title: Preclinical investigations into the antipsychotic potential of the novel histamine H3 receptor antagonist GSK207040.
abstract: OBJECTIVE
  To test the novel nonimidazole histamine H3 receptor antagonist 5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazapin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide (GSK207040) in a series of behavioral and neurochemical paradigms designed to evaluate its antipsychotic potential.
  
  
  METHODS
  Acute orally administered GSK207040 was investigated for its capacity to reverse a 24-h-induced deficit in novel object recognition memory, deficits in prepulse inhibition (PPI) induced by isolation rearing, and hyperlocomotor activity induced by amphetamine. The acute neurochemical effects of GSK207040 were explored by analyzing rat anterior cingulate cortex microdialysates for levels of dopamine, noradrenaline, and acetylcholine and by c-fos immunohistochemistry. The potential for interaction with the antipsychotic dopamine D2 receptor antagonist haloperidol was explored behaviorally (spontaneous locomotor activity and catalepsy), biochemically (plasma prolactin), and via ex vivo receptor occupancy determinations.
  
  
  RESULTS
  GSK207040 significantly enhanced object recognition memory (3 mg/kg) and attenuated isolation rearing-induced deficits in PPI (1.0 and 3.2 mg/kg) but did not reverse amphetamine-induced increases in locomotor activity. There was no evidence of an interaction of GSK207040 with haloperidol. GSK207040 (3.2 mg/kg) raised extracellular concentrations of dopamine, noradrenaline, and acetylcholine in the anterior cingulate cortex and c-fos expression in the core of the nucleus accumbens was increased at doses of 3.2 and 10.0 mg/kg.
  
  
  CONCLUSIONS
  The behavioral and neurochemical profile of GSK207040 supports the potential of histamine H3 receptor antagonism to treat the cognitive and sensory gating deficits of schizophrenia. However, the failure of GSK207040 to reverse amphetamine-induced locomotor hyperactivity suggests that the therapeutic utility of histamine H(3) receptor antagonism versus positive symptoms is less likely, at least following acute administration.
authors.affiliation: GlaxoSmithKline, New Frontiers Science Park (North), Third Avenue, Harlow, Essex, CM195AW, UK. eric_2_southam@gsk.com
authors.forename: Eric
authors.initials: E
authors.lastname: Southam
authors.forename: Jackie
authors.initials: J
authors.lastname: Cilia
authors.forename: Jane E
authors.initials: JE
authors.lastname: Gartlon
authors.forename: Marie L
authors.initials: ML
authors.lastname: Woolley
authors.forename: Laurent P
authors.initials: LP
authors.lastname: Lacroix
authors.forename: Carol A
authors.initials: CA
authors.lastname: Jennings
authors.forename: Jane E
authors.initials: JE
authors.lastname: Cluderay
authors.forename: Charlie
authors.initials: C
authors.lastname: Reavill
authors.forename: Claire
authors.initials: C
authors.lastname: Rourke
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.forename: Lee A
authors.initials: LA
authors.lastname: Dawson
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Medhurst
authors.forename: Declan N C
authors.initials: DN
authors.lastname: Jones