The Effects of Non-selective Dopamine Receptor Activation by Apomorphine in the Mouse Hippocampus

  • Luis Enrique Arroyo-García
  • Rubén Antonio Vázquez-Roque
  • Alfonso Díaz
  • Samuel Treviño
  • Fidel De La Cruz
  • Gonzalo Flores
  • Antonio Rodríguez-Moreno


Apomorphine is a dopamine receptor agonist that activates D1–D5 dopamine receptors and that is used to treat Parkinson’s disease (PD). However, the effect of apomorphine on non-motor activity has been poorly studied, and likewise, the effects of dopaminergic activation in brain areas that do not fulfill motor functions are unclear. The aim of this study was to determine how dopamine receptor activation affects behavior, as well as plasticity, morphology, and oxidative stress in the hippocampus. Adult mice were chronically administered apomorphine (1 mg/kg for 15 days), and the effects on memory and learning, synaptic plasticity, dendritic length, inflammatory responses, and oxidative stress were evaluated. Apomorphine impaired learning and long-term memory in mice, as evaluated in the Morris water maze test. In addition, electrophysiological recording of field excitatory postsynaptic potentials (fEPSP) indicated that the long-term potentiation (LTP) of synaptic transmission in the CA1 region of the hippocampus was fully impaired by apomorphine. In addition, a Sholl analysis of Golgi-Cox stained neurons showed that apomorphine reduced the total length of dendrites in the CA1 region of the hippocampus. Finally, there were more reactive astrocytes and oxidative stress biomarkers in mice administered apomorphine, as measured by GFAP immunohistochemistry and markers of redox balance, respectively. Hence, the non-selective activation of dopaminergic receptors in the hippocampus by apomorphine triggers deficiencies in learning and memory, it prevents LTP, reduces dendritic length, and provokes neuronal damage.


Dopamine receptor Apomorphine Hippocampus Learning and memory Plasticity Dendritic length Oxidative stress 



We acknowledge the assistance of Dr. Mark Sefton in the preparation of this manuscript and the technical assistance of Dr. Yuniesky Andrade-Talavera. This work received financial support from the following grants: AR-M (MINECO/FEDER BFU2012-38208 and the Junta de Andalucía P11-CVI-7290) and GF (VIEP-BUAP Number FLAG-2016 and CONACYT Number 252808).


  1. 1.
    Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (2002) Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J Pharmacol Exp Ther 303(2):791–804CrossRefPubMedGoogle Scholar
  2. 2.
    Chen JJ, Obering C (2005) A review of intermittent subcutaneous apomorphine injections for the rescue management of motor fluctuations associated with advanced Parkinson’s disease. Clin Ther 27:1710–1724CrossRefPubMedGoogle Scholar
  3. 3.
    Menon R, Stacy M (2007) Apomorphine in the treatment of Parkinson’s disease. Expert Opin Pharmacother 8:1941–1950CrossRefPubMedGoogle Scholar
  4. 4.
    Jenner P, Katzenschlager R (2016) Apomorphine-pharmacological properties and clinical trials in Parkinson’s disease. Parkinsonism Relat Disord 33(Suppl 1):S13–S21CrossRefPubMedGoogle Scholar
  5. 5.
    Albersen M, Orabi H, Lue TF (2012) Evaluation and treatment of erectile dysfunction in the aging male: a mini-review. Gerontology 58:3–14CrossRefPubMedGoogle Scholar
  6. 6.
    Van Der Kam EL, Coolen JC, Ellenbroek BA, Cools AR (2005) The effects of stress on alcohol consumption: mild acute and sub-chronic stressors differentially affect apomorphine susceptible and unsusceptible rats. Life Sci 6:1759–1770Google Scholar
  7. 7.
    Haleem DJ, Ikram H, Haider S, Parveen T, Haleem MA (2013) Enhancement and inhibition of apomorphine-induced sensitization in rats exposed to immobilization stress: relationship with adaptation to stress. Pharmacol Biochem Behav 112:22–28CrossRefPubMedGoogle Scholar
  8. 8.
    Sanguedo FV, Dias FR, Bloise E, Cespedes IC, Giraldi-Guimarães A, Samuels RI, Carey RJ, Carrera MP (2014) Increase in medial frontal cortex ERK activation following the induction of apomorphine sensitization. Pharmacol Biochem Behav 118:60–68CrossRefPubMedGoogle Scholar
  9. 9.
