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Accessible Unlicensed Requires Authentication Published by De Gruyter September 4, 2018

Understanding the role of dopamine in conditioned and unconditioned fear

Marcus L. Brandão and Norberto C. Coimbra


Pharmacological and molecular imaging studies in anxiety disorders have primarily focused on the serotonin system. In the meantime, dopamine has been known as the neurotransmitter of reward for 60 years, particularly for its action in the nervous terminals of the mesocorticolimbic system. Interest in the mediation by dopamine of the well-known brain aversion system has grown recently, particularly given recent evidence obtained on the role of D2 dopamine receptors in unconditioned fear. However, it has been established that excitation of the mesocorticolimbic pathway, originating from dopaminergic (DA) neurons from the ventral tegmental area (VTA), is relevant for the development of anxiety. Among the forebrain regions innervated by this pathway, the amygdala is an essential component of the neural circuitry of conditioned fear. Current findings indicate that the dopamine D2 receptor-signaling pathway connecting the VTA to the basolateral amygdala modulates fear and anxiety, whereas neural circuits in the midbrain tectum underlie the expression of innate fear. The A13 nucleus of the zona incerta is proposed as the origin of these DA neurons projecting to caudal structures of the brain aversion system. In this article we review data obtained in studies showing that DA receptor-mediated mechanisms on ascending or descending DA pathways play opposing roles in fear/anxiety processes. Dopamine appears to mediate conditioned fear by acting at rostral levels of the brain and regulate unconditioned fear at the midbrain level.


The research was supported by FAPESP (process no. 2016/04620-1, Funder Id: 10.13039/501100001807) and CNPq (process no. 02651/2014-4).

  1. Conflict of interest

  2. The authors have no conflicts of interest to declare.


Acquas, E., Carboni, E., Leone, P., and Di Chiara, G. (1989). SCH 23390 blocks drug-conditioned place-preference and place-aversion: anhedonia (lack of reward) or apathy (lack of motivation) after dopamine-receptor blockade? Psychopharmacology (Berl.) 99, 151–155.257202710.1007/BF00442800Search in Google Scholar

Aghajanian, G.K. and Bunney, B.S. (1977). Dopamine ‘autoreceptors’: pharmacological characterization by microiontophoretic single-cell recording studies. Naunyn-Schmiedeberg’s Arch. Pharmacol. 297, 1–7.10.1007/BF00508803Search in Google Scholar

Albrechet-Souza, L., Carvalho, M.C., and Brandão, M.L. (2013). D1-like receptors in the nucleus accumbens shell regulate the expression of contextual fear conditioning and activity of the anterior cingulate cortex in rats. Int. J. Neuropsychopharmacol. 16, 1045–1057.10.1017/S146114571200082X22964037Search in Google Scholar

Baldessarini, J. (1996). Drugs and the treatment of psychiatric disorders. Goodman and Gilman’s the pharmacological basis of therapeutics. J.G. Hardman, L.E. Limbird, P.B. Molinoff, R.W. Ruddon, and A.G. Gilman, eds. 9th edition. (New York: McGraw-Hill), pp. 399–430.Search in Google Scholar

Bariselli, S., Clangetas, C., Tzanoulinou, S., and Bellone, C. (2016). Ventral tegmental area subcircuits process rewarding and aversive experiences. J. Neurochem. 139, 1071–1080.2754649110.1111/jnc.13779Search in Google Scholar

Baskerville, T.A. and Douglas, A.J. (2008). Interactions between dopamine and oxytocin in the control of sexual behaviour. Prog. Brain Res. 170, 277–290.1865588910.1016/S0079-6123(08)00423-8Search in Google Scholar

Beninger, R.J., Mason, S.T., Phillips, A.G., and Fibiger, H.C. (1980). The use of conditioned suppression to evaluate the nature of neuroleptic-induced avoidance deficits. J. Pharmacol. Exp. Ther. 213, 623–627.6110768Search in Google Scholar

Biagioni, A.F., de Freitas, R.L., da Silva, J.A., de Oliveira, R.C., de Oliveira, R., Alves, V.M., and Coimbra, N.C. (2013). Serotonergic neural links from the dorsal raphe nucleus modulate defensive behaviours organised by the dorsomedial hypothalamus and the elaboration of fear-induced antinociception via locus coeruleus pathways. Neuropharmacology 67, 379–394.2320135110.1016/j.neuropharm.2012.10.024Search in Google Scholar

