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Global Depletion of Dopamine Using Intracerebroventricular 6-Hydroxydopamine Injection Disrupts Normal Circadian Wheel-Running Patterns and PERIOD2 Expression in the Rat Forebrain

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Abstract

Normal circadian rhythms of behavior are disrupted in disorders involving the dopamine (DA) system, such as Parkinson’s disease. We have reported previously using unilateral injections of the catecholamine toxin, 6-hydroxydopamine (6-OHDA), into the medial forebrain bundle that DA signaling regulates daily expression of the clock protein, PERIOD2 (PER2), in the dorsal striatum of the rat. In the present study, we made widespread lesions of DA fibers using large injections of 6-OHDA into the third ventricle to determine the involvement of DA in normal daily rhythms of wheel-running activity and PER2 patterns in the suprachiasmatic nucleus (SCN) and several regions of the limbic forebrain. Rats injected with 6-OHDA and housed in constant darkness were less active in the wheel and showed a disorganized pattern of activity in which wheel running was not confined to a specific phase over 24 h. The 6-OHDA injection had no effect on the daily PER2 pattern in the SCN, but blunted the normal rise in PER2 in the dorsal striatum. 6-OHDA also blunted PER2 expression in the periventricular nucleus of the hypothalamus, a region in which a daily PER2 pattern has not been previously reported in male rats, and in the oval nucleus of the bed nucleus of the stria terminalis, but not in the central nucleus of the amygdala. These results indicate that DA plays a prominent role in regulating circadian activity at both behavioral and molecular levels.

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References

  • Abarca C, Albrecht U, Spanagel R (2002) Cocaine sensitization and reward are under the influence of circadian genes and rhythm. Proc Natl Acad Sci USA 99:9026–9030

    Article  PubMed  CAS  Google Scholar 

  • Alheid GF, Heimer L (1988) New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: the striatopallidal, amygdaloid, and corticopetal components of substantia innominata. Neuroscience 27:1–39

    Article  PubMed  CAS  Google Scholar 

  • Amir S, Robinson B (2006) Thyroidectomy alters the daily pattern of expression of the clock protein, PER2, in the oval nucleus of the bed nucleus of the stria terminalis and central nucleus of the amygdala in rats. Neurosci Lett 407:254–257

    Article  PubMed  CAS  Google Scholar 

  • Amir S, Lamont EW, Robinson B, Stewart J (2004) A circadian rhythm in the expression of PERIOD2 protein reveals a novel SCN-controlled oscillator in the oval nucleus of the bed nucleus of the stria terminalis. J Neurosci 24:781–790

    Article  PubMed  CAS  Google Scholar 

  • Amir S, Harbour VL, Robinson B (2006) Pinealectomy does not affect diurnal PER2 expression in the rat limbic forebrain. Neurosci Lett 399:147–150

    Article  PubMed  CAS  Google Scholar 

  • Aoi M, Date I, Tomita S, Ohmoto T (2000) GDNF induces recovery of the nigrostriatal dopaminergic system in the rat brain following intracerebroventricular or intraparenchymal administration. Acta Neurochir (Wien) 142:805–810

    Article  CAS  Google Scholar 

  • Ben V, Bruguerolle B (2000) Effects of bilateral striatal 6-OHDA lesions on circadian rhythms in the rat: a radiotelemetric study. Life Sci 67:1549–1558

    Article  PubMed  CAS  Google Scholar 

  • Ben-Jonathan N, Hnasko R (2001) Dopamine as a prolactin (PRL) inhibitor. Endocr Rev 22:724–763

    Article  PubMed  CAS  Google Scholar 

  • Boulamery A, Simon N, Vidal J, Bruguerolle B (2010) Effects of L-Dopa on circadian rhythms of 6-OHDA striatal lesioned rats: a radiotelemetric study. Chronobiol Int 27:251–264

    Article  PubMed  CAS  Google Scholar 

  • Bruguerolle B, Simon N (2002) Biologic rhythms and Parkinson’s disease: a chronopharmacologic approach to considering fluctuations in function. Clin Neuropharmacol 25:194–201

    Article  PubMed  Google Scholar 

  • Cai Y, Liu S, Sothern RB, Xu S, Chan P (2010) Expression of clock genes Per1 and Bmal1 in total leukocytes in health and Parkinson’s disease. Eur J Neurol 17:550–554

    Article  PubMed  CAS  Google Scholar 

  • Castaneda TR, de Prado BM, Prieto D, Mora F (2004) Circadian rhythms of dopamine, glutamate and GABA in the striatum and nucleus accumbens of the awake rat: modulation by light. J Pineal Res 36:177–185

    Article  PubMed  CAS  Google Scholar 

  • Davis M, Walker DL, Lee Y (1997) Amygdala and bed nucleus of the stria terminalis: differential roles in fear and anxiety measured with the acoustic startle reflex. Philos Trans R Soc Lond B Biol Sci 352:1675–1687