    Haleem DJ, Farhan M (2015) Inhibition of apomorphine-induced behavioral sensitization in rats pretreated with fluoxetine. Behav Pharmacol 26:159–166CrossRefPubMedGoogle Scholar
  10. 10.
    Björklund A, Dunnett SB (2007) Dopamine neuron systems in the brain: an update. Trends Neurosci 30:194–202CrossRefPubMedGoogle Scholar
  11. 11.
    Lammel S, Hetzel A, Häckel O, Jones I, Liss B, Roeper J (2008) Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system. Neuron 57:760–773CrossRefPubMedGoogle Scholar
  12. 12.
    Bodea GO, Blaess S (2015) Establishing diversity in the dopaminergic system. FEBS Lett 589:3773–3785CrossRefPubMedGoogle Scholar
  13. 13.
    Tindell AJ, Berridge KC, Zhang J, Peciña S, Aldridge JW (2005) Ventral pallidal neurons code incentive motivation: amplification by mesolimbic sensitization and amphetamine. Eur J Neurosci 22:2617–2634CrossRefPubMedGoogle Scholar
  14. 14.
    Schmidt WJ, Beninger RJ (2006) Behavioural sensitization in addiction, schizophrenia, Parkinson’s disease and dyskinesia. Neurotox Res 10:161–166CrossRefPubMedGoogle Scholar
  15. 15.
    Zhu J, Chen Y, Zhao N, Cao G, Dang Y, Han W, Xu M, Chen T (2012) Distinct roles of dopamine D3 receptors in modulating methamphetamine-induced behavioral sensitization and ultrastructural plasticity in the shell of the nucleus accumbens. J Neurosci Res 90:895–904CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Vanderschuren LJ, Pierce RC (2010) Sensitization processes in drug addiction. Curr Top Behav Neurosci 3:179–195CrossRefPubMedGoogle Scholar
  17. 17.
    Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 18:247–291CrossRefPubMedGoogle Scholar
  18. 18.
    Robinson TE, Berridge KC (2003) Addiction. Annu Rev Psychol 54:25–53CrossRefPubMedGoogle Scholar
  19. 19.
    Morris RG, Moser EI, Riedel G, Martin SJ, Sandin J, Day M, O'Carroll C (2003) Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory. Philos Trans R Soc Lond Ser B Biol Sci 358:773–786CrossRefGoogle Scholar
  20. 20.
    Lisman JE, Grace AA (2005) The hippocampal-VTA loop: controlling the entry of information into long-term memory. Neuron 46:703–713CrossRefPubMedGoogle Scholar
  21. 21.
    McNamara CG, Tejero-Cantero Á, Trouche S, Campo-Urriza N, Dupret D (2014) Dopaminergic neurons promote hippocampal reactivation and spatial memory persistence. Nat Neurosci 17:1658–1660CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Rosen ZB, Cheung S, Siegelbaum SA (2015) Midbrain dopamine neurons bidirectionally regulate CA3-CA1 synaptic drive. Nat Neurosci 18:1763–1771CrossRefPubMedGoogle Scholar
  23. 23.
    Gourgiotis I, Kampouri NG, Koulouri V, Lempesis IG, Prasinou MD, Georgiadou G, Pitsikas N (2012) Nitric oxide modulates apomorphine-induced recognition memory deficits in rats. Pharmacol Biochem Behav 102:507–614CrossRefPubMedGoogle Scholar
  24. 24.
    Ikram H, Haleem DJ (2011) Attenuation of apomorphine-induced sensitization by buspirone. Pharmacol Biochem Behav 99:444–450CrossRefPubMedGoogle Scholar
  25. 25.
    Lazcano Z, Solis O, Bringas ME, Limón D, Diaz A, Espinosa B, García-Peláez I, Flores G et al (2014) Unilateral injection of Ab25-35 in the hippocampus reduces the number of dendritic spines in hyperglycemic rats. Synapse 68:585–594Google Scholar
  26. 26.
    Negrete-Díaz JV, Sihra TS, Delgado-García JM, Rodríguez-Moreno A (2007) Kainate receptor-mediated presynaptic inhibition converges with presynaptic inhibition mediated by group II mGluRs and long-term depression at the hippocampal mossy fiber-CA3 synapse. J Neural Transm 114:1425–1431CrossRefPubMedGoogle Scholar
  27. 27.
