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Licensing opportunity
DI 98/01, DI 00/48

Mutant mice deleted for different nicotinic acetylcholine receptor subunits

Inventors: Jean-Pierre CHANGEUX et al.

 Description of invention:

The present ready-to-use animal models can be used to analyze the role of nicotine in learning and behaviour, the pharmacology of nicotine, nicotine addiction, and disease states involving deficits in the nicotinic system. In addition, potential therapies for nicotine addiction or deficits in the nicotinic system can be tested with the transgenic animals.

In the nervous central system, nicotine has been described to be involved in: 

 
Addictions (tobacco, alcohol, cocaine …)
 Many aspects of behavior including learning, memory, control of locomotion and social behavior (ADHD and autism)
 Some neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s dementia

The pharmacological and behavioral effects of nicotine involve the neuronal acetylcholine nicotinic receptor (nAChRs), but many of the underlying mechanisms remain unclear.

 Antoine Taly et al, Nature Review Drug Discovery, Vol 8, September 2009 

Two mouse models are now available at Institut Pasteur: 

 Alpha6 nAChR subunit Knockout
 Alpha4 nAChR subunit Knockout 


Alpha6 nAChR subunit Knockout Mouse Model (ACNA6)

Alpha6 nAChR subunit Knockout Mouse Model (ACNA6) is available

C57BL/6J background
Animals are maintained at Charles River. They are healthy and breed normally.
Exclusive to Institut Pasteur

Pharmacology
• α6β2 association is likely to form functional nAChRs mediating nicotine addiction
• α6 subunit expression profile is restricted to dopaminergic and noradrenergic neurons (mainly substantia nigra, ventral tegmental area and locus coeruleus) 

Detection of α6 mRNA in the brain of Wt and α6 -/- animals, by in situ hybridization with an oligonucleotide located in the sixth exon of the α6 gene. In Wt animals, α6 mRNA is detected in SN/VTA neurons, LC and RGC. No signal above background levels is detected in α6 -/- animals. Champtiaux et al 2002

Behavior phenotype
• Unable to maintain intra-venous self-administration of nicotine

Pathology-related phenotype
• Parkinson’s disease is characterized by a selective degeneration of substantia nigra dopaminergic neurons
• α6 knock out mice could provide a useful tool for designing nicotine-like drugs to prevent Parkinson’s disease and nicotine addiction, while trying to limit cardiovascular risks associated.

 Champtiaux et al. J Neurosci 2002, 2003; Pons et al., J Neurosci 2008

IP status
 European patent published on July 04th, 2003 as EP1315417



Alpha4 nAChR subunit Knockout Mouse Model (ACNA4)

Alpha4 nAChR subunit Knockout Mouse Model (ACNA4) is available

C57BL/6J background
Animals are maintained at Charles River. They are healthy and breed normally.

Pharmacology
• Most widely expressed subunit in the nervous system associated with β2
• Mice exhibit a hyperdopaminergic state
• Strongly attenuated sensitivity to nicotine administration
• Strongly attenuated nicotine binding sites

Electrophysiology
• Altered firing properties of dopaminergic neurons

Behavior phenotype
• Unable to maintain self-administration of nicotine
• Show altered analgesia and anxiety profiles

 Marubio et al. Nature 1999; Marubio et al. Eur J Neurosci. 2003; Pons et al. J Neurosci 2008

IP status
 US granted patent published on June 26th, 2001 as US6252132 


Contact: Noémie Pellegrin, Licensing Manager - Office of Technology Transfer
Institut Pasteur - 28 rue du Docteur Roux, 75724 Paris cedex 15, France
Tel: +33 (0)1 45 68 81 73 - Fax: (0)1 40 61 37 32 - email: noemie.pellegrin@pasteur.fr