Bolton, A.D., Murata, Y., Kirchner, R., Kim, S.Y., Young, A., Dang, T., Yanagawa, Y., and Constantine-Paton, M. (2015). A diencephalic dopamine source provides input to the superior colliculus, where D1 and D2 receptors segregate to distinct functional zones. Cell Rep. 13, 1003–1015.10.1016/j.celrep.2015.09.04626565913Search in Google Scholar

Brandão, M.L., Anseloni, V.Z., Pandossio, J.E., De Araujo, J.E., and Castilho, V.M. (1999). Neurochemical mechanisms of the defensive behavior in the dorsal midbrain. Neurosci. Biobehav. Rev. 23, 863–875.1054106110.1016/S0149-7634(99)00038-XSearch in Google Scholar

Brandão, M.L., Troncoso, A.C., de Souza Silva, M.A., and Huston, J.P. (2003). The relevance of neuronal substrates of defense in the midbrain tectum to anxiety and stress: empirical and conceptual considerations. Eur. J. Pharmacol. 463, 225–233.10.1016/S0014-2999(03)01284-612600713Search in Google Scholar

Brandão, M.L., Borelli, K.G., Nobre, M.J., Santos, J.M., Albrechet-Souza, L., Oliveira, A.R., and Martinez, R.C. (2005). Gabaergic regulation of the neural organization of fear in the midbrain tectum. Neurosci. Biobehav. Rev. 29, 1299–1311.1608458910.1016/j.neubiorev.2005.04.013Search in Google Scholar

Brandão, M.L., de Oliveira, A.R., Muthuraju, S., Colombo, A.C., Saito, V.M., and Talbot, T. (2015). Dual role of dopamine D2-like receptors in the mediation of conditioned and unconditioned fear. FEBS Lett. 589, 3433–3437.10.1016/j.febslet.2015.02.036Search in Google Scholar

Brischoux, F., Chakraborty, S., Brierley, D.I., and Ungless, M.A. (2009). Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli. Proc. Natl. Acad. Sci. USA 106, 4894–4899.10.1073/pnas.0811507106Search in Google Scholar

Broiz, A.C., Bassi, G.S., de Souza Silva, M.A., and Brandão, M.L. (2012). Effects of neurokinin-1 and 3-receptor antagonists on the defensive behavior induced by electrical stimulation of the dorsal periaqueductal gray. Neuroscience 201, 134–145.2212316810.1016/j.neuroscience.2011.11.031Search in Google Scholar

Burgdorf, J. and Panksepp, J. (2006). The neurobiology of positive emotions. Neurosci. Biobehav. Rev. 30, 173–187.10.1016/j.neubiorev.2005.06.00116099508Search in Google Scholar

Carvalho, J.D.M., de Oliveira, A.R., da Silva, R.C.B., and Brandão, M.L. (2009). A comparative study on the effects of the benzodiazepine midazolam and the dopamine agents, apomorphine and sulpiride, on rat behavior in the two-way avoidance test. Pharmacol. Biochem. Behav. 92, 351–356.10.1016/j.pbb.2009.01.00119353757Search in Google Scholar

Charney, D.S. and Deutch, A. (1996). A functional neuroanatomy of anxiety and fear: implications for the pathophysiology and treatment of anxiety disorders. Crit. Rev. Neurobiol. 10, 419–446.10.1615/CritRevNeurobiol.v10.i3-4.708978989Search in Google Scholar

Coimbra, N.C., Calvo, F., Almada, R.C., Freitas, R.L., Paschoalin-Maurin, T., Dos Anjos-Garcia, T., Elias-Filho, D.H., Ubiali, W.A., Lobão-Soares, B., and Tracey, I. (2017). Opioid neurotransmission modulates defensive behavior and fear-induced antinociception in dangerous environments. Neuroscience 354, 178–195.10.1016/j.neuroscience.2017.04.03228457818Search in Google Scholar

Cuadra, G., Zurita, A., Lacerra, C., and Molina, V. (1999). Chronic stress sensitizes frontal cortex dopamine release in response to a subsequent novel stressor: reversal by naloxone. Brain Res. Bull. 48, 303–308.10.1016/S0361-9230(98)00179-810229338Search in Google Scholar

Da Silva, J.A., Biagioni, A.F., Almada, R.C., de Freitas, R.L., and Coimbra, N.C. (2017). Panicolytic-like effects caused by substantia nigra pars reticulata pretreatment with low doses of endomorphin-1 and high doses of CTOP or the NOP receptors antagonist JTC-801 in male Rattus norvegicus. Psychopharmacology 234, 3009–3025.2885640610.1007/s00213-017-4678-6Search in Google Scholar

