Abstract
The present study investigated the role of dopamine D2 receptors (D2Rs) of the dorsal hippocampus (DH) and the nucleus accumbens (NAc) and the effect of their dopaminergic activities on anxiety-like behavior and aversive learning using a test-retest elevated plus-maze (EPM) paradigm in male Wistar rats. Guide cannulae were implanted to allow microinjection of D2R agonist quinpirole or antagonist sulpiride. The pre-test intra-NAc microinjection of quinpirole (0.0625–0.25 μg/rat) or sulpiride (0.125–0.5 μg/rat) increased the percentage of time spent in the open arms (%OAT) of EPM, suggesting an anxiolytic-like effect. However, an increase in open-arm avoidance was observed in the control rats when retested in the EPM, suggesting aversive information storage. Furthermore, a similar result was obtained in the quinpirole-treated rats. In contrast, the sulpiride-treated rats failed to demonstrate further open-arm avoidance, thus proposing an aversive learning deficit. The intra-DH microinjection of drugs alone induced an anxiolytic-like effect and learning deficit. The quinpirole (0.125 μg/rat) injected into each site had no effect on the response induced by sulpiride injected into another site. Finally, a subthreshold dose of quinpirole in both sites did not alter the %OAT; on the contrary, it preserved the aversive memory. The sulpiride induced an anxiolytic-like effect and a learning deficit. Our data suggests that the involvement of D2Rs in the interactions of DH-NAc dopaminergic system helps regulate anxiety-related behavior and EPM-associative memory.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ahmadi H, Nasehi M, Rostami P, Zarrindast MR (2013) Involvement of the nucleus accumbens shell dopaminergic system in prelimbic NMDA-induced anxiolytic-like behaviors. Neuropharmacology 71:112–123. https://doi.org/10.1016/j.neuropharm.2013.03.017
Alcaro A, Huber R, Panksepp J (2007) Behavioral functions of the mesolimbic dopaminergic system: an affective neuroethological perspective. Brain Res Rev 56:283–321. https://doi.org/10.1016/j.brainresrev.2007.07.014
Bertoglio LJ, Carobrez AP (2000) Previous maze experience required to increase open arms avoidance in rats submitted to the elevated plus-maze model of anxiety. Behav Brain Res 108:197–203
Bertoglio LJ, Joca SR, Guimaraes FS (2006) Further evidence that anxiety and memory are regionally dissociated within the hippocampus. Behav Brain Res 175:183–188. https://doi.org/10.1016/j.bbr.2006.08.021
Brandao ML, Anseloni VZ, Pandossio JE et al (1999) Neurochemical mechanisms of the defensive behavior in the dorsal midbrain. Neurosci Biobehav Rev 23:863–875
Cardenas FP, Lamprea MR, Silveira R et al (2000) Dissociation of memory and anxiety in a repeated elevated plus-maze paradigm: forebrain cholinergic mechanisms. Behav Brain Res 117:97–105
Carobrez AP, Bertoglio LJ (2005) Ethological and temporal analyses of anxiety-like behavior: the elevated plus-maze model 20 years on. Neurosci Biobehav Rev 29:1193–1205. https://doi.org/10.1016/j.neubiorev.2005.04.017
Carvalho JD, de Oliveira AR, da Silva RC, Brandao ML (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
Carvalho LR, Vasconcellos PC, Mantovani W et al (2005) Measurements of biogenic hydrocarbons and carbonyl compounds emitted by trees from temperate warm Atlantic rainforest, Brazil. J Env Monit 7:493–499. https://doi.org/10.1039/b414881a
Cools AR, Ellenbroek B, Heeren D, Lubbers L (1993) Use of high and low responders to novelty in rat studies on the role of the ventral striatum in radial maze performance: effects of intra-accumbens injections of sulpiride. Can J Physiol Pharmacol 71:335–342
Cruz-Morales SE, Santos NR, Brandao ML (2002) One-trial tolerance to midazolam is due to enhancement of fear and reduction of anxiolytic-sensitive behaviors in the elevated plus-maze retest in the rat. Pharmacol Biochem Behav 72:973–978
de Oliveira AR, Reimer AE, Brandao ML (2006) Dopamine D2 receptor mechanisms in the expression of conditioned fear. Pharmacol Biochem Behav 84:102–111. https://doi.org/10.1016/j.pbb.2006.04.012
Dringenberg HC, Levine Y, Menard JL (2008) Electrical stimulation of dorsal, but not ventral hippocampus reduces behavioral defense in the elevated plus maze and shock-probe burying test in rats. Behav Brain Res 186:143–147. https://doi.org/10.1016/j.bbr.2007.07.030
