Brazilian Journal of Medical and Biological Research (21) 34: 675-682 Effects of diazepam and SB 26553 in SHR and Lewis rats ISSN 1-879X 675 Strain-dependent effects of diazepam and the 5-HT 2B/2C receptor antagonist SB 26553 in spontaneously hypertensive and Lewis rats tested in the elevated plus-maze R.N. Takahashi 1, O. Berton 2,3, P. Mormède 2 and F. Chaouloff 2 1 Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brasil 2 NeuroGénétique et Stress, INSERM U471-INRA, Bordeaux, France 3 UCB Pharma, Preclinical CNS Research, Braine-L Alleud, Belgium Correspondence R.N. Takahashi Departamento de Farmacologia, UFSC R. Ferreira Lima, 82 8815-42 Florianópolis, SC Brasil Fax: +55-48-222-4164 E-mail: takahashi@farmaco.ufsc.br Presented at the XIII Annual Meeting of the Federação de Sociedades de Biologia Experimental, Caxambu, MG, Brazil, August 26-29, 1998. Received September 15, 2 Accepted February 5, 21 Abstract Key words Anxiety Diazepam Elevated plus-maze Lewis rats Spontaneously hypertensive rats Locomotor activity m-chlorophenylpiperazine SB 26553 Introduction Braz J Med Biol Res 34(5) 21
676 R.N. Takahashi et al. Material and Methods Subjects Procedure Braz J Med Biol Res 34(5) 21
Effects of diazepam and SB 26553 in SHR and Lewis rats 677 Material Statistical analysis Results Behavioral effects of diazepam Behavioral effects of SB 26553 Braz J Med Biol Res 34(5) 21
678 R.N. Takahashi et al. Discussion Figure 1 - Effects of diazepam administered ip (3 min before testing) in Lewis (LEW) and spontaneously hypertensive rats (SHR) tested for 5 min in the elevated plus-maze. Results are reported as the mean ± SEM for 9-1 rats. + P<.5 for the interstrain difference between vehicle-treated rats (Tukey test). P<.5, at least for the effects of diazepam against vehicle (Dunn or Tukey test). Open arm entries (%) 8 6 4 2 LEW SHR Time in open arms (%) 8 6 4 2 +..37.75 1.5..37.75 1.5 12 15 1 12 Closed arm entries 8 6 4 Total arm entries 9 6 2 3..37.75 1.5..37.75 1.5 Diazepam (mg/kg) Diazepam (mg/kg) Braz J Med Biol Res 34(5) 21
Effects of diazepam and SB 26553 in SHR and Lewis rats 679 Open arm entries (%) 8 6 4 2 + LEW SHR Time in open arms (%) 8 6 4 2 + Figure 2 - Effects of SB 26553 administered ip (3 min before testing) in Lewis (LEW) and spontaneously hypertensive rats (SHR) tested for 5 min in the elevated plus-maze. Results are reported as the mean ± SEM for 6-1 rats. + P<.5 for the interstrain difference between vehicle-treated rats (Dunn or Tukey test). P<.5, at least for the effects of SB 26553 against vehicle (Tukey test).. 1.25 2.5 5.. 1.25 2.5 5. 15 12 2 15 Closed arm entries 9 6 3 Total arm entries 1 5 +. 1.25 2.5 5.. 1.25 2.5 5. SB 26553 (mg/kg) SB 26553 (mg/kg) Beam breaks LEW SHR.9% NaCl mcpp (1.5 mg/kg) 4 3 2 1 + Figure 3 - Effects of m-chlorophenylpiperazine (mcpp) and saline administered ip on vehicle- and SB 26553- pretreated Lewis (LEW) and spontaneously hypertensive rats (SHR) 2 min before testing in activity cages for 15 min. These animals were immediately injected with saline or mcpp after completion of the plus-maze test (same rats as in Figure 2). Results are reported as the mean ± SEM for 6-1 rats. + P<.5 for the interstrain difference between vehicle-pretreated (mcppinjected) rats (Tukey test). P<.5, at least for the difference from vehicle-pretreated (saline-injected) rats (Tukey test)... 1.25 2.5 5. SB 26553 (mg/kg) Braz J Med Biol Res 34(5) 21
68 R.N. Takahashi et al. Braz J Med Biol Res 34(5) 21
