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Involvement of Dopamine D2 and 5-HT IA Receptors in Roxindole-Induced Antinociception

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Indi an Journal of Experiment al Biology Vol. 37, March 1999, pp. 23 4-237 Involvement of dopamine D2 and 5-HT IA receptors in roxindole-induced antinociception Ipe Ninan & S K Kulkarni* Ph armaco logy Di vision, Universit y In stitute of Pharmaceutical Sciences, Panj ab Uni versity, Chand igarh )60014, Indi a Received 23 March 1998; revi sed 27 November 1998 Rox i Il dole. a DA O2 receptor ago ni st (2-1 6 mglkg) produ ced dose-dependent i ncrease in percent age <I ntinociceptio nT he effect whi ch was bl ocked by DA O2 antago ni st (-)s ulpiride (50 mglkg) and 5-HTIAr eceptor antagoni st (-) pin do lol (5 mg/kgl. Rox in do le (4 and 8 mglkg) reversed both nalo xo ne (20 mglkg)-induced hyperalgesia and reserpine (2 mg/kg)-i nduced hyperalgesia. Th is reversal was sensiti ve to blockade by both (-)su lpiri cte (50 mglkg) and (-) pindolol (5 mg/kg). The presen t stud y s~ges t s th at ro xindol e-induced ant inocicepti on is mediated by postsynaptic DA D2 and 5-HTIA rece pt ors. Rox indole (EMD 49980) is a representati ve of a new severe pain associated with various states of di sease class of dopaminergic drugs, I. e., the indolyl affecting the nervous system, such as. the thalamic butylamines. whi ch lac k structural similarities with syndrome, herpes zoster and Parkinson's either ri gid dopamine (DA ) analogs or ergot di sease' 1.l 2.'J.'4. and a recent study showed that 8-0H deri vatives '. Rox indole ex hibits potent , long lasting DPA T inhibits nociceptive responses by stimulating lS and hi ghl y se le cti ve agoni sti c ac ti ons at presynaptic postsy naptic 5- HT IA recept ors . Dl recept ors with out sti mul atin g pos tsy naptic D2 The present study was undert aken to investi gate the 2 recept ors even at hi gh doses . This selec ti vity makes rol e of D2 and 5-HTI Ar ecept ors in the antinoc iception rox indole a pre-eminent candidate for a novel type of produced by rox indole in nai ve and reserpinised antipsyc hoti c drug wi th out neurological side effects mice. whi ch limit th e usefuln ess of conventi onal D2 Materials and! Methods recept or bl ockers. Within th e past few years, several Allima/s--8 alb/C mi ce (bred in Central Animal new putati ve. selecti ve DA autoreceptor agoni sts House facility of Panj ab Uni versity), weighing 20-25 have been developed, among them are the transfu sed g, were housed under a standard 12 h Iightll2 h dark analog of 3-PPP, (-)-HW 165 , the cycle. The animals were acclimatized to the transdih ydroergo lin e terguri de and the amino­ laboratory condi tions with free access to food and ergo lin es SDZ 208-9 12 (ref. 3-5). Interest in these water for 24 h before th e ex periment. All experiments putati ve DA Ll ut oreceptor ago ni sts derives largely were undert aken between 09.00 and 13.00 h. from th eir potential use as non-class ical antipsychoti c Technique--The nocicepti ve threshold was drugs. Rox indole, bes id es it s affinit y for Dl receptors, 2 determined as the tail-flick latencies eli cited in has affinity for the 5-HT' A recept or als0 . response to noxI.o us ra dlant' heat·. 16 17 B ase Im' e Consid erable clini cal ev idence suggests th at DA latencies to tail-fl ick withdrawal from th e radi ant heat rece pt or-medi ated mec hani sms may play an important source (3 -4 s) were established. A cut off time of 10 s ro le in modul atin g pa in in humans. A number of was observed to prevent any inj ury to the tail. A animal studies ha ve showed th at DA is involved in minimum of three tria ls, at 2 min intervals, were the regul ati on of noc icepti on. However, th e data recorded for each animal before the test. reported are contradic tory and DA agonis ts have been 6 Antinocicepti on was calcul ated accord ing to the shown to produce either antinocicepti on .7 or 8 y foll owin g fo rmul a: % an tinociceptio ll = 100x(test hyperalgesia . or to have both effects 10. However, latency - basel in e latency) / ( 10 - base li ne latency). some DA agonists have been reported to suppress the Drugs-Roxindo le mesy late (EMD 49980, Merck *Co rres pondent auth or KGaA Biomed Res CNS, Germany), (-) sulp iride NINAN & KULKARNI : DA D2 AND 5-HT1A RECEPTORS IN