title: Contribution of both M1 and M4 receptors to muscarinic agonist-mediated attenuation of the cocaine discriminative stimulus in mice.
abstract: BACKGROUND
  We previously showed that muscarinic agonists with M(1) and/or M(4) receptor affinities attenuated cocaine discrimination and self-administration in wild-type mice but not in M(1)/M(4) double-knockout mice.
  
  
  OBJECTIVE
  This study aims to elucidate the respective contributions of M(1) and M(4) receptors to this effect.
  
  
  METHODS
  Knockout mice lacking either the M(1) subtype (M                               (1)                                         (-/-)                            ) or the M(4) subtype (M                               (4)                                         (-/-)                            ) and wild-type mice were trained to discriminate 10 mg/kg cocaine from saline. Muscarinic ligands were tested for modulation of cocaine discrimination: xanomeline (M(1)/M(4)-preferring agonist), VU0357017 (M(1)-selective partial agonist), 77-LH-28-1 (M(1) agonist), and BQCA (M(1)-selective positive allosteric modulator).
  
  
  RESULTS
  Xanomeline produced rightward shifts in the cocaine dose-effect curve in all three genotypes, but most robustly in wild-type mice. VU0357017 produced rightward shifts in the cocaine dose-effect curve in wild-type and M                               (4)                                         (-/-)                             mice, but not in M                               (1)                                         (-/-)                             mice. Response rates were suppressed by xanomeline in wild-type and M                               (1)                                         (-/-)                             but not in M                               (4)                                         (-/-)                             mice and were unaltered by VU0357017. 77-LH-28-1 and BQCA also showed evidence of attenuating cocaine's discriminative stimulus, but at doses that suppressed responding or had other undesirable effects. Intriguingly, both VU0357017 and 77-LH-28-1 exhibited U-shaped dose-effect functions in attenuating cocaine discrimination. None of the drugs substituted for the cocaine stimulus.
  
  
  CONCLUSIONS
  Attenuation of the cocaine stimulus by VU0357017 depended upon M(1) receptors, and full effects of xanomeline depended upon both M(1) and M(4) receptors. Therefore M(1)-selective agonists and mixed M(1)/M(4) agonists may be promising leads for developing medications that block cocaine's effects.
authors.affiliation: Alcohol and Drug Abuse Research Center, McLean Hospital/Harvard Medical School, Belmont, MA, USA. mthomsen@mclean.harvard.edu
authors.forename: Morgane
authors.initials: M
authors.lastname: Thomsen
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Wessell
authors.forename: Brian S
authors.initials: BS
authors.lastname: Fulton
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
authors.forename: S Barak
authors.initials: SB
authors.lastname: Caine
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004193:Discrimination Learning / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology*; D043643:Receptor, Muscarinic M1 / Q000819:agonists* / Q000502:physiology; D043588:Receptor, Muscarinic M4 / Q000819:agonists* / Q000502:physiology; D012646:Self Administration
chemical_list: D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1; D043588:Receptor, Muscarinic M4; D003042:Cocaine