefrontal cortex modulate the expression of contextual fear conditioning. Int J Neuropsychopharmacol 13:1163–1173

    Article  CAS  PubMed  Google Scholar 

  • Marsch R, Foeller E, Rammes G, Bunck M, Kossl M, Holsboer F, Zieglgansberger W, Landgraf R, Lutz B, Wotjak CT (2007) Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice. J Neurosci 27:832–839

    Article  CAS  PubMed  Google Scholar 

  • Mezey E, Toth ZE, Cortright DN, Arzubi MK, Krause JE, Elde R, Guo A, Blumberg PM, Szallasi A (2000) Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human. Proc Natl Acad Sci USA 97:3655–3660

    Article  CAS  PubMed  Google Scholar 

  • Moreira FA, Aguiar DC, Terzian AL, Guimaraes FS, Wotjak CT (2011) Cannabinoid type 1 receptors and transient receptor potential vanilloid type 1 channels in fear and anxiety-two sides of one coin? Neuroscience 204:186–192

    Article  PubMed  Google Scholar 

  • Owens NC, Verberne AJ (2001) Regional haemodynamic responses to activation of the medial prefrontal cortex depressor region. Brain Res 919:221–231

    Google Scholar 

  • Pamplona FA, Prediger RD, Pandolfo P, Takahashi RN (2006) The cannabinoid receptor agonist WIN 55,212-2 facilitates the extinction of contextual fear memory and spatial memory in rats. Psychopharmacology (Berl) 188(4):641–649

    Article  CAS  Google Scholar 

  • Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates. Academic Press, New York

    Google Scholar 

  • Quigley KS, Sarter MF, Hart SL, Berntson GG (1994) Cardiovascular effects of the benzodiazepine receptor partial inverse agonist FG 7142 in rats. Behav Brain Res 62(1):11–20

    Article  CAS  PubMed  Google Scholar 

  • Radley JJ, Gosselink KL, Sawchenko PE (2009) A discrete GABAergic relay mediates medial prefrontal cortical inhibition of the neuroendocrine stress response. J Neurosci 29:7330–7340

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Resstel LB, Alves FH, Reis DG, Crestani CC, Correa FM, Guimaraes FS (2008a) Anxiolytic-like effects induced by acute reversible inactivation of the bed nucleus of stria terminalis. Neuroscience 154:869–876

    Article  CAS  PubMed  Google Scholar 

  • Resstel LB, Corrêa FM (2005) Pressor and tachycardic responses evoked by microinjections of L-glutamate into the medial prefrontal cortex of unanaesthetized rats. Eur J Neurosci 21:2513–2520

    Google Scholar 

  • Resstel LB, Correa FM (2006) Involvement of the medial prefrontal cortex in central cardiovascular modulation in the rat. Auton Neurosci 126–127:130–138

    Article  PubMed  Google Scholar 

  • Resstel LB, Correa FM, Guimaraes FS (2008b) The expression of contextual fear conditioning involves activation of an NMDA receptor-nitric oxide pathway in the medial prefrontal cortex. Cereb Cortex 18:2027–2035

    Article  PubMed  Google Scholar 

  • Resstel LB, Joca SR, Correa FM, Guimaraes FS (2008c) Effects of reversible inactivation of the dorsal hippocampus on the behavioral and cardiovascular responses to an aversive conditioned context. Behav Pharmacol 19:137–144

    Article  PubMed  Google Scholar 

  • Resstel LB, Joca SR, Moreira FA, Correa FM, Guimaraes FS (2006) Effects of cannabidiol and diazepam on behavioral and cardiovascular responses induced by contextual conditioned fear in rats. Behav Brain Res 172:294–298

    Article  PubMed  Google Scholar 

  • Roberts JC, Davis JB, Benham CD (2004) [3H]Resiniferatoxin autoradiography in the CNS of wild-type and TRPV1 null mice defines TRPV1 (VR-1) protein distribution. Brain Res 995:176–183

    Article  CAS  PubMed  Google Scholar 

  • Rubino T, Realini N, Castiglioni C, Guidali C, Vigano D, Marras E, Petrosino S, Perletti G, Maccarrone M, Di Marzo V, Parolaro D (2008) Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex. Cereb Cortex 18:1292–1301

    Article  CAS  PubMed  Google Scholar 

  • Sanchez JF, Krause JE, Cortright DN (2001) The distribution and regulation of vanilloid receptor VR1 and VR1 5' splice variant RNA expression in rat. Neuroscience 107:373–381