ROXINDOLE-INDUCED ANllNOCICEPTION 235 hydrochl oride (Research Biochemicals Inc, MA, dissolved in a drop of dilute HCI, volume made up USA), naloxone hydrochloride (Sigma, USA), (-) with di stilled water and pH adequately adjusted. All pindolol (Ranbaxy, India) and reserpine (Loba the drugs were administered intraperitoneally in a Chemicals, India) were used in the study. The drug constant volume of I m1I1oo g of body weight. The solutions were made in di stilled water, except selection of doses was based on previous reports from reserpine and (-) pindolol. Reserpine was dissolved our laboratory. Each group comprised 5-10 mice In a drop of gl acial acetic ac id while pindolol was Reserpine (2 mglkg) was administered 4 h prior Table I-Reversal of naloxone-induced hyperalgesia by roxindole and its modifi cation by (-) sulpiride and (-) pindolol in mice No. Treatment (mg/kg) % Antinociception (Mean±SE) Saline O.ss±oo 2 Naloxone (20) -36.27±4.26 3 Roxindole (4)+Naloxone (20) 2 1.60±1.63' 4 Roxindole (S)+Naloxone (20) S.04±O.S7" S Sul piride (SO)+Roxindole (4)+Naloxone (20) 0. 16±O. lOh 6 Sulpiride (SO)+Roxindole (S)+Naloxone (20) - S.6S±O.3S C 7 Pindolol (S)+Roxindole (4)+Naloxone (20) -9. IS±O.42h S Pindolol (S)+Roxindole (S)+Naloxone (20) - 10.4±O.06C "P<O .OO I as compared to group 2; hp<O.OO I as compared to group 3; cP<O.OO I as compared to group 4 90 80 ::E -w en 70 +f c: CU 60 Q) ::E c: 50 0 ;; Q. Q) 40 .2 u 30 c:0 ;; a c: 20 a « b C 0~ d 10 b 0 2 4 8 16 2 4 8 16 2 4 8 16 Saline Sulpiride (50) Pindolol (5) Fi g. I-Anti nociceptive effect of roxindole (2- 16 mg/kg) and its modification by (-) sulpiride (SO mg/kg) and (-) pindolol (5 mg/kg) in mi ce. a. h .c. ~ P<O.OO 1 as compared to roxindole (2, 4 , S and 16 mg/kg) groups, respectively. 236 INDIAN J EXP BIOL, MARCH 1999 Tab le 2-Reversal of reserpine (4 h post)-induced hyperalgt:sia by Reserpine (2 mglkg, 4 hr prior) pre-treatment roxi ndole and its modification by (-) sulpiride and (-) pindolol significantly reduced percentage antinociception. The respectively in mice reserpine-induced reduction in the nociceptive No. Treatment (mg/kg) % threshold was reversed by roxindole (4 and 8 mglkg) Antinociception (P<O.OOI). Both (-) sulpiride (50 mglkg) and (-) (Mean±SE) Saline O.8S±OO pindolol (5 mglkg) blocked the reversal of hyperalgesia by roxindole (P<O.OOI) (Table 2). 2 Reserpine (2) -1 8.30±O.SI 3 Reserpine (2)+Roxindole (4) l2,46±O.78a Discussion The present. study demonstrates that acute a 4 Reserpine (2)+Roxi ndole (8) 23.34±1.36 administration of D2 autoreceptor selective agonist, roxindole produced an antinociceptive response in 5 Reserpine (2)+Sulp iride (50)+Roxindole (4) - 12.93±O.13h mice. Previously, Verma and Kulkarni' (1993) have 6 Reserpine (2)+Sulpiride (50)+Roxindole (8) - I 1. 04±O.78c reported that DA agoni sts such as B-HT 920, bromocriptine and apomorphine produced 7 Reserpine (2)+Pindolol (S)+Roxindole (4) - 13 .09±O.74h 7 antinociception . The antinociceptive response 8 Reserp ine (2)+Pindolol (S)+Roxindole -(8) - IO.41±O,42c elicited by roxindole was blocked by (-) sulpiride, a D2 antagonist and (-) pindolol, a selective 5-HTIA ·P<O.OOI as compared to group 2; hp<O.OOI as compared to group antagonist. The available literature suggests the 3: c P<O.OO I as compared to group 4 involvement of postsynaptic O2 receptors in antmoctceptlOn. 7' 18. 19 . PrevlOu' s stud t' es s howe d t hat D 2 and naloxone 15 min prior to the experiment. agoni sts do not show antinociceptive effect at doses Roxindole was administered 30 min prior to the test. which stimulate autoreceptors'. Therefore, the The DA receptor ant agoni sts (-)sulpiride and 5-HT IA possibility of involvement of presynaptic D2 receptors ant agoni st (-) pindolol were administered 30 min in this antinociceptive effect is rare. The prior to the agoni sts. anti nociceptive effect produced by roxindole was STaTis Ti cal analysis- The data was analyzed using blocked by both (-) sulpiride, a selective O2 one way ANOV A foll owed by student's (-test and antagoni st and (-) pindolol, a 5-HTIA antagonist. It is P<0.05 was considered statist icall y significant. known that 5-HTIA receptors control DA neurotransmission in several brain areas20.21 .22. The 5- Results HTI A agoni st, 8-0H DPAT increases locomotor 2 AIl Till ociceptive effecT of roxindole and its reversal acti vi ty in rats ] .24 .