Effects of diazepam and SB 26553 in SHR and Lewis rats 681 Acknowledgments References 1. Whitton P & Curzon G (199). Anxiogeniclike effect of infusing 1-(3-chlorophenyl) piperazine (mcpp) into the hippocampus. Psychopharmacology, 1: 138-14. 2. Kennett GA (1993). 5-HT 1C receptors and their therapeutic relevance. Current Opinion in Investigation Drugs, 2: 317-362. 3. Kennett GA (1992). 5-HT 1C receptor antagonists have anxiolytic-like actions in the rat social interaction model. Psychopharmacology, 17: 379-384. 4. Kennett GA, Pittaway K & Blackburn TP (1994). Evidence that 5-HT 2C receptor antagonists are anxiolytic in the rat Geller- Seifter model of anxiety. Psychopharmacology, 114: 9-96. 5. Forbes IT, Kennett GA, Gadre A, Ham P, Hayward CJ, Martin RT, Thompson M, Wood MD, Baxter GS, Glen A, Murphy OE, Stewart B & Blackburn TP (1993). N- (1-Methyl-5-indolyl)-N -(3-pyridyl)urea hydrochloride: the first selective 5-HT 1C receptor antagonist. Journal of Medicinal Chemistry, 36: 114-117. 6. Kennett GA, Bailey F, Piper DC & Blackburn TP (1995). Effect of SB 2646A, a 5-HT 2C /5-HT 2B receptor antagonist, in two conflict models of anxiety. Psychopharmacology, 118: 178-182. 7. Kennett GA, Wood MD, Bright F, Cilia J, Piper DC, Gager T, Thomas D, Baxter GS, Forbes IT, Ham P & Blackburn TP (1996). In vitro and in vivo profile of SB 26553, a potent 5-HT 2C /5-HT 2B receptor antagonist with anxiolytic-like properties. British Journal of Pharmacology, 117: 427-434. 8. Griebel G, Perrault G & Sanger DJ (1997). A comparative study of the effects of selective and non-selective 5-HT 2 receptor subtype antagonists in rat and mouse models of anxiety. Neuropharmacology, 36: 793-82. 9. Kennett GA & Curzon G (1988). Evidence that mcpp may have behavioral effects mediated by 5-HT 1C receptors. British Journal of Pharmacology, 94: 137-147. 1. Kulikov A, Aguerre S, Berton O, Ramos A, Mormède P & Chaouloff F (1997). Central serotonergic systems in the spontaneously hypertensive and Lewis rat strains that differ in the elevated plus-maze test of anxiety. Journal of Pharmacology and Experimental Therapeutics, 281: 775-784. 11. Pellow S, Chopin P, File SE & Briley M (1985). Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. Journal of Neuroscience Methods, 14: 149-167. 12. Ramos A, Berton O, Mormède P & Chaouloff F (1997). A multiple-test study of anxiety-related behaviours in six inbred rat strains. Behavioural Brain Research, 85: 57-69. 13. File SE (1991). The biological basis of anxiety. In: Meltzer HY & Nerozzi D (Editors), Current Practices and Future Developments in the Pharmacotherapy of Mental Disorders. Elsevier, Amsterdam, The Netherlands, 159-165. Braz J Med Biol Res 34(5) 21
682 R.N. Takahashi et al. 14. Cruz APM, Frei F & Graeff F (1994). Ethopharmacological analysis of rat behavior on the elevated plus-maze. Pharmacology, Biochemistry and Behavior, 49: 171-176. 15. Smith CC, Hauser E, Renaud NK, Leff A, Aksentijevich S, Chrousos GP, Wilder RL, Gold PW & Sternberg EM (1992). Increased hypothalamic [ 3 H]-flunitrazepam binding in hypothalamic-pituitary-adrenal axis hyporesponsive Lewis rats. Brain Research, 569: 295-299. 16. Pesold C & Treit D (1994). The septum and amygdala differentially mediate the anxiolytic effects of benzodiazepines. Brain Research, 638: 295-31. 17. Pesold C & Treit D (1995). The central and basolateral amygdala differentially mediate the anxiolytic effects of benzodiazepines. Brain Research, 671: 213-221. 18. McCreary AC & Cunningham KA (1999). Effects of the 5-HT 2C/2B antagonist SB 26553 on hyperactivity induced by cocaine. Neuropsychopharmacology, 2: 556-564. 19. Lejeune F, Gobert A, Rivet JM & Millan MJ (1997). Serotonin (5-HT) 2C receptors inhibit the activity of mesocortical and mesolimbic dopaminergic pathways: a combined dialysis and electrophysiological analysis. Society for Neuroscience Abstracts, 23: 975. 2. De Deurwaerdère P & Spampinato U (1999). Role of serotonin 2A and serotonin 2B/2C receptor subtypes in the control of accumbal and striatal dopamine release elicited in vivo by dorsal raphe nucleus electrical stimulation. Journal of Neurochemistry, 73: 133-142. 21. Di Giovanni G, De Deurwaerdère P, Di Mascio M, Di Matteo V, Esposito E & Spampinato U (1999). Selective blockade of serotonin-2c/2b receptors enhances mesolimbic and mesostriatal dopaminergic function: a combined in vivo electrophysiological and microdialysis study. Neuroscience, 91: 587-597. Braz J Med Biol Res 34(5) 21