Datla, K.P., Ahier, R.G., Young, A.M., Gray, J.A., and Joseph, M.H. (2002). Conditioned appetitive stimulus increases extracellular dopamine in the nucleus accumbens of the rat. Eur. J. Neurosci. 16, 1987–1993.1245306210.1046/j.1460-9568.2002.02249.xSearch in Google Scholar

Davis, M. (1992). The role of the amygdala in fear-potentiated startle: implications for animal models of anxiety. Trends Pharmacol. Sci. 13, 35–41.10.1016/0165-6147(92)90014-W1542936Search in Google Scholar

Davis, M. and Whalen, P.J. (2001). The amygdala: vigilance and emotion. Mol. Psychiatr. 6, 13–34.10.1038/ in Google Scholar

Davis, M., Rainnie, D., and Cassell, M. (1994). Neurotransmission in the rat amygdala related to fear and anxiety. Trends Neurosci. 17, 208–214.10.1016/0166-2236(94)90106-67520203Search in Google Scholar

De la Mora, M.P., Gallegos-Cari, A., Crespo-Ramirez, M., Marcellino, D., Hansson, A.C., and Fuxe, K. (2012). Distribution of dopamine D2 receptors in the rat amygdala and their role in the modulation of unconditioned fear and anxiety. Neuroscience 201, 252–266.10.1016/j.neuroscience.2011.10.04522100273Search in Google Scholar

De la Mora, M.P., Pérez-Carrera, D., Crespo-Ramírez, M., Tarakanov, A., Fuxe, K., and Borroto-Escuela, D.O. (2016). Signaling in dopamine D2 receptor-oxytocin receptor heterocomplexes and its relevance for the anxiolytic effects of dopamine and oxytocin interactions in the amygdala of the rat. Biochem. Biophys. Acta 1862, 2075–2085.Search in Google Scholar

De Oliveira, A.R., Reimer, A.E., and Brandão, M.L. (2006). Dopamine D2 receptor mechanisms in the expression of conditioned fear. Pharmacol. Biochem. Behav. 84, 102–111.10.1016/j.pbb.2006.04.01216780936Search in Google Scholar

De Oliveira, A.R., Reimer, A.E., and Brandão, M.L. (2009). Role of dopamine receptors in the ventral tegmental area in conditioned fear. Behav. Brain Res. 199, 271–277.10.1016/j.bbr.2008.12.00419111792Search in Google Scholar

De Oliveira, A.R., Reimer, A.E., de Macedo, C.E.A., de Carvalho, M.C., Silva, M.A.D.S., and Brandão, M.L. (2011). Conditioned fear is modulated by D2 receptor pathway connecting the ventral tegmental area and basolateral amygdala. Neurobiol. Learn. Mem. 95, 37–45.10.1016/j.nlm.2010.10.00520955808Search in Google Scholar

De Oliveira, A.R., Reimer, A.E., Reis, F.M., and Brandão, M.L. (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, 379–389.2268277710.1016/j.euroneuro.2012.05.007Search in Google Scholar

De Oliveira, A.R., Colombo, A.C., Muthuraju, S., Almada, R.C., and Brandão, M.L. (2014). Dopamine D2-like receptors modulate unconditioned fear: role of the inferior colliculus. PLoS One 9, e104228.10.1371/journal.pone.010422825133693Search in Google Scholar

De Souza Caetano, K.A., De Oliveira, A.R., and Brandão, M.L. (2013). Dopamine D2 receptors modulate the expression of contextual conditioned fear: role of the ventral tegmental area and the basolateral amygdala. Behav. Pharmacol. 24, 264–274.2375151910.1097/FBP.0b013e32836356c4Search in Google Scholar

Deutch, A.Y., Tam, S.Y., and Roth, R.H. (1985). Footshock and conditioned stress increase 3,4-dihydroxyphenylacetic acid (DOPAC) in the ventral tegmental area but not substantia nigra. Brain Res. 333, 143–146.10.1016/0006-8993(85)90134-93995282Search in Google Scholar

Di Scala, G. and Sandner, G. (1989). Conditioned place aversion produced by FG 7142 is attenuated by haloperidol. Psychopharmacology (Berl.) 99, 176–80.10.1007/BF004428042508151Search in Google Scholar

Dos Anjos-Garcia, T., Ullah, F., Falconi-Sobrinho, L.L., and Coimbra, N.C. (2017). CB1 cannabinoid receptor-mediated anandamide signalling reduces the defensive behaviour evoked through GABAA receptor blockade in the dorsomedial division of the ventromedial hypothalamus. Neuropharmacology 113, 156–166.2706291310.1016/j.neuropharm.2016.04.003Search in Google Scholar

