Bayram YILMAZ, Süleyman SANDAL, Sinan CANPOLAT, Selim KUTLU, Haluk KELEŞTİMUR

Kappa opioid modulation of serotonergic neurotransmission in the hypothalamus, Hippocampus and striatum in the male rat

Amaç: Bu çalışma, kappa opioid reseptörlerinin hipotalamus, hipokampus ve striatum'da serotonerjik nörotransmisyon üzerine modülatör etkilerinin araştırılması amacıyla yapıldı. Gereç ve Yöntem: Deneylerde kullanılan toplam 32 erkek Sprague-Dawley sıçan dört gruba ayrıldı. Anestezi altına alınan sıçanlar stereotaksik cihaza yerleştirildikten sonra, U-50488H (κ agonist, 50µg/kg), Nor-Binaltorphimine (Nor-BIN, kappa antagonist, 50µg/kg) veya U-50488H + Nor-BIN intraserebroventriküler (ICV) yolla infüze edildi. Kontrol grubunu oluşturan hayvanlara ise aynı yolla serum fizyolojik uygulandı. ICV infüzyonlardan 30 dk sonra tüm sıçanlar dekapite edilerek beyinleri hızla kuru buz üzerine alındı. Mikrodiseksiyon yöntemiyle hipokampus, hipotalamus ve striatum bölgeleri çıkartılarak sıvı nitrojende donduruldu. Bu beyin bölgelerindeki 5-hydroxytryptamin (5-HT) ve 5-hydroxyindole acetic acid (5-HIAA, 5-HT metaboliti) düzeyleri HPLC-ECD yöntemiyle belirlendi. Bulgular: 5-HT ve 5-HIAA değerleri (ng/gr doku) U-50488H grubu hipotalamus ve hipokampus bölgelerinde kontrol grubuna göre anlamlı derecede azaldı (p

Anahtar Kelimeler:

Sinaptik transmisyon, 3, 4-Dikloro-N-metil-N-(2-(1-pirolidinil)-siklohekzil)-benzeneasetamit, (trans)-izomer, Reseptörler, opioid, kappa, Serotonin, Sıçan, Sprague-Dawley, Modeller, hayvan

Kappa opioid reseptörlerin sıçan hipokampus, hipotalamus ve striatum bölgelerinde serotonerjik nörotransmisyonu modülasyonu

Objectives: We have investigated the modulatory effects of κ-opioid receptors on the central serotonergic system in the hypothalamus, hippocampus and striatum. Materials and Methods: Male Sprague-Dawley rats (n=32) used in the experiments were divided into four groups. Anaesthetized animals were mounted on a stereotaxic apparatus and intracerebroventricularly infused with U-50488H (κ-agonist, 50µg/kg), Nor-BIN (κ-antagonist, 50µg/kg) or U-50488H + Nor-BIN. Control group received saline alone. All animals were decapitated 30 mins after infusions. Hypothalamus, hippocampus and striatum were microdissected and snap frozen. Concentrations of 5-hydroxytryptamin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA, 5-HT metabolite) in these brain regions were determined by HPLC-ECD. Results: 5-HT and 5-HIAA values in the hypothalamus and hippocampus of U-50488H-treated group were significantly decreased compared to control group (p<0.01 and p<0.05). Indoleamine levels (ng/gr tissue) in the κ-antagonist group were found to be similar to or slightly lower than the control values (p<0.05). Nor-BIN reversed the U-50488H inhibition of 5-HT release in the agonist+antagonist treated group (p<0.001). 5-HT levels in the striatum of all three groups were significantly higher than control group (p<0.01), 5-HIAA concentrations in the same brain region significantly decreased (p<0.001). Ratio of 5-HIAA/5-HT in the hypothalamus, hippocampus and striatum was significantly (p<0.05 and p<0.001, respectively) lowered by the κ-agonist. Conclusion: These results suggest that κ-opioid receptors modulate serotonergic neurotransmission in the hypothalamus, hippocampus and striatum.

Keywords:

Synaptic Transmission, 3, 4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer, Receptors, Opioid, kappa, Serotonin, Rats, Sprague-Dawley, Models, Animal,

