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Pharmacopsychiatry 2016; 49(04): 142-145
DOI: 10.1055/s-0042-105018
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Conserved Hypothalamic c-Fos Activation Pattern Induced by the mGlu5 Receptor Antagonist MPEP during Peri-pubertal Development in Mice

I. Inta
1   RG Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany
2   Division of Pediatric Endocrinology, University Children’s Hospital Heidelberg, Germany
,
M. Bettendorf
2   Division of Pediatric Endocrinology, University Children’s Hospital Heidelberg, Germany
,
P. Gass
1   RG Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany
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Publikationsverlauf

received 16. November 2015
revised 07. März 2016

accepted 09. März 2016

Publikationsdatum:
21. April 2016 (online)

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Abstract

Introduction: 2-Methyl-6-(phenylethynyl)pyridine (MPEP) is a selective mGlu5 receptor (mGluR5) antagonist intensively studied as potential novel anxiolytic drug. In the adult, MPEP activates stress-related areas, including the paraventricular nucleus of the hypothalamus (PVNh). However, it is unknown if MPEP targets similar structures in the juvenile brain as well.

Methods: Here we examined by immunohistochemical methods the induction pattern of the neuronal activity marker c-Fos by MPEP at peri-pubertal stages (postnatal day P16, P24, P32 and P40) in C57BL6/N mice.

Results: Despite the previously reported sharply diminished hypothalamic mGluR5 expression during postnatal development, we found a highly conserved PVNh activation by MPEP together with c-Fos expression in the extended amygdala. Interestingly, MPEP also robustly activated the paraventricular nucleus of the thalamus (PVT) and suprachiasmatic nucleus (SCN), regions associated with the modulation of circadian rhythms.

Discussion: These results indicate a conserved activation pattern induced by MPEP in the young vs. adult brain especially in brain areas regulating stress and circadian rhythms and may be of importance regarding the effect of mGluR5 antagonists in the treatment of mood disorders during juvenile development.

