title: Varenicline improves motor and cognitive deficits and decreases depressive-like behaviour in late-stage YAC128 mice.
abstract: Studies in the post mortem human brain and in genetic mouse model suggest that dysfunctional cholinergic neurotransmission, through a loss of agonist rather than receptors may be a significant contributing factor to HD pathology. If correct, pharmacological replacement may therefore be a potential treatment strategy. We have investigated whether chronic administration of the selective nicotinic partial agonist varenicline improved motor, cognitive and affective symptoms in a transgenic mouse model of Huntington's disease.
  
  
  
  The performance of 15 month old YAC128 mice and age-matched wild-type littermates was assessed in the rotarod, T-maze, novel object recognition, novelty suppressed feeding and forced swim tests prior to and after treatment with varenicline (5 mg/kg/day for 28 days via miniosmotic pump). Thymidine analogues, whilst DARPP32 and EM48 immunohistochemistry were used to assess the effect of varenicline on progenitor cell proliferation and survival, medium spiny neurons and aggregate formation respectively.
  
  
  
  Chronic treatment with varenicline significantly improved motor coordination, delay-dependent memory and reduced depressive-like behaviour in late stage YAC128 mice. Varenicline also produced genotype-independent improvements in recognition memory and reduced anxiety. In addition, varenicline displayed anxiolytic effects and improved spatial memory in the absence of compromised function. Functional improvements were accompanied by neuropathological changes including increased aggregate formation, neuroprotection and increased progenitor cell proliferation and survival.
  
  
  
  Our findings provide evidence that administration of an exogenous nicotinic agonist may be of clinical benefit in the treatment of late-stage Huntington's disease.
authors.affiliation: School of Pharmacy, Division of Health Sciences, University of Otago, Dunedin, New Zealand; Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand. Electronic address: ailsa.mcgregor@otago.ac.nz.
authors.forename: Ailsa L
authors.initials: AL
authors.lastname: McGregor
authors.affiliation: School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
authors.forename: Gary
authors.initials: G
authors.lastname: D'Souza
authors.affiliation: Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand; School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
authors.forename: Donghyo
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Pharmacology & Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Tingle
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D003863:Depression / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009069:Movement Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D058953:Neural Stem Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D000068580:Varenicline / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D018722:Nicotinic Agonists; D000068580:Varenicline
keywords: Huntington's disease; Nicotinic agonist; YAC128 mouse