Eslimi D, Oryan S, Nasehi M, Zarrindast MR (2011) Effects of opioidergic systems upon anxiolytic-like behaviors induced in cholestatic rats. Eur J Pharmacol 670:180–185. https://doi.org/10.1016/j.ejphar.2011.08.024
Fendt M, Fanselow MS (1999) The neuroanatomical and neurochemical basis of conditioned fear. Neurosci Biobehav Rev 23:743–760
File SE, Kenny PJ, Cheeta S (2000) The role of the dorsal hippocampal serotonergic and cholinergic systems in the modulation of anxiety. Pharmacol Biochem Behav 66:65–72
Floresco SB, Phillips AG (2001) Delay-dependent modulation of memory retrieval by infusion of a dopamine D1 agonist into the rat medial prefrontal cortex. Behav Neurosci 115:934–939
Frey U, Schroeder H, Matthies H (1990) Dopaminergic antagonists prevent long-term maintenance of posttetanic LTP in the CA1 region of rat hippocampal slices. Brain Res 522:69–75
Fujishiro H, Umegaki H, Suzuki Y et al (2005) Dopamine D2 receptor plays a role in memory function: implications of dopamine-acetylcholine interaction in the ventral hippocampus. Psychopharmacol 182:253–261. https://doi.org/10.1007/s00213-005-0072-x
Garcia AM, Martinez R, Brandao ML, Morato S (2005) Effects of apomorphine on rat behavior in the elevated plus-maze. Physiol Behav 85:440–447. https://doi.org/10.1016/j.physbeh.2005.04.027
Gasbarri A, Sulli A, Packard MG (1997) The dopaminergic mesencephalic projections to the hippocampal formation in the rat. Prog Neuro-Psychopharmacol Biol Psychiatry 21:1–22
Ghizoni DM, Joao LM, Moratelli Neto L et al (2006) The effects of metabolic stress and vagotomy on emotional learning in an animal model of anxiety. Neurobiol Learn Mem 86:107–116. https://doi.org/10.1016/j.nlm.2006.01.005
Gianlorenco AC, Canto-de-Souza A, Mattioli R (2011) Microinjection of histamine into the cerebellar vermis impairs emotional memory consolidation in mice. Brain Res Bull 86:134–138. https://doi.org/10.1016/j.brainresbull.2011.05.014
Goto Y, Otani S, Grace AA (2007) The Yin and Yang of dopamine release: a new perspective. Neuropharmacology 53:583–587. https://doi.org/10.1016/j.neuropharm.2007.07.007
Kudolo J, Tabassum H, Frey S et al (2010) Electrical and pharmacological manipulations of the nucleus accumbens core impair synaptic plasticity in the dentate gyrus of the rat. Neuroscience 168:723–731. https://doi.org/10.1016/j.neuroscience.2010.04.015
LaLumiere RT, Nawar EM, McGaugh JL (2005) Modulation of memory consolidation by the basolateral amygdala or nucleus accumbens shell requires concurrent dopamine receptor activation in both brain regions. Learn Mem 12:296–301. https://doi.org/10.1101/lm.93205
Louilot A, Besson C (2000) Specificity of amygdalostriatal interactions in the involvement of mesencephalic dopaminergic neurons in affective perception. Neuroscience 96:73–82
Martinez A, Pittaluga S, Rudelius M et al (2008) Expression of the interferon regulatory factor 8/ICSBP-1 in human reactive lymphoid tissues and B-cell lymphomas: a novel germinal center marker. Am J Surg Pathol 32:1190–1200. https://doi.org/10.1097/PAS.0b013e318166f46a
Menard J, Treit D (2001) The anxiolytic effects of intra-hippocampal midazolam are antagonized by intra-septal L-glutamate. Brain Res 888:163–166
Nasehi M, Piri M, Nouri M et al (2010) Involvement of dopamine D1/D2 receptors on harmane-induced amnesia in the step-down passive avoidance test. Eur J Pharmacol 634:77–83. https://doi.org/10.1016/j.ejphar.2010.02.027
Nasehi M, Sahebgharani M, Haeri-Rohani A, Zarrindast MR (2009) Effects of cannabinoids infused into the dorsal hippocampus upon memory formation in 3-days apomorphine-treated rats. Neurobiol Learn Mem 92:391–399. https://doi.org/10.1016/j.nlm.2009.05.005
Nazari-Serenjeh F, Rezayof A (2013) Cooperative interaction between the basolateral amygdala and ventral tegmental area modulates the consolidation of inhibitory avoidance memory. Prog Neuro-Psychopharmacology Biol Psychiatry 40:54–61. https://doi.org/10.1016/j.pnpbp.2012.10.003
Nazari-Serenjeh F, Rezayof A, Zarrindast MR (2011) Functional correlation between GABAergic and dopaminergic systems of dorsal hippocampus and ventral tegmental area in passive avoidance learning in rats. Neuroscience 196:104–114. https://doi.org/10.1016/j.neuroscience.2011.08.073
