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Central administration of muscimol phase-shifts the mammalian circadian clock

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Summary

The suprachiasmatic nucleus (SCN) of the hypothalamus contains a neural oscillatory system which regulates many circadian rhythms in mammals. Immunohistochemical evidence indicates that a relatively high density of GABAergic neurons exist in the suprachiasmatic region. Since intraperitoneal injections of the benzodiazepine, triazolam, have been shown to induce phase shifts in the free-running circadian rhythm of locomotor activity in the golden hamster, the extent to which microinjections of muscimol, a specific agonist for gamma-aminobutyric acid (GABA), may cause phase-shifts in hamster activity rhythms was investigated. Stereotaxically implanted guide cannulae aimed at the region of the SCN were used to deliver repeated microinjections in individual animals. A phase-response curve (PRC) generated from microinjections of muscimol revealed that the magnitude and direction of permanent phase-shifts in the activity rhythm were associated with the time of administration. The PRC generated for muscimol was characterized by maximal phase-advances induced 6 h before activity onset and by maximal phase-delays which occurred 6 h after activity onset. The PRC for muscimol had a shape similar to a PRC previously generated for the short-acting benzodiazepine, triazolam. Single microinjections of different doses of muscimol given 6 h before activity onset induced phase-advances in a dose-dependent fashion. Histological analysis revealed that phase shifts induced by the administration of muscimol were associated with the proximity of the injection site to the SCN area. These data indicate that a GABAergic system may exist within the suprachiasmatic region as part of a central biological clock responsible for the regulation of the circadian rhythm of locomotor activity in the golden hamster.

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Abbreviations

CT :

circadian time

GABA :

gamma-aminobutyric acid

OC :

optic chiasm

PRC :

phase-response curve

SEM :

standard error of mean

SCN :

suprachiasmatic nuclei

T :

track

IIIV :

third ventricle

References

  • Albers HE, Ferris CF (1984) Neuropeptide Y: role in light-dark cycle entrainment of hamster circadian rhythms. Neurosci Lett 50:163–168

    Google Scholar 

  • Andrews PR, Johnston GAR (1979) Commentary: GABA agonists and antagonists. Biochem Pharmacol 28:2697–2702

    Google Scholar 

  • Barker JL, Owen DG (1986) Electrophysiological pharmacology of GABA and diazepam in cultured CNS neurons. In: Olsen RW, Venter JC (eds) Benzodiazepine/GABA receptors and chloride channels: structural and functional properties. AR Liss, New York, pp 135–165

    Google Scholar 

  • Boulos Z, Rusak B (1982) Circadian phase response curves for dark pulses in the hamster. J Comp Physiol 146:411–417

    Google Scholar 

  • Bruunmeyer SE (1987) The GABA benzodiazepine receptor chloride ionophore complex — nature and modulation. Prog Neuropsychopharm Biol Psychiatr 11:365–387

    Google Scholar 

  • Card JP, Moore RW (1984) The suprachiasmatic nucleus of the golden hamster: immunocytochemical analysis of cell and fiber distribution. Neuroscience 13:415–431

    Google Scholar 

  • Daan S, Pittendrigh CS (1976) A functional analysis of circadian pacemakers in nocturnal rodents. II. The variability of phase response curves. J Comp Physiol 106:253–266

    Google Scholar 

  • Enna SJ, Karbon EW (1986) GABA receptors: an overview. In: Olsen RW, Venter JC (eds) Benzodiazepine/GABA receptors and chloride channels: structure and functional properties. AR Liss, New York, pp 41–56

    Google Scholar 

  • Gilman AG, Goodman LS, Gilman A (1980) Goodman and Gilman's the pharmacological basis of therapeutics. In: Gilman AG, Goodman LS, Gilman A (eds) Goodman and Gilman's the pharmacological basis of therapeutics, 6th edn. Macmillan, New York, pp 344–346

    Google Scholar 

  • Haefely WE, Kyberz M, Gereck M, Mohler H (1985) Recent advances in the molecular pharmacology of benzodiazepine receptors and in the structure-activity relationships of their agonists and antagonists. In: Testa B (ed) Advances in drug research. Academic Press, London, pp 171–179

    Google Scholar 

  • Houpt TA, Mistlberger RE, Moore-ede MC (1987) Optic enucleation attenuates the phase shifting effects of diazepam on hamster circadian rhythms. Soc Neurosci Abstr Pt1 13:422

    Google Scholar 

  • Inouye ST, Takahashi J, Wollnik F, Turek F (1988) Inhibition of protein synthesis phase shifts a circadian pacemaker in the mammalian SCN. Am J Physiol 255:R1055-R1058

    Google Scholar 

  • Johnson RF, Smale L, Moore RY, Morin LP (1988) Lateral geniculate lesions block circadian phase-shift responses to a benzodiazepine. Proc Natl Acad Sci USA 85:5301–5304

    Google Scholar 

  • Karobath M, Supavilai P (1986) Depressant drug interactions with benzodiazepine/GABA receptors. In: Olsen RW, Venter JC (eds) Benzodiazepine/GABA receptors and chloride channels: structural and functional properties. AR Liss, New York, pp 185–193

    Google Scholar 

  • Krogsgaard-Larsen P (1988) GABA synaptic mechanisms: stereochemical and conformational requirements. Med Res Rev 8:27–56

    Google Scholar 

  • Lader M (1983) Introduction to psychopharmacology. Upjohn Scope Publications, Michigan, pp 99–100

