Abstract
Considering the complexity of aversive information processing and defensive response expression, a combined action of stress modulators may be required for an optimal performance during threatening situations. Dopamine is now recognized as one of the most active modulators underlying states of fear and anxiety. On the other hand, activation of hypothalamic–pituitary–adrenocortical (HPA) axis, which leads to the release of corticosterone in rodents, has been considered a key part of the stress response. The current study is an extension of prior work investigating modulatory effects of dopamine and corticosterone on conditioned fear expression. We have showed that corticosterone, acting through mineralocorticoid receptors in the ventral tegmental area (VTA), upregulates dopaminergic system in the basolateral amygdala (BLA), enabling the expression of conditioned freezing response. The novel question addressed here is whether VTA–BLA dopaminergic signaling is necessary for increases in corticosterone during conditioned fear expression. Using site-specific treatment with D2-like agonist quinpirole (VTA) and D2-like antagonist sulpiride (BLA), we evaluated freezing and plasma corticosterone in rats exposed to a light used as aversive conditioned stimulus (CS). Intra-VTA quinpirole and intra-BLA sulpiride significantly decreased freezing expression in the conditioned fear test, but this anxiolytic-like effect of the dopaminergic drugs was not associated with changes in plasma corticosterone concentrations. Altogether, data suggest that interferences with the ability of the CS to activate the dopaminergic VTA–BLA pathway reduce the expression of freezing, but activation of the HPA axis seems to occur upstream of the recruitment of dopaminergic mechanisms in conditioned fear states.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Barr GA, Moriceau S, Shionoya K, Muzny K, Gao P, Wang S, Sullivan RM (2009) Transitions in infant learning are modulated by dopamine in the amygdala. Nat Neurosci 12:1367–1369. doi:10.1038/nn.2403
Bolles RC, Collier AC (1976) The effect of predictive cues on freezing in rats. Anim Learn Behav 4:6–8. doi:10.3758/bf03211975
Brandão ML, de Oliveira AR, Muthuraju S, Colombo AC, Saito VM, Talbot T (2015) Dual role of dopamine D2-like receptors in the mediation of conditioned and unconditioned fear. FEBS Lett 589:3433–3437. doi:10.1016/j.febslet.2015.02.036
Butts KA, Weinberg J, Young AH, Phillips AG (2011) Glucocorticoid receptors in the prefrontal cortex regulate stress-evoked dopamine efflux and aspects of executive function. Proc Natl Acad Sci USA 108:18459–18464. doi:10.1073/pnas.1111746108
Carrive P (2000) Conditioned fear to environmental context: cardiovascular and behavioral components in the rat. Brain Res 858:440–445
Coco ML, Kuhn CM, Ely TD, Kilts CD (1992) Selective activation of mesoamygdaloid dopamine neurons by conditioned stress: attenuation by diazepam. Brain Res 590:39–47
Cordero MI, Merino JJ, Sandi C (1998) Correlational relationship between shock intensity and corticosterone secretion on the establishment and subsequent expression of contextual fear conditioning. Behav Neurosci 112:885–891
de Kloet ER, Reul JM, Sutanto W (1990) Corticosteroids and the brain. J Steroid Biochem Mol Biol 37:387–394
de la Mora MP, Gallegos-Cari A, Arizmendi-Garcia Y, Marcellino D, Fuxe K (2010) Role of dopamine receptor mechanisms in the amygdaloid modulation of fear and anxiety: structural and functional analysis. Prog Neurobiol 90:198–216. doi:10.1016/j.pneurobio.2009.10.010
de Oliveira AR, Reimer AE, Brandão ML (2006) Dopamine D2 receptor mechanisms in the expression of conditioned fear. Pharmacol Biochem Behav 84:102–111. doi:10.1016/j.pbb.2006.04.012
de Oliveira AR, Reimer AE, Brandão ML (2009) Role of dopamine receptors in the ventral tegmental area in conditioned fear. Behav Brain Res 199:271–277. doi:10.1016/j.bbr.2008.12.004
de Oliveira AR, Reimer AE, de Macedo CE, de Carvalho MC, Silva MA, Brandão ML (2011) Conditioned fear is modulated by D2 receptor pathway connecting the ventral tegmental area and basolateral amygdala. Neurobiol Learn Mem 95:37–45. doi:10.1016/j.nlm.2010.10.005
de Oliveira AR, Reimer AE, Reis FM, Brandão ML (2013) Conditioned fear response is modulated by a combined action of the hypothalamic-pituitary-adrenal axis and dopamine activity in the basolateral amygdala. Eur Neuropsychopharmacol 23:379–389. doi:10.1016/j.euroneuro.2012.05.007
de Oliveira AR, Colombo AC, Muthuraju S, Almada RC, Brandão ML (2014a) Dopamine D2-like receptors modulate unconditioned fear: role of the inferior colliculus. PLoS ONE 9:e104228. doi:10.1371/journal.pone.0104228
de Oliveira AR, Reimer AE, Brandão ML (2014b) Mineralocorticoid receptors in the ventral tegmental area regulate dopamine efflux in the basolateral amygdala during the expression of conditioned fear. Psychoneuroendocrinology 43:114–125. doi:10.1016/j.psyneuen.2014.02.010