Essig, J. and Felsen, G. (2016). Warning! Dopaminergic modulation of the superior colliculus. Trends Neurosci. 39, 2–4.2671785210.1016/j.tins.2015.12.002Search in Google Scholar

Evans, S., Shergill, S.S., and Averbeck, B.B. (2010). Oxytocin decreases aversion to angry faces in an associative learning task. Neuropsychopharmacology 35, 2502–2509.10.1038/npp.2010.110Search in Google Scholar

Falconi-Sobrinho, L.L., dos Anjos-Garcia, T.D., de Oliveira, R., and Coimbra, N.C. (2017). Decrease in NMDA receptor-signalling activity in the anterior cingulate cortex diminishes defensive behaviour and unconditioned fear-induced antinociception elicited by GABAergic tonic inhibition impairment in the posterior hypothalamus. Eur. Neuropsychopharmacology 27, 1120–1131.10.1016/j.euroneuro.2017.09.002Search in Google Scholar

Feenstra, M.G.P. and Botterblom, M.H. (1996). Rapid sampling of extracellular dopamine in the rat prefrontal cortex during food consumption, handling and exposure to novelty. Brain Res. 742, 17–24.911739110.1016/S0006-8993(96)00945-6Search in Google Scholar

Feenstra, M.G.P., Botterblom, M.H.A., and Van Uum, J.F.M. (1995). Novelty-induced increase in dopamine release in the rat prefrontal cortex in vivo: inhibition by diazepam. Neurosci. Lett. 189, 81–84.10.1016/0304-3940(95)11456-77609924Search in Google Scholar

Floresco, S.B., Yang, C.R., Phillips, A.G., and Blaha, C.D. (1998). Basolateral amygdala stimulation evokes glutamate receptor-dependent dopamine efflux in the nucleus accumbens of the anaesthetized rat. Eur. J. Neurosci. 10, 1241–1251.974977810.1046/j.1460-9568.1998.00133.xSearch in Google Scholar

Galloway, M.P., Wolff, M.E., and Roth, R.H. (1986). Regulation of dopamine synthesis in the medial prefrontal cortex is mediated by release modulating autoreceptors: studies in vivo. J. Pharmacol. Exp. Ther. 236, 689–698.3081705Search in Google Scholar

Garcia, A.M., Martinez, R., Brandão, M.L., and Morato, S. (2005). Effects of apomorphine on rat behavior in the elevated plus-maze. Physiol. Behav. 85, 440–447.1600210310.1016/j.physbeh.2005.04.027Search in Google Scholar

Goldstein, M., Harada, K., Meller, E., Schalling, M., and Hokfelt, T. (1990). Dopamine autoreceptors: biochemical, pharmacological, and morphological studies. Ann. N. Y. Acad. Sci. 604, 169–175.197734610.1111/j.1749-6632.1990.tb31991.xSearch in Google Scholar

Goldstein, L.E., Rasmusson, A.M., Bunney, B.S., and Roth, R.H. (1996). Role of the amygdala in the coordination of behavioral, neuroendocrine, and prefrontal cortical monoamine responses to psychological stress in the rat. J. Neurosci. 16, 4787–4798.876466510.1523/JNEUROSCI.16-15-04787.1996Search in Google Scholar

Graeff, F.G., Guimarães, F.S., De Andrade, T.G., and Deakin, J.F. (1996). Role of 5-HT in stress, anxiety, and depression. Pharmacol. Biochem. Behav. 54, 129–141.872855010.1016/0091-3057(95)02135-3Search in Google Scholar

Greba, Q., Gifkins, A., and Kokkinidis, L. (2001). Inhibition of amygdaloid dopamine D2 receptors impairs emotional learning measured with fear-potentiated startle. Brain Res. 899, 218–226.10.1016/S0006-8993(01)02243-011311883Search in Google Scholar

Guarraci, F.A. and Kapp, B.S. (1999). An electrophysiological characterization of ventral tegmental area dopaminergic neurons during differential Pavlovian fear conditioning in the awake rabbit. Behav. Brain Res. 99, 169–179.10.1016/S0166-4328(98)00102-810512583Search in Google Scholar

Guarraci, F.A., Frohardt, R.J., Falls, W.A., and Kapp, B.S. (2000). The effects of intra-amygdaloid infusions of a D2 dopamine receptor antagonist on Pavlovian fear conditioning. Behav. Neurosci. 114, 647–651.10.1037/0735-7044.114.3.64710883814Search in Google Scholar

Gurevich, E.V. and Joyce, J.N. (1999). Distribution of dopamine D3 receptor expressing neurons in the human forebrain: comparison with D2 receptor-expressing neurons. Neuropsychopharmacology 20, 60–80.10.1016/S0893-133X(98)00066-99885786Search in Google Scholar