    Article  CAS  PubMed  Google Scholar 

  • Schulkin J, Morgan MA, Rosen JB (2005) A neuroendocrine mechanism for sustaining fear. Trends Neurosci 28:629–635

    Article  CAS  PubMed  Google Scholar 

  • Sierra-Mercado D Jr, Corcoran KA, Lebron-Milad K, Quirk GJ (2006) Inactivation of the ventromedial prefrontal cortex reduces expression of conditioned fear and impairs subsequent recall of extinction. Eur J Neurosci 24:1751–1758

    Article  PubMed  Google Scholar 

  • Sierra-Mercado D, Padilla-Coreano N, Quirk GJ (2011) Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear. Neuropsychopharmacology 36:529–538

    Article  PubMed  Google Scholar 

  • Sikand P, Premkumar LS (2007) Potentiation of glutamatergic synaptic transmission by protein kinace C-mediated sensitization of TRPV1 at the first sensory synapse. J Physiol 581:631–647

    Article  PubMed  Google Scholar 

  • Starowicz K, Nigam S, Di Marzo V (2007) Biochemistry and pharmacology of endovanilloids. Pharmacol Ther 114:13–33

    Article  CAS  PubMed  Google Scholar 

  • Szallasi A, Blumberg PM (1999) Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol Rev 51:159–212

    CAS  PubMed  Google Scholar 

  • Szallasi A, Di Marzo V (2000) New perspectives on enigmatic vanilloid receptors. Trends Neurosci 23:491–497

    Article  CAS  PubMed  Google Scholar 

  • Tavares RF, Correa FM, Resstel LB (2009) Opposite role of infralimbic and prelimbic cortex in the tachycardiac response evoked by acute restraint stress in rats. J Neurosci Res 87(11):2601–2607

    Article  CAS  PubMed  Google Scholar 

  • Terzian AL, Aguiar DC, Guimaraes FS, Moreira FA (2009) Modulation of anxiety-like behaviour by Transient Receptor Potential Vanilloid Type 1 (TRPV1) channels located in the dorsolateral periaqueductal gray. Eur Neuropsychopharmacol 19:188–195

    Article  CAS  PubMed  Google Scholar 

  • Toth A, Boczan J, Kedei N, Lizanecz E, Bagi Z, Papp Z, Edes I, Csiba L, Blumberg PM (2005) Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain. Brain Res Mol Brain Res 135:162–168

    Article  CAS  PubMed  Google Scholar 

  • Verberne AJ, Owens NC (1998) Cortical modulation of the cardiovascular system. Prog Neurobiol 54:149–168

    Article  CAS  PubMed  Google Scholar 

  • Vidal-Gonzalez I, Vidal-Gonzalez B, Rauch SL, Quirk GJ (2006) Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fear. Learn Mem 13(6):728–733

    Article  PubMed  Google Scholar 

  • Xing J, Li J (2007) TRPV1 receptor mediates glutamatergic synaptic input to dorsolateral periaqueductal gray (dl-PAG) neurons. J Neurophysiol 97:503–511

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to thank I.A.C. Fortunato and J.C. Aguiar for the technical help. A.L. Terzian is supported by the CNPq scholarship (process 290008/2009-3). This research was supported by grants from FAPESP (2011/07332-3), CNPq, and FAEPA.

Conflict of interest

The authors declare no conflicts of interests.

Author information

Authors and Affiliations

  1. Max-Planck Institute of Psychiatry, Munich, Germany

    Ana Luisa B. Terzian

  2. Graduate School of Systemic Neuroscience, Ludwig-Maximilian Universität, Munich, Germany

    Ana Luisa B. Terzian

  3. Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, 14049-900, Ribeirão Preto, São Paulo, Brazil

    Daniel Gustavo dos Reis, Francisco S. Guimarães, Fernando M. A. Corrêa & Leonardo B. M. Resstel

  4. Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Av. Bandeirantes 3900, 14049-900, Ribeirão Preto, São Paulo, Brazil

    Francisco S. Guimarães & Leonardo B. M. Resstel

Authors
  1. Ana Luisa B. Terzian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Gustavo dos Reis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francisco S. Guimarães
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fernando M. A. Corrêa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Leonardo B. M. Resstel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leonardo B. M. Resstel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Terzian, A.L.B., dos Reis, D.G., Guimarães, F.S. et al. Medial prefrontal cortex Transient Receptor Potential Vanilloid Type 1 (TRPV1) in the expression of contextual fear conditioning in Wistar rats. Psychopharmacology 231, 149–157 (2014). https://doi.org/10.1007/s00213-013-3211-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-013-3211-9

Keywords

Search

Navigation