    Google Scholar 

  • McGeer PL, Eccles JC, McGeer EG (1987) Inhibitory amino acid transmitters. In: Molecular neurobiology of the mammalian brain, 2nd edn. Plenum Press, New York, pp 197–226

    Google Scholar 

  • Meijer JH, van der Zee EA, Dietz M (1988) Glutamate phase shifts circadian activity rhythms in hamsters. Neurosci Lett 86:177–183

    Google Scholar 

  • Moore RY (1982) The suprachiasmatic nucleus and the organization of a circadian system. Trends Neurosci 5:404–407

    Google Scholar 

  • Moore RY, Gustafson EL, Card JP (1984) Identical immunoreactivity of afferents to the rat suprachiasmatic nucleus with antisera against avian pancreatic polypeptide and neuropeptide Y. Cell Tissue Res 236:41–46

    Google Scholar 

  • Mrosovsky N (1988) Phase response curves for social entrainment. J Comp Physiol A 162:35–46

    Google Scholar 

  • Nielson M, Honore T, Braestrup C (1985) Radiation inactivation of brain [35S] t-butylbicyclophosphorothionate binding sites reveals complicated molecular arrangements of the GABA/benzodiazepine receptor chloride channel complex. Biochem Pharmacol 34:3633–3642

    Google Scholar 

  • Pickard GE (1982) The afferent connections of the suprachiasmatic nucleus of the golden hamster with emphasis on the retinohypothalamic projection. J Comp Neurol 211:65–83

    Google Scholar 

  • Ralph MR, Menaker M (1985) Bicuculline blocks circadian phase delays but not advances. Brain Res 325:362–365

    Google Scholar 

  • Ralph MR, Menaker M (1986) Effects of diazepam on circadian phase advances and delays. Brain Res 372:405–408

    Google Scholar 

  • Roberts E (1986) GABA: the road to transmitter status. In: Olsen RW, Venter JC (eds) Benzodiazepine/GABA receptors and chloride channels: structural and functional properties. AR Liss, New York, pp 1–39

    Google Scholar 

  • Rosenwasser AM, Adler NT (1986) Structure and function in circadian timing systems: evidence for multiple coupled circadian oscillators. Neurosci Biobehav Rev 10:431–448

    Google Scholar 

  • Saano V (1987) GABA-benzodiazepine receptor complex and drug actions. Med Biol 65:167–173

    Google Scholar 

  • Stephenson FA, Barnard EA (1986) Purification and characterization of the brain GABA/benzodiazepine receptor. In: Olsen RW, Venter JC (eds) Benzodiazepine/GABA receptors and chloride channels: structural and functional properties. AR Liss, New York, pp 261–274

    Google Scholar 

  • Swanson LW, Cowan WM, Jones EG (1974) An autoradiographic study of the efferent connections of the ventral lateral geniculate nucleus in the albino rat and the cat. J Comp Neurol 156:143–163

    Google Scholar 

  • Takahashi JS, Turek FW (1987) Anisomycin, an inhibitor of protein synthesis, perturbs the phase of a mammalian circadian pacemaker. Brain Res 405:199–203

    Google Scholar 

  • Takahashi JS, Zatz M (1982) Regulation of circadian rhythmicity. Science 217:1102–1111

    Google Scholar 

  • Turek FW (1985) Circadian neural rhythms in mammals. Annu Rev Physiol 47:49–64

    Google Scholar 

  • Turek FW, Losee-Olson SH (1986) A benzodiazepine used in the treatment of insomnia phase-shifts the mammalian circadian clock. Nature 321:167–168

    Google Scholar 

  • Turek FW, Losee-Olson SH (1987) Dose response curve for the phase-shifting effect of triazolam on the mammalian circadian clock. Life Sci 40:1033–1038

    Google Scholar 

  • Turek FW, Losee-Olsen S (1988) The circadian rhythm of LH release can be shifted by injections of a benzodiazepine in female golden hamsters. Endocrinology 122:756–758

    Google Scholar 

  • Van den Pol AN (1986) Gamma-aminobutyrate, gastrin releasing peptide, serotonin, somatostatin, and vasopressin: ultrastructural immunocytochemical localization in presynaptic axons in the suprachiasmatic nucleus. Neuroscience 17:643–659

    Google Scholar 

  • Van den Pol AN, Tsujimoto KL (1985) Neurotransmitters of the hypothalamic suprachiasmatic nucleus: immunocytochemical analysis of 25 neuronal antigens. Neuroscience 15:1049–1086

    Google Scholar 

  • Van Reeth O, Vanderhaeghen JJ, Turek FW (1988) A benzodiazepine antagonist, RO 15-1788 can block the phase-shifting effects of triazolam on the mammalian circadian clock. Brain Res 444:333–339

    Google Scholar 

  • Vitorica J, Park D, Chin G, Blas AL de (1988) Monoclonal antibodies and conventional antisera to the GABAa receptor/benzodiazepine receptor/Cl-channel complex. J Neurosci 8:615–622

    Google Scholar 

  • Wamsley JK, Donald GR, Olsen RW (1986) The benzodiazepine/barbiturate-sensitive convulsant/GABA receptor/chloride ionophore complex: autoradiographic localization of individual components. In: Olsen RW, Venter JC (eds) Benzodiazepine/GABA receptors and chloride channels: structural and functional properties. AR Liss, New York, pp 299–313

    Google Scholar 

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Smith, R.D., Inouye, S.I.T. & Turek, F.W. Central administration of muscimol phase-shifts the mammalian circadian clock. J. Comp. Physiol. 164, 805–814 (1989). https://doi.org/10.1007/BF00616752

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