Hurd, Y.L., Suzuki, M., and Sedvall, G.C. (2001). D1 and D2 dopamine receptor mRNA expression in whole hemisphere sections of the human brain. J. Chem. Neuroanat. 22, 127–137.10.1016/S0891-0618(01)00122-311470560Search in Google Scholar

Ikemoto, S. and Panksepp, J. (1999). The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking. Brain Res. Rev. 31, 6–41.10.1016/S0165-0173(99)00023-5Search in Google Scholar

Inoue, T., Tsuchiya, K., and Koyama, T. (1996). Effects of typical and atypical antipsychotic drugs on freezing behavior induced by conditioned far. Pharmacol. Biochem. Behav. 55, 195–201.10.1016/S0091-3057(96)00064-0Search in Google Scholar

Jackson, M.E. and Moghaddam, B. (2001). Amygdala regulation of nucleus accumbens dopamine output is governed by the prefrontal cortex. J. Neurosci. 21, 676–681.1116044610.1523/JNEUROSCI.21-02-00676.2001Search in Google Scholar

Kebabian, J.W. and Calne, D.B. (1979). Multiple receptors for dopamine. Nature 277, 93–96.10.1038/277093a0215920Search in Google Scholar

Knobloch, H.S. and Grinevich, V. (2014). Evolution of oxytocin pathways in the brain of vertebrates. Front. Behav. Neurosci. 8, 31.24592219Search in Google Scholar

Kroner, S., Rosenkranz, J.A., Grace, A.A., and Barrionuevo, G. (2005). Dopamine modulates excitability of basolateral amygdala neurons in vitro. J. Neurophysiol. 93, 1598–1610.10.1152/jn.00843.200415537813Search in Google Scholar

Labuschagne, I., Phan, K.L., Wood, A., Angstadt, M., Chua, P., Heinrichs, M., Stout, J.C., and Nathan, P.J. (2010). Oxytocin attenuates amygdala reactivity to fear in generalized social anxiety disorder. Neuropsychopharmacology 35, 2403–2413.10.1038/npp.2010.12320720535Search in Google Scholar

Lammel, S., Ion, D.I., Roeper, J., and Malenka, R.C. (2011). Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli. Neuron 70, 855–862.2165858010.1016/j.neuron.2011.03.025Search in Google Scholar

Lancaster, K., Carter, C.S., Pournajafi-Nazarloo, H., Karaoli, T., Lillard, T.S., Jack, A., Davis, J.M., Morris, J.P., and Connelly, J.J. (2015). Plasma oxytocin explains individual differences in neural substrates of social perception. Front. Hum. Neurosci. 9, 132.25852519Search in Google Scholar

LeDoux, J. (1994). The amygdala: contributions to fear and stress. Semin. Neurosci. 6, 231–237.10.1006/smns.1994.1030Search in Google Scholar

Louilot, A. and Besson, C. (2000). Specificity of amygdalostriatal interactions in the involvement of mesencecephalic dopaminergic neurons in affective perception. Neurosci. 96, 73–82.10.1016/S0306-4522(99)00530-8Search in Google Scholar

Love, T.M. (2014). Oxytocin, motivation and the role of dopamine. Pharmacol. Biochem. Behav. 119, 49–60.2385052510.1016/j.pbb.2013.06.011Search in Google Scholar

Macedo, C.E., Castilho, V.M., De Souza Silva, M.A., and Brandão, M.L. (2002). Dual 5-HT mechanisms in basolateral and central nuclei of the amygdala in the regulation of the defensive behavior induced by electrical stimulation of the inferior colliculus. Brain Res. Bull. 59, 189–195.1243174810.1016/S0361-9230(02)00862-6Search in Google Scholar

Macedo, C.E., Cuadra, G., Molina, V., and Brandão, M.L. (2005a). Aversive stimulation of the inferior colliculus changes dopamine and serotonin extracellular levels in the frontal cortex: modulation by the basolateral nucleus of the amygdala. Synapse 55, 58–66.10.1002/syn.20094Search in Google Scholar

Macedo, C.E., Martinez, R.C.R., de Souza Silva, M.A., and Brandão, M.L. (2005b). Increases in extracellular levels of 5-HT and dopamine in the basolateral, but not in the central, nucleus of amygdala induced by aversive stimulation of the inferior colliculus. Eur. J. Neurosci. 21, 1131–1138.10.1111/j.1460-9568.2005.03939.xSearch in Google Scholar