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    Mehta Hiren R et al. IRJP 2011, 2 (12), 132-138 INTERNATIONAL RESEARCH JOURNAL OF PHARMACY ISSN 2230 – 8407 Available online www.irjponline.com Review Article NEW INSIGHTS INTO MOLECULAR TARGETS FOR DEPRESSION Mehta Hiren R1*, Prakash B. Thakkar2, Vishal R. Vekariya3, Indermeet Singh Anand4 1Gujarat Technological University, Ahmedabad, India 2Shri Sarvajanik Pharmacy College, Mehsana-384001, Gujarat, India 3National Institute of Pharmaceutical Education and Research (NIPER), Guwahati-781032, Assam, India 4 Professor and HOD of Pharmacology, Shri Sarvajanik Pharmacy College, Mehsana - 384001, Gujarat, India Article Received on: 19/10/11 Revised on: 20/11/11 Approved for publication: 17/12/11 *E-mail: [email protected] ABSTRACT Major depressive disorder is a heritable neuropsychiatric syndrome characterized by relatively subtle cellular and molecular alterations localized to a complex network of neural substrates. Various forms of psychotherapy, pharmacotherapy, and electroconvulsive therapy (ECT) are currently the most commonly used antidepressant treatments. Despite adequate care with currently available treatments, up to 70% of depressed patients have residual symptoms, and, even with more aggressive therapies, 20% or more may show only a limited response. The need for newer compounds to treat depression is still an ever growing concern due to the enormous societal and famifications of depression. This review covers all the monoaminergic (SSRI/5-HT1A antagonists, SSRI/5-HT2C antagonists, SSRI/alpha-2 adrenergic antagonists, triple reuptake inhibitors, dopamine agonists, targeting GABA) and beyond monoaminergic strategies including corticotropin-releasing factor (CRF)-1 receptor antagonists, Inhibition of glucocorticoid function, substance P (Nk-1) antagonists, MCH1 receptor antagonists, Gal3 receptor antagonists, arginine vasopressin as the potential novel targets for depression.
  • Phencyclidine Increases Forebrain Monoamine Metabolism in Rats and Monkeys: Modulation by the Isomers of HA966

    Phencyclidine Increases Forebrain Monoamine Metabolism in Rats and Monkeys: Modulation by the Isomers of HA966

    The Journal of Neuroscience, March 1, 1997, 17(5):1769–1775 Phencyclidine Increases Forebrain Monoamine Metabolism in Rats and Monkeys: Modulation by the Isomers of HA966 J. David Jentsch,1 John D. Elsworth,2,3 D. Eugene Redmond Jr.,2,4 and Robert H. Roth2,3 Departments of 1Neurobiology, 2Psychiatry, 3Pharmacology, and 4Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06510 The noncompetitive NMDA receptor antagonist phencyclidine enantiomer altered the effect of PCP on DA turnover in the (PCP) has psychotomimetic properties in humans and activates nucleus accumbens or the PCP-induced increases in serotonin the frontal cortical dopamine innervation in rats, findings that turnover in PFC. PCP (0.3 mg/kg, i.m.) exerted regionally se- have contributed to a hyperdopaminergic hypothesis of schizo- lective effects on the dopaminergic and serotonergic innerva- phrenia. In the present studies, the effects of the enantiomers of tion of the monkey frontal cortex, effects blocked by pretreat- 3-amino-1-hydroxypyrrolid-2-one (HA966) on PCP-induced ment with S-(2)HA966 (3 mg/kg, i.m.). Importantly, these data changes in monoamine metabolism in the forebrain of rats and demonstrate that in the primate, PCP has potent effects on monkeys were examined, because HA966 has been shown dopamine transmission in the frontal cortex, a brain region previously to attenuate stress- or drug-induced activation of thought to be dysfunctional in schizophrenia. In addition, a role dopamine systems. In rats, PCP (10 mg/kg, i.p.) potently acti- for S-(2)HA966 as a modulator of cortical monoamine trans- vated dopamine (DA) turnover in the medial prefrontal cortex mission in primates is posited.