    Article  PubMed  CAS  Google Scholar 

  • Erb S, Salmaso N, Rodaros D, Stewart J (2001) A role for the CRF-containing pathway from central nucleus of the amygdala to bed nucleus of the stria terminalis in the stress-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 158:360–365

    Article  CAS  Google Scholar 

  • Freeman ME, Kanyicska B, Lerant A, Nagy G (2000) Prolactin: structure, function, and regulation of secretion. Physiol Rev 80:1523–1631

    PubMed  CAS  Google Scholar 

  • González S, Scorticati C, García-Arencibia M, de Miguel R, Ramos JA, Fernández-Ruiz J (2006) Effects of rimonabant, a selective cannabinoid CB1 receptor antagonist, in a rat model of Parkinson’s disease. Brain Res 1073–1074:209–219

    Article  PubMed  Google Scholar 

  • Gunn DG, Naismith SL, Lewis SJ (2010) Sleep disturbances in Parkinson disease and their potential role in heterogeneity. J Geriatr Psychiatry Neurol 23:131–137

    Article  PubMed  Google Scholar 

  • Harbour VL, Robinson B, Amir S (2010) Variations in daily expression of the circadian clock protein, PER2, in the rat limbic forebrain during stable entrainment to a long light cycle. J Mol Neurosci. doi:10.1007/s12031-010-9469-z

    PubMed  Google Scholar 

  • Hasue RH, Shammah-Lagnado SJ (2002) Origin of the dopaminergic innervation of the central extended amygdala and accumbens shell: a combined retrograde tracing and immunohistochemical study in the rat. J Comp Neurol 454:15–33

    Article  PubMed  CAS  Google Scholar 

  • Hood S, Cassidy P, Cossette MP, Weigl Y, Verwey M, Robinson B, Stewart J, Amir S (2010) Endogenous dopamine regulates the rhythm of expression of the clock protein PER2 in the rat dorsal striatum via daily activation of D2 dopamine receptors. J Neurosci 30:14046–14058

    Article  PubMed  CAS  Google Scholar 

  • Imbesi M, Yildiz S, Dirim Arslan A, Sharma R, Manev H, Uz T (2009) Dopamine receptor-mediated regulation of neuronal “clock” gene expression. Neuroscience 158:537–544

    Article  PubMed  CAS  Google Scholar 

  • Kriegsfeld LJ, Korets R, Silver R (2003) Expression of the circadian clock gene Period 1 in neuroendocrine cells: an investigation using mice with a Per1::GFP transgene. Eur J Neurosci 17:212–220

    Article  PubMed  Google Scholar 

  • Lamont EW, Robinson B, Stewart J, Amir S (2005) The central and basolateral nuclei of the amygdala exhibit opposite diurnal rhythms of expression of the clock protein Period2. Proc Natl Acad Sci USA 102:4180–4184

    Article  PubMed  CAS  Google Scholar 

  • Paulson PE, Robinson TE (1994) Relationship between circadian changes in spontaneous motor activity and dorsal versus ventral striatal dopamine neurotransmission assessed with on-line microdialysis. Behav Neurosci 108:624–635

    Article  PubMed  CAS  Google Scholar 

  • Perrin JS, Segall LA, Harbour VL, Woodside B, Amir S (2006) The expression of the clock protein PER2 in the limbic forebrain is modulated by the estrous cycle. Proc Natl Acad Sci USA 103:5591–5596

    Article  PubMed  CAS  Google Scholar 

  • Ramanathan C, Nunez AA, Martinez GS, Schwartz MD, Smale L (2006) Temporal and spatial distribution of immunoreactive PER1 and PER2 proteins in the suprachiasmatic nucleus and peri-suprachiasmatic region of the diurnal grass rat (Arvicanthis niloticus). Brain Res 1073–1074:348–358

    Article  PubMed  Google Scholar 

  • Reppert SM, Weaver DR (2002) Coordination of circadian timing in mammals. Nature 418:935–941

    Article  PubMed  CAS  Google Scholar 

  • Rodríguez Díaz M, Abdala P, Barroso-Chinea P, Obeso J, González-Hernández T (2001) Motor behavioural changes after intracerebroventricular injection of 6-hydroxydopamine in the rat: an animal model of Parkinson’s disease. Behav Brain Res 122:79–92

    Article  PubMed  Google Scholar 

  • Rosenblad C, Kirik D, Devaux B, Moffat B, Phillips HS, Björklund A (1999) Protection and regeneration of nigral dopaminergic neurons by neurturin or GDNF in a partial lesion model of Parkinson’s disease after administration into the striatum or the lateral ventricle. Eur J Neurosci 11:1554–1566