    Andrade-Talavera Y, Duque-Feria P, Paulsen O, Rodríguez-Moreno A (2016) Presynaptic spike timing-dependent long-term depression in the mouse hippocampus. Cereb Cortex 26:411–421CrossRefGoogle Scholar
  28. 28.
    Pérez-Villegas EM, Negrete-Díaz JV, Porras-García ME, Ruiz R, Carrión AM, Rodríguez-Moreno A, Armengol JA (2017) Mutation of the HERC 1 ubiquitin ligase impairs associative learning in the lateral amygdala. Mol Neurobiol 55:1157–1168. CrossRefPubMedGoogle Scholar
  29. 29.
    Flores G, Alquicer G, Silva-Gómez AB, Zaldivar G, Stewart J, Quirion R, Srivastava LK (2005) Alterations in dendritic morphology of prefrontal cortical and nucleus accumbens neurons in post-pubertal rats after neonatal excitotoxic lesions of the ventral hippocampus. Neuroscience 133:463–470CrossRefPubMedGoogle Scholar
  30. 30.
    Torres-García ME, Solís O, Patricio A, Rodríguez-Moreno A, Camacho-Abrego I, Limón ID, Flores G (2012) Dendritic morphology changes in neurons from the prefrontal cortex, hippocampus and nucleus accumbens in rats after lesion of the thalamic reticular nucleus. Neuroscience 223:429–438CrossRefPubMedGoogle Scholar
  31. 31.
    Gibb R, Kolb B (1998) A method for vibratome sectioning of Golgi-Cox stained whole rat brain. J Neurosci Methods 79(1):1–4CrossRefPubMedGoogle Scholar
  32. 32.
    Robinson TE, Kolb B (1997) Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. J Neurosci 17:8491–8497PubMedGoogle Scholar
  33. 33.
    Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, New YorkGoogle Scholar
  34. 34.
    Kolb B, Firgie M, Gibb R, Gorny G, Rowntree S (1998) Age, experience and the changing brain. Neurosci Biobehav Rev 22:143–159CrossRefPubMedGoogle Scholar
  35. 35.
    Sholl DA (1953) Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat 87:387–406PubMedPubMedCentralGoogle Scholar
  36. 36.
    Silva-Gomez AB, Rojas D, Juarez I, Flores G (2003) Decreased dendritic spine density on prefrontal cortical and hippocampal pyramidal neurons in postweaning social isolation rats. Brain Res 983:128–136CrossRefPubMedGoogle Scholar
  37. 37.
    Vega E, de Gómez-Villalobos M, J, Flores G (2004) Alteration in dendritic morphology of pyramidal neurons from the prefrontal cortex of rats with renovascular hypertension. Brain Res 1021:112–138Google Scholar
  38. 38.
    Díaz A, Treviño S, Guevara J, Muñoz-Arenas G, Brambila E, Espinosa B, Moreno-Rodríguez A, Lopez-Lopez G et al (2016) Energy drink administration in combination with alcohol causes an inflammatory response and oxidative stress in the hippocampus and temporal cortex of rats. Oxidative Med Cell Longev 2016:8725354Google Scholar
  39. 39.
    Bringas ME, Morales-Medina JC, Flores-Vivaldo Y, Negrete-Díaz JV, Aguilar-Alonso P, León-Chávez BA, Lazcano-Ortiz Z, Monroy E et al (2012) Clozapine administration reverses behavioral, neuronal, and nitric oxide disturbances in the neonatal ventral hippocampus rat. Neuropharmacology 62:1848–1857Google Scholar
  40. 40.
    Gerard-Monnier D, Erdelmeier I, Regnard K, Moze-Henry N, Yadan JC, Chaudiere J (1998) Reactions of 1-methyl-2-phenylindole with malondialdehyde and 4 hydroxyalkenals. Analytical applications to a colorimetric assay of lipid peroxidation. Chem Res Toxicol 11:1176–1183CrossRefPubMedGoogle Scholar
  41. 41.
    Rahman I, Kode A, Biswas SK (2006) Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nat Protoc 1:3159–3165CrossRefPubMedGoogle Scholar
  42. 42.