de Souza Caetano KA, de Oliveira AR, Brandão ML (2013) Dopamine D2 receptors modulate the expression of contextual conditioned fear: role of the ventral tegmental area and the basolateral amygdala. Behav Pharmacol 24:264–274. doi:10.1097/FBP.0b013e32836356c4
Fadok JP, Dickerson TM, Palmiter RD (2009) Dopamine is necessary for cue-dependent fear conditioning. J Neurosci 29:11089–11097. doi:10.1523/JNEUROSCI.1616-09.2009
Fendt M, Fanselow MS (1999) The neuroanatomical and neurochemical basis of conditioned fear. Neurosci Biobehav Rev 23:743–760
Ikemoto S, Goeders NE (1998) Microinjections of dopamine agonists and cocaine elevate plasma corticosterone: dissociation effects among the ventral and dorsal striatum and medial prefrontal cortex. Brain Res 814:171–178
Indovina I, Robbins TW, Nunez-Elizalde AO, Dunn BD, Bishop SJ (2011) Fear-conditioning mechanisms associated with trait vulnerability to anxiety in humans. Neuron 69:563–571. doi:10.1016/j.neuron.2010.12.034
Lupien SJ, McEwen BS (1997) The acute effects of corticosteroids on cognition: integration of animal and human model studies. Brain Res Brain Res Rev 24:1–27
Martinez RC, Oliveira AR, Macedo CE, Molina VA, Brandão ML (2008) Involvement of dopaminergic mechanisms in the nucleus accumbens core and shell subregions in the expression of fear conditioning. Neurosci Lett 446:112–116. doi:10.1016/j.neulet.2008.09.057
Mason JW (1968) “Over-all” hormonal balance as a key to endocrine organization. Psychosom Med 30(Suppl):791–808
McEwen BS, Weiss JM, Schwartz LS (1969) Uptake of corticosterone by rat brain and its concentration by certain limbic structures. Brain Res 16:227–241
Nader K, LeDoux JE (1999) Inhibition of the mesoamygdala dopaminergic pathway impairs the retrieval of conditioned fear associations. Behav Neurosci 113:891–901
Ninomiya EM, Martynhak BJ, Zanoveli JM, Correia D, da Cunha C, Andreatini R (2010) Spironolactone and low-dose dexamethasone enhance extinction of contextual fear conditioning. Prog Neuropsychopharmacol Biol Psychiatry 34:1229–1235. doi:10.1016/j.pnpbp.2010.06.025
Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, Hard Cover edn. Elsevier Science, Amsterdam
Pezze MA, Feldon J (2004) Mesolimbic dopaminergic pathways in fear conditioning. Prog Neurobiol 74:301–320. doi:10.1016/j.pneurobio.2004.09.004
Phelps EA, LeDoux JE (2005) Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 48:175–187. doi:10.1016/j.neuron.2005.09.025
Reimer AE, de Oliveira AR, Brandão ML (2012) Glutamatergic mechanisms of the dorsal periaqueductal gray matter modulate the expression of conditioned freezing and fear-potentiated startle. Neuroscience 219:72–81. doi:10.1016/j.neuroscience.2012.06.005
Reis FM, Albrechet-Souza L, Franci CR, Brandão ML (2012) Risk assessment behaviors associated with corticosterone trigger the defense reaction to social isolation in rats: role of the anterior cingulate cortex. Stress 15:318–328. doi:10.3109/10253890.2011.623740
Reis FM, Almada RC, Fogaca MV, Brandão ML (2015) Rapid activation of glucocorticoid receptors in the prefrontal cortex mediates the expression of contextual conditioned fear in rats. Cereb Cortex. doi:10.1093/cercor/bhv103
Rodrigues SM, LeDoux JE, Sapolsky RM (2009) The influence of stress hormones on fear circuitry. Annu Rev Neurosci 32:289–313. doi:10.1146/annurev.neuro.051508.135620
Roozendaal B, Koolhaas JM, Bohus B (1992) Central amygdaloid involvement in neuroendocrine correlates of conditioned stress responses. J Neuroendocrinol 4:483–489. doi:10.1111/j.1365-2826.1992.tb00196.x
Sapolsky R (2009) Any kind of mother in a storm. Nat Neurosci 12:1355–1356. doi:10.1038/nn1109-1355
Verheij MM, Cools AR (2009) Accumbal noradrenaline that contributes to the alpha-adrenoceptor-mediated release of dopamine from reserpine-sensitive storage vesicles in the nucleus accumbens is derived from alpha-methyl-para-tyrosine-sensitive pools. J Neural Transm 116:389–394. doi:10.1007/s00702-009-0190-4
Zweifel LS, Fadok JP, Argilli E et al (2011) Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety. Nat Neurosci 14:620–626. doi:10.1038/nn.2808
Acknowledgments
Research was supported by FAPESP (Proc. No. 10/50669-6; Proc. No. 16/04620-1). AE Reimer holds Post-Doctoral fellowship from FAPESP (Proc. No. 13/04741-5; Proc. No. 15/20487-7).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
de Oliveira, A.R., Reimer, A.E., Reis, F.M.C.V. et al. Dopamine D2-like receptors modulate freezing response, but not the activation of HPA axis, during the expression of conditioned fear. Exp Brain Res 235, 429–436 (2017). https://doi.org/10.1007/s00221-016-4805-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00221-016-4805-3