Macedo, C.E., Ruiz-Martinez, R.C., Albrechet-Souza, L., Molina, V.A., and Brandão, M.L. (2007). 5-HT2- and D1-mechanisms of the basolateral nucleus of the amygdala enhance conditioned fear and impair unconditioned fear. Behav. Brain Res. 177, 100–108.10.1016/j.bbr.2006.10.03117126419Search in Google Scholar

Maia, T.V. (2010). Two-factor theory, the actor-critic model, and conditioned avoidance. Learn. Behav. 38, 50–67.2006534910.3758/LB.38.1.50Search in Google Scholar

Martinez, R.C.R., Oliveira, A.R., Macedo, C.E., Molina, V.A., and Brandão, M.L. (2008). Involvement of dopaminergic mechanisms in the nucleus accumbens core and shell subregions in the expression of fear conditioning. Neurosci. Lett. 446, 112–116.1883532610.1016/j.neulet.2008.09.057Search in Google Scholar

McNaughton, N. and Corr, P.J. (2004). A two-dimensional neuropsychology of defense: fear/anxiety and defensive distance. Neurosci. Biobehav. Rev. 28, 285–305.10.1016/j.neubiorev.2004.03.00515225972Search in Google Scholar

Meador-Woodruff, J.H., Mansour, A., Civelli, O., and Watson, S.J. (1991a). Distribution of D2 dopamine receptor mRNA in the primate brain. Prog. Neuropsychopharmacol. Biol. Psychiatr. 15, 885–893.10.1016/0278-5846(91)90016-TSearch in Google Scholar

Meador-Woodruff, J.H., Mansour, A., Healy, D.J., Kuehn, R., Zhou, Q.Y., Bunzow, J.R., Akil, H., Civelli, O., and Watson Jr, S.J. (1991b). Comparison of the distributions of D1 and D2 dopamine receptor mRNAs in rat brain. Neuropsychopharmacology 5, 231–242.Search in Google Scholar

Messanvi, F., Eggens-Meijer, E., Roozendaal, B., and van der Want, J.J. (2013). A discrete dopaminergic projection from the incertohypothalamic A13 cell group to the dorsolateral periaqueductal gray in rat. Front. Neuroanat. 7, 1–14.Search in Google Scholar

Millan, M.J. (2003). The neurobiology and control of anxious states. Prog. Neurobiol. 70, 83–244.10.1016/S0301-0082(03)00087-X12927745Search in Google Scholar

Missale, C., Nash, S.R., Robinson, S.W., Jaber, M., and Caron, M.C. (1998). Dopamine receptors: from structure to function. Physiol. Rev. 78, 189–225.10.1152/physrev.1998.78.1.1899457173Search in Google Scholar

Moutoussis, M., Bentall, R.P., Williams, J., and Dayan, P. (2008). A temporal difference account of avoidance learning. Netw. Comput. Neural Syst. 19, 137–160.10.1080/09548980802192784Search in Google Scholar

Muthuraju, S., Nobre, M.J., Saito, V.M.N., and Brandão, M.L. (2014). Distinct effects of haloperidol in the mediation of conditioned fear in the mesolimbic system and processing of unconditioned aversive information in the inferior colliculus. Neurosci. 261, 195–206.10.1016/j.neuroscience.2013.11.063Search in Google Scholar

Muthuraju, S., Talbot, T., and Brandão, M.L. (2016). Dopamine D2 receptors regulate unconditioned fear in deep layers of the superior colliculus and dorsal periaqueductal gray. Behav. Brain Res. 297, 116–123.10.1016/j.bbr.2015.10.00526455877Search in Google Scholar

Nader, K. and LeDoux, J.E. (1999). Inhibition of the mesoamygdala dopaminergic pathway impairs the retrieval of conditioned fear associations. Behav. Neurosci. 113, 891–901.10.1037/0735-7044.113.5.89110571473Search in Google Scholar

Navratilova, E., Xie, J.Y., Okun, A., Qu, C., Eyde, N., Ci, S., Ossipov, M.H., King, T., Field, H.L., and Porreca, F. (2012). Pain relief produces negative reinforcement through activation of mesolimbic reward-valuation circuitry. Proc. Natl. Acad. Sci. USA 109, 20709–20713.10.1073/pnas.1214605109Search in Google Scholar

Olds, J. and Milner, P. (1954). Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J. Comp. Physiol. Psychol. 47, 419–427.10.1037/h005877513233369Search in Google Scholar

Paschoalin-Maurin, T., dos Anjos-Garcia, T., Falconi-Sobrinho, L.L., de Freitas, R.L., Coimbra, J.P.C., Laure, C.J., and Coimbra, N.C. (2018). The rodent-versus-wild snake paradigm as a model for studying anxiety- and panic-like behaviors: face, construct and predictive validities. Neuroscience 369, 336–349.2918382910.1016/j.neuroscience.2017.11.031Search in Google Scholar