    Article  PubMed  CAS  Google Scholar 

  • Sadakierska-Chudy A, Haduch A, Gołembiowska K, Daniel WA (2010) Effects of low doses of intracerebroventricular 6-OHDA on the levels of monoaminergic neurotransmitters in rat brain structures. Pharmacol Rep 62:1225–1230

    PubMed  CAS  Google Scholar 

  • Sahar S, Zocchi L, Kinoshita C, Borrelli E, Sassone-Corsi P (2010) Regulation of BMAL1 protein stability and circadian function by GSK3beta-mediated phosphorylation. PLoS ONE 5:e8561

    Article  PubMed  Google Scholar 

  • Schurov IL, Hepworth TJ, Hastings MH (2002) Dopaminergic signalling in the rodent neonatal suprachiasmatic nucleus identifies a role for protein kinase A and mitogen-activated protein kinase in circadian entrainment. Eur J Neurosci 15:223–232

    Article  PubMed  Google Scholar 

  • Segall LA, Amir S (2010) Exogenous corticosterone induces the expression of the clock protein, PERIOD2, in the oval nucleus of the bed nucleus of the stria terminalis and the central nucleus of the amygdala of adrenalectomized and intact rats. J Mol Neurosci 42:176–182

    Article  PubMed  CAS  Google Scholar 

  • Segall LA, Perrin JS, Walker CD, Stewart J, Amir S (2006) Glucocorticoid rhythms control the rhythm of expression of the clock protein, Period2, in oval nucleus of the bed nucleus of the stria terminalis and central nucleus of the amygdala in rats. Neuroscience 140:753–757

    Article  PubMed  CAS  Google Scholar 

  • Sellix MT, Egli M, Poletini MO, McKee DT, Bosworth MD, Fitch CA, Freeman ME (2006) Anatomical and functional characterization of clock gene expression in neuroendocrine dopaminergic neurons. Am J Physiol Regul Integr Comp Physiol 290:R1309–R1323

    Article  PubMed  CAS  Google Scholar 

  • Spanagel R, Pendyala G, Abarca C, Zghoul T, Sanchis-Segura C, Magnone MC, Lascorz J, Depner M, Holzberg D, Soyka M, Schreiber S, Matsuda F, Lathrop M, Schumann G, Albrecht U (2005) The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption. Nat Med 11:35–42

    Article  PubMed  CAS  Google Scholar 

  • Thompson RH, Swanson LW (2003) Structural characterization of a hypothalamic visceromotor pattern generator network. Brain Res Brain Res Rev 41:153–202

    Article  PubMed  CAS  Google Scholar 

  • Verwey M, Khoja Z, Stewart J, Amir S (2007) Differential regulation of the expression of Period2 protein in the limbic forebrain and dorsomedial hypothalamus by daily limited access to highly palatable food in food-deprived and free-fed rats. Neuroscience 147:277–285

    Article  PubMed  CAS  Google Scholar 

  • Verwey M, Khoja Z, Stewart J, Amir S (2008) Region-specific modulation of PER2 expression in the limbic forebrain and hypothalamus by nighttime restricted feeding in rats. Neurosci Lett 440:54–58

    Article  PubMed  CAS  Google Scholar 

  • Waddington Lamont E, Harbour VL, Barry-Shaw J, Renteria Diaz L, Robinson B, Stewart J, Amir S (2007) Restricted access to food, but not sucrose, saccharine, or salt, synchronizes the expression of Period2 protein in the limbic forebrain. Neuroscience 144:402–411

    Article  PubMed  CAS  Google Scholar 

  • Watson RE Jr, Wiegand SJ, Clough RW, Hoffman GE (1986) Use of cryoprotectant to maintain long-term peptide immunoreactivity and tissue morphology. Peptides 7:155–159

    Article  PubMed  CAS  Google Scholar 

  • Weaver DR, Rivkees SA, Reppert SM (1992) D1-dopamine receptors activate c-fos expression in the fetal suprachiasmatic nuclei. Proc Natl Acad Sci USA 89:9201–9204

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Center for Studies in Behavioral Neurobiology/Centre de Recherche en Neurobiologie Comportementale, Concordia University, 7141 Sherbrooke Street West, Montreal, QC, H4B 1R6, Canada

    Luciana Gravotta, Alex M. Gavrila, Suzanne Hood & Shimon Amir

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  1. Luciana Gravotta
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  2. Alex M. Gavrila
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  3. Suzanne Hood
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  4. Shimon Amir
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Correspondence to Shimon Amir.

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Gravotta, L., Gavrila, A.M., Hood, S. et al. Global Depletion of Dopamine Using Intracerebroventricular 6-Hydroxydopamine Injection Disrupts Normal Circadian Wheel-Running Patterns and PERIOD2 Expression in the Rat Forebrain. J Mol Neurosci 45, 162–171 (2011). https://doi.org/10.1007/s12031-011-9520-8

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