Key words

glutamate - hypothalamus - anxiety - circadian rhythms - puberty
 

  • References

  • 1 Gasparini F, Lingenhohl K, Stoehr N et al. 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 1999; 38: 1493-1503
    CrossrefPubMedGoogle Scholar
  • 2 Tatarczynska E, Klodzinska A, Chojnacka-Wojcik E et al. Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist. Br J Pharmacol 2001; 132: 1423-1430
    CrossrefPubMedGoogle Scholar
  • 3 Sagar SM, Sharp FR, Curran T. Expression of c-fos protein in brain: metabolic mapping at the cellular level. Science 1988; 240: 1328-1331
    CrossrefPubMedGoogle Scholar
  • 4 Kiessling M, Gass P. Immediate early gene expression in experimental epilepsy. Brain Pathol 1993; 3: 381-393
    CrossrefPubMedGoogle Scholar
  • 5 Kiessling M, Gass P. Stimulus-transcription coupling in focal cerebral ischemia. Brain Pathol 1994; 4: 77-83
    PubMedGoogle Scholar
  • 6 Gass P, Herdegen T. Neuronal expression of AP-1 proteins in excitotoxic-neurodegenerative disorders and following nerve fiber lesions. Prog Neurobiol 1995; 47: 257-290
    CrossrefPubMedGoogle Scholar
  • 7 Sumner BE, Cruise LA, Slattery DA et al. Testing the validity of c-fos expression profiling to aid the therapeutic classification of psychoactive drugs. Psychopharmacology (Berl) 2004; 171: 306-321
    CrossrefPubMedGoogle Scholar
  • 8 Salminen O, Lahtinen S, Ahtee L. Expression of Fos protein in various rat brain areas following acute nicotine and diazepam. Pharmacol Biochem Behav 1996; 54: 241-248
    CrossrefPubMedGoogle Scholar
  • 9 Beck CH. Acute treatment with antidepressant drugs selectively increases the expression of c-fos in the rat brain. J Psychiatry Neurosci 1995; 20: 25-32
    PubMedGoogle Scholar
  • 10 Morelli M, Pinna A, Ruiu S et al. Induction of Fos-like-immunoreactivity in the central extended amygdala by antidepressant drugs. Synapse 1999; 31: 1-4
    CrossrefPubMedGoogle Scholar
  • 11 Li X, Need AB, Baez M et al. Metabotropic glutamate 5 receptor antagonism is associated with antidepressant-like effects in mice. J Pharmacol Exp Ther 2006; 319: 254-259
    CrossrefPubMedGoogle Scholar
  • 12 Belozertseva IV, Kos T, Popik P et al. Antidepressant-like effects of mGluR1 and mglu5 receptor antagonists in the rat forced swim and the mouse tail suspension tests. Eur Neuropsychopharmacol 2007; 17: 172-179
    CrossrefPubMedGoogle Scholar
  • 13 Inta D, Filipovic D, Lima-Ojeda JM et al. The mGlu5 receptor antagonist MPEP activates specific stress-related brain regions and lacks neurotoxic effects of the NMDA receptor antagonist MK-801: significance for the use as anxiolytic/antidepressant drug. Neuropharmacology 2012; 62: 2034-2039
    CrossrefPubMedGoogle Scholar
  • 14 Catania MV, Landwehrmeyer GB, Testa CM et al Metabotropic glutamate receptors are differentially regulated during development. Neuroscience 1994; 61: 481-495
    CrossrefPubMedGoogle Scholar
  • 15 Casabona G, Knopfel T, Kuhn R et al. Expression and coupling to polyphosphoinositide hydrolysis of group I metabotropic glutamate receptors in early postnatal and adult rat brain. Eur J Neurosci 1997; 9: 12-17
    CrossrefPubMedGoogle Scholar
  • 16 Clarkson J, Boon WC, Simpson ER et al. Postnatal development of an estradiol-kisspeptin positive feedback mechanism implicated in puberty onset. Endocrinology 2009; 150: 3214-3220
    CrossrefPubMedGoogle Scholar
  • 17 Insanally MN, Albanna BF, Bao S. Pulsed noise experience disrupts complex sound representations. J Neurophysiol 2010; 103: 2611-2617
    CrossrefPubMedGoogle Scholar
  • 18 Chourbaji S, Zacher C, Sanchis-Segura C et al. Social and structural housing conditions influence the development of a depressive-like phenotype in the learned helplessness paradigm in male mice. Behav Brain Res 2005; 164: 100-106
    CrossrefPubMedGoogle Scholar
  • 19 Cruz-Martín A, Crespo M, Portera-Cailliau C. Delayed stabilization of dendritic spines in fragile X mice. J Neurosci 2010; 30: 7793-7803
    CrossrefPubMedGoogle Scholar
  • 20 Herdegen T, Blume A, Buschmann T et al. Expression of ATF-2, SRF and CREB in the adult rat brain following generalized seizures, nerve fiber lesions and ultraviolet irradiation. Neuroscience 1997; 81: 199-212
    CrossrefPubMedGoogle Scholar
  • 21 Bisler S, Schleicher A, Gass P et al. Expression of c-Fos, ICER, Krox-24 and JunB in the whisker-to-barrel pathway of rats: time course of induction upon whisker stimulation by tactile exploration of an enriched environment. J Chem Neuroanat 2002; 23: 187-98
    CrossrefPubMedGoogle Scholar
  • 22 Gass P, Prior P, Kiessling M. Correlation between seizure intensity and stress protein expression after limbic epilepsy in the rat brain. Neuroscience 1995; 65: 27-36
    CrossrefPubMedGoogle Scholar
  • 23 Filipovic D, Zlatkovic J, Inta D et al. Chronic isolation stress predisposes the frontal cortex but not the hippocampus to the potentially detrimental release of cytochrome c from mitochondria and the activation of caspase-3. J Neurosci Res 2011; 89: 1461-14670
    CrossrefPubMedGoogle Scholar
  • 24 Johnson MP, Kelly G, Chamberlain M. Changes in rat serum corticosterone after treatment with metabotropic glutamate receptor agonists or antagonists. J Neuroendocrinol 2001; 13: 670-677
    CrossrefPubMedGoogle Scholar
  • 25 Radley JJ, Sawchenko PE. A common substrate for prefrontal and hippocampal inhibition of the neuroendocrine stress response. J Neurosci 2011; 31: 9683-9695
    CrossrefPubMedGoogle Scholar
  • 26 Scaccianoce S, Matrisciano F, Del Bianco P et al. Endogenous activation of group-II metabotropic glutamate receptors inhibits the hypothalamic-pituitary-adrenocortical axis. Neuropharmacology 2003; 44: 555-561
    CrossrefPubMedGoogle Scholar
  • 27 Davis M, Walker DL, Miles L et al. Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs anxiety. Neuropsychopharmacology 2010; 35: 105-135
    CrossrefPubMedGoogle Scholar
  • 28 Dabrowska J, Hazra R, Guo JD et al. Central CRF neurons are not created equal: phenotypic differences in CRF-containing neurons of the rat paraventricular hypothalamus and the bed nucleus of the stria terminalis. Front Neurosci 2013; 7: 156
    PubMedGoogle Scholar
  • 29 Singewald GM, Rjabokon A, Singewald N et al. The modulatory role of the lateral septum on neuroendocrine and behavioral stress responses. Neuropsychopharmacology 2011; 36: 793-804
    CrossrefPubMedGoogle Scholar
  • 30 Anthony TE, Dee N, Bernard A et al. Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit. Cell 2014; 156: 522-536
    CrossrefPubMedGoogle Scholar
  • 31 Hsu DT, Kirouac GJ, Zubieta JK et al. Contributions of the paraventricular thalamic nucleus in the regulation of stress, motivation, and mood. Front Behav Neurosci 2014; 8: 73
    PubMedGoogle Scholar
  • 32 Moga MM, Weis RP, Moore RY. Efferent projections of the paraventricular thalamic nucleus in the rat. J Comp Neurol 1995; 359: 221-238
    CrossrefPubMedGoogle Scholar
  • 33 Park D, Lee S, Jun K et al. Translation of clock rhythmicity into neural firing in suprachiasmatic nucleus requires mGluR-PLCbeta4 signaling. Nat Neurosci 2003; 6: 337-338
    CrossrefPubMedGoogle Scholar
  • 34 Gannon RL, Millan MJ. Positive and negative modulation of circadian activity rhythms by mGluR5 and mGluR2/3 metabotropic glutamate receptors. Neuropharmacology 2011; 60: 209-215
    CrossrefPubMedGoogle Scholar
  • 35 Inta D, Vogt MA, Luoni A et al. Significant increase in anxiety during aging in mGlu5 receptor knockout mice. Behav Brain Res 2013; 241C: 27-31
    PubMedGoogle Scholar