title: The cytisine derivatives, CC4 and CC26, reduce nicotine-induced conditioned place preference in zebrafish by acting on heteromeric neuronal nicotinic acetylcholine receptors.
abstract: BACKGROUND
  Cigarette smoking is one of the most serious health problems worldwide and people trying to stop smoking have high rates of relapse. Zebrafish (Danio rerio), by combining pharmacological and behavioral assays, is a promising animal model for rapidly screening new compounds to induce smoking cessation.
  
  
  OBJECTIVE
  This study aims to identify possible acetylcholine nicotinic receptors (nAChRs) involved in mediating nicotine (NIC)-induced conditioned place preference (CPP) in zebrafish and investigate the effect of the CC4 and CC26 cytisine derivatives in reducing NIC-induced CPP.
  
  
  METHODS
  CPP was evaluated using a two-compartment chamber, and the zebrafish were given CC4 (0.001-5 mg/kg), CC26 (0.001-1 mg/kg), cytisine (0.1-2.5 mg/kg), and varenicline (1-10 mg/kg) alone or with NIC (0.001 mg/kg). Swimming activity was evaluated using a square observational chamber. The affinity of the nicotinic ligands for native zebrafish brain nAChRs was evaluated by binding studies using [(3)H]-Epibatidine (Epi) and [(125)I]-αBungarotoxin (αBgtx) radioligands, and their subtype specificity was determined by means of electrophysiological assay of oocyte-expressed α4β2 and α7 subtypes.
  
  
  RESULTS
  CC4 and CC26 induced CPP with an inverted U-shaped dose-response curve similar to that of NIC. However, when co-administered with NIC, they blocked its reinforcing or slightly aversive effect. Binding and electrophysiological studies showed that this effect was due to binding to high-affinity heteromeric but not α7-containing receptors.
  
  
  CONCLUSIONS
  We have further characterized CC4 and identified a new compound (CC26) that may be active in inducing smoking cessation. Zebrafish is a very useful model for screening new compounds that can affect the rewarding properties of NIC.
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Ponzoni
authors.forename: Daniela
authors.initials: D
authors.lastname: Braida
authors.forename: Luca
authors.initials: L
authors.lastname: Pucci
authors.forename: Donzelli
authors.initials: D
authors.lastname: Andrea
authors.forename: Francesca
authors.initials: F
authors.lastname: Fasoli
authors.forename: Irene
authors.initials: I
authors.lastname: Manfredi
authors.forename: Roger L
authors.initials: RL
authors.lastname: Papke
authors.forename: Clare
authors.initials: C
authors.lastname: Stokes
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cannazza
authors.forename: Francesco
authors.initials: F
authors.lastname: Clementi
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gotti
authors.forename: Mariaelvina
authors.initials: M
authors.lastname: Sala
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000378:metabolism*; D000068580:Varenicline; D015027:Zebrafish
chemical_list: C000601971:1,2-bis(cytisin-12-yl)ethane; C000601970:1,4-bis(cytisin-12-yl)-2-butyne; D000470:Alkaloids; D001552:Benzazepines; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011810:Quinoxalines; D011978:Receptors, Nicotinic; D009538:Nicotine; D000068580:Varenicline