Peris, J., MacFadyen, K., Smith, J.A., de Kloet, A., Wang, L., and Krause, E.G. (2017). Oxytocin receptors are expressed on dopamine and glutamate neurons in the mouse ventral tegmental area that project to nucleus accumbens and other mesolimbic targets. J. Comp. Neurol. 525, 1094–1108.10.1002/cne.2411627615433Search in Google Scholar

Pezze, M.A. and Feldon, J. (2004). Mesolimbic dopaminergic pathways in fear conditioning. Prog. Neurobiol. 74, 301–320.10.1016/j.pneurobio.2004.09.00415582224Search in Google Scholar

Pezze, M.A., Bast, T., and Feldon, J. (2003). Significance of dopamine transmission in the rat medial prefrontal cortex for conditioned fear. Cereb. Cortex 13, 371–380.1263156610.1093/cercor/13.4.371Search in Google Scholar

Pezze, M.A., Marshall, H.J., Domonkos, A., and Cassaday, H.J. (2016). Effects of dopamine D1 modulation of the anterior cingulate cortex in a fear conditioning procedure. Prog. Neuropsychopharmacol. Biol. Psychiatr. 65, 60–67.10.1016/j.pnpbp.2015.08.015Search in Google Scholar

Plaven-Sigray, P., Hedman, E., Victorsson, P., Matheson, G.J., Forsberg, A., Diurfeldt, D.R., Ruck, C., Halldin, C., Lindefors, N., and Cervenka, S. (2017). Extrastriatal dopamine D2-receptor availability in social anxiety disorder. Eur. Neuropsychopharmacol. 27, 462–469.2837707510.1016/j.euroneuro.2017.03.007Search in Google Scholar

Posluns, D. (1962). An analysis of chlorpromazine-induced suppression of the avoidance response. Psychopharmacologia 3, 361–373.10.1007/BF0040832113985655Search in Google Scholar

Reis, F.L., Masson, S., de Oliveira, A.R., and Brandão, M.L. (2004). Dopaminergic mechanisms in the conditioned and unconditioned fear as assessed by the two-way avoidance and light switch-off tests. Pharmacol. Biochem. Behav. 79, 359–365.1550131310.1016/j.pbb.2004.08.006Search in Google Scholar

Root, D.H., Mejias-Aponte, C.A., Qi, J., and Morales, M. (2014). Role of glutamatergic projections from ventral tegmental area to lateral habenula in aversive conditioning. J. Neurosci. 34, 13906–13910.10.1523/JNEUROSCI.2029-14.201425319687Search in Google Scholar

Rosenkranz, J.A. and Grace, A.A. (2002). Cellular mechanisms of infralimbic and prelimbic prefrontal cortical inhibition and dopaminergic modulation of basolateral amygdala neurons in vivo. J. Neurosci. 22, 324–337.10.1523/JNEUROSCI.22-01-00324.200211756516Search in Google Scholar

Salamone, J.D. (1994). The involvement of nucleus accumbens dopamine in appetitive and aversive motivation. Behav. Brain. Res. 61, 117–133.10.1016/0166-4328(94)90153-88037860Search in Google Scholar

Sapolsky, R. (1999). Any kind of mother in a storm. Nat. Neurosci. 12, 1355–1356.Search in Google Scholar

Sarnyai, Z. and Kovacs, G.L. (2014). Oxytocin in learning and addiction: from early discoveries to the present. Pharmacol. Biochem. Behav. 119, 3–9.10.1016/j.pbb.2013.11.01924280016Search in Google Scholar

Sauer, C., Montag, C., Reuter, M., and Kirsch, P. (2013). Imaging oxytocin×dopamine interactions: an epistasis effect of CD38 and COMT gene variants influences the impact of oxytocin on amygdala activation to social stimuli. Front Neurosci. 7, 45.23554586Search in Google Scholar

Seeman, P. and Van Tol, H.H.M. (1994). Dopamine receptor pharmacology. Trends Pharmacol. Sci. 15, 264–270.10.1016/0165-6147(94)90323-97940991Search in Google Scholar

Skuse, D.H. and Gallagher, L. (2009). Dopaminergic-neuropeptide interactions in the social brain. Trends Cogn. Sci. 13, 27–35.10.1016/j.tics.2008.09.00719084465Search in Google Scholar

Sokoloff, P. and Schwartz, J.C. (1995). Novel dopamine receptors half a decade later. Trends Pharmacol. Sci. 16, 270–275.10.1016/S0165-6147(00)89044-67482988Search in Google Scholar

