Reduction of extracellular dopamine and metabolite concentrations in rat striatum by low doses of acute cyamemazine
- 65 Downloads
The low incidence of extrapyramidal effects with atypical neuroleptics has been ascribed to their 5-HT2A- and 5-HT2C-serotonin receptor antagonistic properties. On the other hand, the acute increase in striatal dopamine release by submaximal dopamine D2 autoreceptor blockade can be respectively reduced and increased by 5-HT2A- and 5-HT2C-antagonists. Cyamemazine is a neuroleptic D2- and 5-HT2A-receptor antagonist, with small antagonistic activity at 5-HT2C receptors and low incidence of extrapyramidal side effects. Therefore, submaximal cyamemazine was tested in rats for its acute action on the extracellular concentrations of dopamine and dopamine metabolites (DOPAC: 3,4,dihydroxyphenylacetic acid and HVA: 4-hydroxy-3-methoxy-phenyl-acetic acid) in the corpus striatum. The serotonin metabolite 5-HIAA (5-hydroxy-indole-acetic acid) was measured in parallel. Rats prepared for microdialysis (striatum) were intraperitoneally given cyamemazine 1 mg/kg, 5 mg/kg or vehicle (n=4 in each group). Dopamine, DOPAC, HVA and 5-HIAA concentrations in perfusates under basal conditions and after stimulation by high K+ were measured by HPLC coupled to electrochemical detection. Cyamemazine 1 mg/kg significantly reduced extracellular concentrations of basal dopamine (−77%), DOPAC (−54%), HVA (−54%) and 5-HIAA (−65%). No such effects were seen with the dose of cyamemazine 5 mg/kg or for K+-evoked dopamine release. In conclusion, submaximal cyamemazine can acutely reduce basal dopamine release and metabolism in the rat striatum. Such unusual action can be explained by the original pharmacological profile of cyamemazine (potent D2- and 5-HT2A-antagonist, with small antagonistic activity at 5-HT2C receptors). Further experiments are required to explain the low incidence of extrapyramidal side actions with cyamemazine.
KeywordsCyamemazine Microdialysis Dopamine Serotonin Striatum Rat
We are greatly indebted to E. Garay (Pharmalex s.a., Paris, France), who helped with the coordination and monitoring of this study.
- Alvarez-Guerra M, d'Alché-Birée F, Wolf WA, Vargas F, Dib M, Garay RP (2000) 5-HT3- and 5-HT2C-receptor antagonist properties of cyamemazine: significance for its clinical anxiolytic activity. Psychopharmacology 147:412–417Google Scholar
- Alvarez-Guerra M, Hameg A, Dib M, Garay RP (2002) 5-HT2A-receptor antagonist properties of cyamemazine in rat and guinea pig smooth muscle. Eur J Pharmacol 454:235–239Google Scholar
- Dubroca JM (1989) L'anxiolyse: intérêt de la cyamémazine. Neuro-Psy :4–7Google Scholar
- Dyr W, Kostowski W (1997) Effects of 5-HT3 receptor agonists on voluntary ethanol intake in rats maintained on a limited access procedure. Alcool 32:455–462Google Scholar
- Garay RP, d'Alché-Birée F (1995) Cyamémazine (Tercian®): profil neuroleptique ou anxiolytique ?. Inf Psychiatr 10:969–970Google Scholar
- Julou L, Ducrot R, Fournel J, Leau O, Bardone MC, Myon J (1961) Etude des propriétés pharmacologiques de la cyano-3 (diméthyl-3' méthyl-2 propyl)-10 phénotiazine ou cyamépromazine (7.204 R.P.) Comptes Rendus Soc Biol 155:1029–1034Google Scholar
- Lucas G, De Deurwaerdère, Caccia S, Spampinato U (2000) The effect of serotoninergic agents on haloperidol-induced striatal dopamine release in vivo: opposite role of 5-HT2A and HT2C receptor subtypes and significance of the haloperidol dose used. Neuropharmacology 39:1053–1063Google Scholar
- Meltzer HY (1999) The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 21 [Suppl 2]:106S–115SGoogle Scholar
- Radat F (1995) Cyamémazine: traitement symptomatique des dimensions anxieuses, impulsives et agressives. Inf Psychiatr 10:967–968Google Scholar
- Sotnikova TD, Gainetdinov RR, Grekhova TV, Rayevsky KS (2001) Effects of intrastriatal infusion of D2 and D3 dopamine receptor preferring antagonists on dopamine release in rat dorsal striatum. Pharmacol Res 43:283–290Google Scholar