    Griffith OW (1980) Determination of glutathione and glutathione disulfide using glutathione reductase and 2-vinylpyridine. Anal Biochem 106:207–212CrossRefPubMedGoogle Scholar
  43. 43.
    Morris RGM (1993) An attempt to dissociate ‘spatial-mapping’ and ‘working-memory’ theories of hippocampal function. In: Seifert W (ed) Neurobiology of the hippocampus. Academic Press, New York, pp. 405–432Google Scholar
  44. 44.
    Gomide V, Bibancos T, Chadi G (2005) Dopamine cell morphology and glial cell hypertrophy and process branching in the nigrostriatal system after striatal 6-OHDA analyzed by specific sterological tools. Int J Neurosci 11:557–582CrossRefGoogle Scholar
  45. 45.
    Cadet JL, Krasnova IN, Jayanthi S, Lyles J (2007) Neurotoxicity of substituted amphetamines: molecular and cellular mechanisms. Neuro Research 11:183–202CrossRefGoogle Scholar
  46. 46.
    Del Rio D, Stewart AJ, Pellegrini N (2005) A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress. Nutr Metab Cardiovasc Dis 15:316–328CrossRefPubMedGoogle Scholar
  47. 47.
    Huang MC, Lin SK, Chen CH, Pan CH, Lee CH, Liu HC (2013) Oxidative stress status in recently abstinent methamphetamine abusers. Psychiatry Clin Neurosci 67:92–100CrossRefPubMedGoogle Scholar
  48. 48.
    Pompella A, Corti A (2015) The changing faces of glutathione, a cellular protagonist. Front Pharmacol 15(6):98Google Scholar
  49. 49.
    Bethus I, Tse D, Morris RGM (2010) Dopamine and memory: modulation of the persistence of memory for novel hippocampal NMDA receptor-dependent paired associates. J Neurosci 30:1610–1618CrossRefPubMedGoogle Scholar
  50. 50.
    Glickstein SB, Hof PR, Schmauss C (2002) Mice lacking dopamine D2 and D3 receptors have spatial working memory deficits. J Neurosci 22(13):5619–5629PubMedGoogle Scholar
  51. 51.
    El-Ghundi M, Fletcher PJ, Drago J, Sibley DR, O'Dowd BF, George SR (1999) Spatial learning deficit in dopamine D(1) receptor knockout mice. Eur J Neuropharmacol 383:95–106CrossRefGoogle Scholar
  52. 52.
    Calabresi P, Saiardi A, Pisani A, Baik JH, Centonze D, Mercuri NB, Bernardi G, Borrelli E (1997) Abnormal synaptic plasticity in the striatum of mice lacking dopamine D2 receptors. J Neurosci 17:4536–4544PubMedGoogle Scholar
  53. 53.
    Bach ME, Barad M, Son H, Zhuo M, Lu YF, Shih R, Mansuy I, Hawkins RD et al (1999) Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. Proc Natl Acad Sci U S A 96:5280–5285Google Scholar
  54. 54.
    Swant J, Chiewa S, Stanwood G, Khoshbouei H (2010) Methamphetamine reduces LTP and increase baseline synaptic transmission in the CA1 region of mouse hippocampus. PLoS One 5:e11382CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    North A, Swant J, Salvatore MF, Gamble-George J, Prins P, Butler B, Mittai MK, Heltsley R et al (2013) Chronic methamphetamine exposure produces a delayed, long-lasting memory deficit. Synapse 67:245–257Google Scholar
  56. 56.
    Granado N, Ortiz O, Suárez LM, Martín ED, Ceña V, Solís JM, Moratalla R (2008) D1 but not D5 dopamine receptors are critical for LTP, spatial learning and LTP-induced arc and zif268 expression in the hippocampus. Cereb Cortex 18:1–12CrossRefPubMedGoogle Scholar
  57. 57.
    Guo F, Zhao J, Zhao D, Wang J, Wang X, Feng Z, Vreugdenhil M, Lu C (2017) Dopamine D4 receptor activation restores CA1 LTP in hippocampal slices from aged mice. Aging Cell 16:1323–1333CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Rodrigues TB, Granado N, Ortiz O, Cerdán S, Moratalla R (2007) Metabolic interactions between glutamatergic and dopaminergic neurotransmitter systems are mediated through D(1) dopamine receptors. J Neurosci Res 85(15):3284–3293CrossRefPubMedGoogle Scholar
  59. 59.