Stuber, G.D., Hnasko, T.S., Britt, J.P., Edwards, R.H., and Bonci, A. (2010). Dopaminergic terminals in the nucleus accumbens but not the dorsal striatum corelease glutamate. J. Neurosci. 30, 8229–8233.10.1523/JNEUROSCI.1754-10.201020554874Search in Google Scholar

Stuber, G.D., Stamatakis, A.M., and Kantak, P.A. (2015). Considerations when using cre-driver rodent lines for studying ventral tegmental area circuitry. Neuron 85, 439–445.10.1016/j.neuron.2014.12.03425611514Search in Google Scholar

Swanson, L.W. (1982). The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res. Bull. 9, 321–353.681639010.1016/0361-9230(82)90145-9Search in Google Scholar

Timothy, C., Costall, B., and Smythe, J.W. (1999). Effects of SCH 23390 and raclopride on anxiety-like behavior in rats tested in the black-white box. Pharmacol. Biochem. Behav. 62, 323–327.10.1016/S0091-3057(98)00157-9Search in Google Scholar

Troncoso, A.C., Osaki, M.Y., Mason, S., Borelli, K.G., and Brandão, M.L. (2003). Apomorphine enhances conditioned responses induced by aversive stimulation of the inferior colliculus. Neuropsychopharmacology 28, 284–291.10.1038/sj.npp.130003412589381Search in Google Scholar

Uribe-Mariño, A., Francisco, A., Castiblanco-Urbina, M.A., Twardowschy, A., Salgado-Rohner, C.J., Crippa, J.A.S., Hallak, J.E.C., Zuardi, A.W., and Coimbra, N.C. (2012). Anti-aversive effects of cannabidiol on innate fear-induced behaviors evoked by an ethological model of panic attacks based on a prey vs the wild snake Epicrates cenchria crassus confrontation paradigm. Neuropsychopharmacology 37, 412–421.10.1038/npp.2011.18821918503Search in Google Scholar

Vallone, D., Picetti, R., and Borrelli, E. (2000). Structure and function of dopamine receptors. Neurosci. Biobehav. Rev. 2, 125–132.Search in Google Scholar

Wadenberg, M.L.G. and Hicks, P.B. (1999). The conditioned avoidance response test re-evaluated: is it a sensitive test for the detection of potentially atypical antipsychotics? Neurosci. Biobehav. Rev. 23, 851–862.10.1016/S0149-7634(99)00037-8Search in Google Scholar

Wagner, C.K., Eaton, M.J., Moore, K.E., and Lookingland, K.J. (1995). Efferent projections from the region of the medial zona incerta containing A13 dopaminergic neurons: a PHA-L anterograde tract-tracing study in the rat. Brain Res. 677, 229–237.10.1016/0006-8993(95)00128-D7552247Search in Google Scholar

Wietzikoski, E.C., Boschen, S.L., Miyoshi, E., Bortolanza, M., dos Santos, L.M., Frnk, M., Brandão, M.L., Winn, P., and Da Cunha, C. (2012). Roles of D1-like dopamine receptors in the nucleus accumbens and dorsolateral striatum in conditioned avoidance responses. Psychopharmacology 219, 159–169.2172075310.1007/s00213-011-2384-3Search in Google Scholar

Wright, C.I., Beijer, A.V.J., and Groenewegen, H.J. (1996). Basal amygdaloid complex afferents to the rat nucleus accumbens are compartmentally organized. J. Neurosci. 16, 1877–1893.877445610.1523/JNEUROSCI.16-05-01877.1996Search in Google Scholar

Young, A.M., Joseph, M.H., and Gray, J.A. (1993). Latent inhibition of conditioned dopamine release in rat nucleus accumbens. Neuroscience 54, 5–9.851584610.1016/0306-4522(93)90378-SSearch in Google Scholar

Young, A.M., Ahier, R.G., Upton, R.L., Joseph, M.H., and Gray, J.A. (1998). Increased extracellular dopamine in the nucleus accumbens of the rat during associative learning of neutral stimuli. Neuroscience 83, 1175–1183.10.1016/S0306-4522(97)00483-19502256Search in Google Scholar

Zarrindast, M.R. and Khakpai, F. (2015). The modulatory role of dopamine in anxiety-like behavior. Arch. Iran Med. 18, 591–603.26317601Search in Google Scholar

Received: 2018-03-16
Accepted: 2018-06-10
Published Online: 2018-09-04
Published in Print: 2019-04-24

©2019 Walter de Gruyter GmbH, Berlin/Boston