Packard MG, White NM (1989) Memory facilitation produced by dopamine agonists: role of receptor subtype and mnemonic requirements. Pharmacol Biochem Behav 33:511–518
Pandaranandaka J, Poonyachoti S, Kalandakanond-Thongsong S (2006) Anxiolytic property of estrogen related to the changes of the monoamine levels in various brain regions of ovariectomized rats. Physiol Behav 87:828–835. https://doi.org/10.1016/j.physbeh.2006.02.002
Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates. Elsevier, New York, NY
Ploeger GE, Spruijt BM, Cools AR (1994) Spatial localization in the Morris water maze in rats: acquisition is affected by intra-accumbens injections of the dopaminergic antagonist haloperidol. Behav Neurosci 108:927–934
Risold PY, Swanson LW (1996) Structural evidence for functional domains in the rat hippocampus. Science (80-) 272:1484–1486
Rodgers RJ, Nikulina EM, Cole JC (1994) Dopamine D1 and D2 receptor ligands modulate the behaviour of mice in the elevated plus-maze. Pharmacol Biochem Behav 49:985–995
Setlow B, McGaugh JL (1998) Sulpiride infused into the nucleus accumbens posttraining impairs memory of spatial water maze training. Behav Neurosci 112:603–610
Stefanski R, Palejko W, Bidzinski A et al (1993) Serotonergic innervation of the hippocampus and nucleus accumbens septi and the anxiolytic-like action of the 5-HT3 receptor antagonists. Neuropharmacology 32:987–993
Stern CA, Do Monte FH, Gazarini L et al (2010) Activity in prelimbic cortex is required for adjusting the anxiety response level during the elevated plus-maze retest. Neuroscience 170:214–222. https://doi.org/10.1016/j.neuroscience.2010.06.080
Tan SE (2008) Roles of hippocampal NMDA receptors and nucleus accumbens D1 receptors in the amphetamine-produced conditioned place preference in rats. Brain Res Bull 77:412–419. https://doi.org/10.1016/j.brainresbull.2008.09.007
Tidey JW, Miczek KA (1996) Social defeat stress selectively alters mesocorticolimbic dopamine release: an in vivo microdialysis study. Brain Res 721:140–149
Wahlstrom D, White T, Luciana M (2010) Neurobehavioral evidence for changes in dopamine system activity during adolescence. Neurosci Biobehav Rev 34:631–648. https://doi.org/10.1016/j.neubiorev.2009.12.007
Walaas I, Fonnum F (1980) Biochemical evidence for gamma-aminobutyrate containing fibres from the nucleus accumbens to the substantia nigra and ventral tegmental area in the rat. Neuroscience 5:63–72
Wall PM, Blanchard RJ, Yang M, Blanchard DC (2003) Infralimbic D2 receptor influences on anxiety-like behavior and active memory/attention in CD-1 mice. Prog Neuro-Psychopharmacology Biol Psychiatry 27:395–410. https://doi.org/10.1016/S0278-5846(02)00356-1
Xu L, Anwyl R, De Vry J, Rowan MJ (1997) Effect of repeated ipsapirone treatment on hippocampal excitatory synaptic transmission in the freely behaving rat: role of 5-HT1A receptors and relationship to anxiolytic effect. Eur J Pharmacol 323:59–68
Yanagihashi R, Yamanouchi K, Ishikawa T (1991) The effects of apomorphine on the hippocampal field potential in freely moving rats: pharmacological evidence of the involvement of D2 receptors. Neuropharmacology 30:177–182
Funding
The authors wish to thank the Iran National Science Foundation (INSF) for providing financial support to this project.
Author information
Authors and Affiliations
Contributions
ME acquired the animal data and wrote the manuscript. MN and MZ were responsible for the study concept, design, and proteomics analysis, as well as assisted with the data analysis and interpretation of findings. All authors critically reviewed the content and approved the final version for publication.
Corresponding author
Ethics declarations
The study was carried out in accordance with ethical standards in all aspects.
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Ebrahimi-Ghiri, M., Nasehi, M. & Zarrindast, MR. The modulatory role of accumbens and hippocampus D2 receptors in anxiety and memory. Naunyn-Schmiedeberg's Arch Pharmacol 391, 1107–1118 (2018). https://doi.org/10.1007/s00210-018-1534-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-018-1534-0