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1) Filip M, Wydra K, Inan SY, Dziedzicka-Wasylewska M, Przegalinski E. Opioid and monoamine systems mediate the discriminative stimulus of tramadol in rats. Eur J Pharmacol 2004; 498: 143-51.
2) Tao R, Auerbach SB. mu-Opioids disinhibit and kappa-opioids inhibit serotonin efflux in the dorsal raphe nucleus. Brain Res 2005; 1049: 70-79.
3) Yoshioka M, Matsumoto M, Togashi H, Smith CB, Saito H. Opioid receptor regulation of 5-hydroxytryptamine release from the rat hippocampus measured by in vivo microdialysis. Brain Res 1993; 613: 74-79.
4) Harris GC, Aston-Jones G: Augmented accumbal serotonin levels decrease the preference for a morphin eassociated environment during withdrawal. Neuropsychopharmacol 2001; 24: 75-85.
5) Tao R, Auerbach SB. Increased extracellular serotonin in rat brain after systemic or intraraphe administration of morphine. J Neurochem 1994; 63: 517-524.
6) Yılmaz B, Gilmore DP. Mu and kappa opioid modulation of the hypothalamic serotonergic neurotransmission in the ovariectomised and steroid-primed rat. Med Sci Res 1999; 27: 91-94.
7) Jolas T, Nestler EJ, Aghajanian GK. Chronic morphine increases GABA tone on serotonergic neurons of the dorsal raphe nucleus: association with an up-regulation of the cyclic AMP pathway. Neurosci 2000; 95: 433-443.
8) Passarelli F, Costa T. Mu and delta opioid receptors inhibit serotonin release in rat hippocampus. J Pharm Exp Ther 1989; 248: 299-305.
9) Tao R, Auerbach SB. Involvement of the dorsal raphe but not median raphe nucleus in morphine-induced increases in serotonin release in the rat forebrain. Neurosci 1995; 68: 553-561.
10) Jolas T, Aghajanian GK. Opioids suppress spontaneous and NMDA-induced inhibitory postsynaptic currentsin the dorsal raphe nucleus of the rat in vitro. Brain Res 1997; 755: 229-245.
11) Pinnock RD. Activation of ∋-opioid receptors depresses electrically evoked excitatory postsynaptic potentials on 5-Htsensitive neurones in the rat dorsal raphe nucleus in vitro. Brain Res 1992; 583: 237-246.
12) Sbrenna S, Marti M, Morari M et al. Modulation of 5- hydroxytryptamine efflux from rat cortical synaptosomes by opioids and nociceptin. Br J Pharmacol 2000; 130: 425-433.
13) Johnson-Davis KL, Hanson GR, Keefe KA. Lack of effect of kappa-opioid receptor agonism on long-term methamphetamineinduced neurotoxicity in rats. Neurotox Res 2003; 5: 273-81.
14) Mansour A, Fox CA, Akil H, Watson SJ. Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci 1995; 18: 22–29.
15) Kalyuzhny AE, Wessendorf MW. Serotonergic and GABAergic neurons in the medial rostral ventral medulla express kappaopioid receptor immunoreactivity. Neurosci 1999; 90: 229-234.
16) Rosin A, van der Ploeg I, Georgieva J. Basal and cocaine-induced opioid receptor gene expression in the rat CNSanalyzed by competitive reverse transcription PCR. Brain Res 2000; 872: 102- 109.
17) Steinbusch HWM. Serotonin-immunoreactive neurons and their projections in the CNS. In: Bjorklund A, Hokfelt T, Kuhar MJ (Editors). Handbook of Chemical Neuroanatomy. Vol. 3, Amsterdam: Elsevier Science Publisher, 1984: 68-125.
18) Makarenko IG, Meguid MM, Ugrumov MV. Distribution of serotonin 5-hydroxytriptamine 1B (5-HT(1B)) receptors in the normal rat hypothalamus. Neurosci Lett 2002; 328: 155-9.
19) Yılmaz B, Gilmore DP, Wilson CA. Inhibition of the preovulatory LH surge in the rat by central noradrenergic mediation: involvement of an anaesthetic (urethane) and opioid receptor agonists. Biogenic Amines 1996; 12: 423-435.
20) Kiss J and Halasz B. Demonstration of serotoninergic axons terminating on luteinizing hormone-releasing hormone neurones in the preoptic area of the rat using a combination of immunocytochemistry and high resolution autoradiography. Neurosci 1985; 14: 69-78.
21) Gopalan C, Gilmore DP, Brown CH, Leigh A. Effects of opiates on biogenic amine turnover in specific hypothalamic areas on the afternoon of pro-oestrus in the rat-II: Serotonin. Biogenic Amines 1989; 6: 607-614.
22) Rivot JP, Pointis D, Besson JM. Morphine increases 5-HT metabolism in the nucleus raphe magnus: an in vivo study in freely moving rats using 5-hydroxyindole electrochemical detection. Brain Res 1998; 446: 333-342.
23) Carlezon Jr WA, Beguin C, Dinieri JA et al. Depressive-like Effects of the {kappa}-Opioid receptor agonist salvinorin A on behavior and neurochemistry in rats. J Pharmacol Exp Ther 2006; 316: In Press. PMID: 16223871