    Lipska BK, Weinberger DR (2000) To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology 23(3):223–239CrossRefPubMedGoogle Scholar
  60. 60.
    Ferreras S, Fernández G, Danelon V, Pisano MV, Masseroni L, Chapleau CA, Krapacher FA, Mlewski EC et al (2017) Cdk5 is essential for amphetamine to increase dendritic spine density in hippocampal pyramidal neurons. Front Cell Neurosci 11:372Google Scholar
  61. 61.
    Flores G, Morales-Medina JC, Diaz A (2016) Neuronal and brain morphological changes in animal models of schizophrenia. Behav Brain Res 301:190–203CrossRefPubMedGoogle Scholar
  62. 62.
    Fanselow MS, Dong HW (2010) Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65:7–19CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Sahay A, Hen R (2007) Adult hippocampal neurogenesis in depression. Nat Neurosci 10:1110–1115CrossRefPubMedGoogle Scholar
  64. 64.
    Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC, Cullinan WE (2003) Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Front Neuroendocrinol 24:151–180CrossRefPubMedGoogle Scholar
  65. 65.
    Belda X, Armario A (2009) Dopamine D1 and D2 dopamine receptors regulate immobilization stress-induced activation of the hypothalamus-pituitary-adrenal axis. Psychopharmacology 206:355–365CrossRefPubMedGoogle Scholar
  66. 66.
    Luo Y, Roth GS (2000) The roles of dopamine oxidative stress and dopamine receptor signaling in aging and age-related neurodegeneration. Antioxid Redox Signal 2:449–460CrossRefPubMedGoogle Scholar
  67. 67.
    Miyazaki I, Asanuma M (2008) Dopaminergic neuron-specific oxidative stress caused by dopamine itself. Acta Med Okayama 62:141–150PubMedGoogle Scholar
  68. 68.
    Ridet JL, Malhotra SK, Privat A, Gage FH (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20:570–577CrossRefPubMedGoogle Scholar
  69. 69.
    Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Kang K, Lee SW, Han JE, Choi JW, Song MR (2014) The complex morphology of reactive astrocytes controlled by fibroblast growth factor signaling. Glia 62:1328–1344CrossRefPubMedGoogle Scholar
  71. 71.
    Garwood CJ, Ratcliffe LE, Simpson JE, Heath PR, Ince PG, Wharton SB (2017) Review: astrocytes in Alzheimer’s disease and other age-associated dementias: a supporting player with a central role. Neuropathol Appl Neurobiol 43:281–298CrossRefPubMedGoogle Scholar
  72. 72.
    Beckman JS, Ye YZ, Chen J, Conger KA (1996) The interactions of nitric oxide with oxygen radicals and scavengers in cerebral ischemic injury. Adv Neurol 71:339–350PubMedGoogle Scholar
  73. 73.
    Morales-Medina JC, Mejorada A, Romero-Curiel A, Flores G (2007) Alterations in dendritic morphology of hippocampal neurons in adult rats after neonatal administration of N-omega-nitro-L-arginine. Synapse 61:785–789CrossRefPubMedGoogle Scholar
  74. 74.
    Morales-Medina JC, Mejorada A, Romero-Curiel A, Aguilar-Alonso P, León-Chávez BA, Gamboa C, Quirion R, Flores G (2008) Neonatal administration of N-omega-nitro-L-arginine induces permanent decrease in NO levels and hyperresponsiveness to locomotor activity by D-amphetamine in postpubertal rats. Neuropharmacology 55:1313–1320CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Laboratorio de Neurociencia Celular y PlasticidadUniversidad Pablo de OlavideSevillaSpain
  2. 2.Laboratorio de Fisiología de la ConductaInstituto Politécnico NacionalMexico CityMexico
  3. 3.Laboratorio de NeuropsiquiatríaInstituto de Fisiología, Benemérita Universidad Autónoma de PueblaPueblaMexico
  4. 4.Facultad de Ciencias QuímicasBenemérita Universidad Autónoma de PueblaPueblaMexico
  5. 5.Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cell BiologyUniversidad Pablo de OlavideSevillaSpain

Personalised recommendations