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Lentiviral expression vectors are powerful tools for gene therapy and long-term gene expression/repression in the mammalian brain. However, no specificity of transduction has been reported so far in the central nervous system. Here we have developed a novel system to achieve a neuronal subtype specific expression in either dopaminergic (DA) or GABAergic neurons. We employed a delivery strategy by which the transgene is not expressed until its activation by Cre recombinase. We successfully tested the system in vitro and then used this novel lentivector, containing loxP sites, in 2 different transgenic mouse lines expressing Cre either in DA or in GABAergic neurons. In both lines the reporter gene was detected exclusively in Cre-positive cells, demonstrating that with this experimental approach we were able to achieve completely specific expression of transgenes delivered by lentiviral vectors. This universal system can be applied to all neural subtypes making use of the growing number of specific Cre driver lines. (Tolu et al., FASEB J.)
In a collaboration with the US pharmaceutical company Pfizer, we used their FDA approved smoking cessation compound, varenicline, marketed also in France under the trade name of Chamtix™. Varenicline is the first ever designer drug used as nicotinic medication.
We studied the effects of 1 mg/kg doses of nicotine and the a4b2* nicotinic acetylcholine receptor (nAChR) partial agonist, varenicline, on extracellular dopamine (DA) levels in the nucleus accumbens (NuAcc) of lentivirally vectorized male mice. Three separate experimental groups were injected with a lentiviral vector transducing the ventral tegmental area (VTA): wild-type C57BL/6J mice with a vector expressing eGFP only, b2 knock-out mice (b2KO) with the eGFP-only vector, and b2KO mice with a bicistronic vector reintroducing b2 and eGFP into the VTA as described before (Maskos et al., 2005). Our results suggest that the neurochemical effects of varenicline as measured by using microdialysis in awake, freely moving mice are mainly mediated via b2* nAChR subunits localized in the VTA. (Reperant et al., Neuropharmacology)
Lentiviral expression vectors are powerful tools for gene therapy and long-term gene expression/repression in the mammalian brain. However, no specificity of transduction has been reported so far in the central nervous system. Here we have developed a novel system to achieve a neuronal subtype specific expression in either dopaminergic (DA) or GABAergic neurons. We employed a delivery strategy by which the transgene is not expressed until its activation by Cre recombinase. We successfully tested the system in vitro and then used this novel lentivector, containing loxP sites, in 2 different transgenic mouse lines expressing Cre either in DA or in GABAergic neurons. In both lines the reporter gene was detected exclusively in Cre-positive cells, demonstrating that with this experimental approach we were able to achieve completely specific expression of transgenes delivered by lentiviral vectors. This universal system can be applied to all neural subtypes making use of the growing number of specific Cre driver lines. (Tolu et al., FASEB J.)
In a collaboration with the US pharmaceutical company Pfizer, we used their FDA approved smoking cessation compound, varenicline, marketed also in France under the trade name of Chamtix™. Varenicline is the first ever designer drug used as nicotinic medication.
We studied the effects of 1 mg/kg doses of nicotine and the a4b2* nicotinic acetylcholine receptor (nAChR) partial agonist, varenicline, on extracellular dopamine (DA) levels in the nucleus accumbens (NuAcc) of lentivirally vectorized male mice. Three separate experimental groups were injected with a lentiviral vector transducing the ventral tegmental area (VTA): wild-type C57BL/6J mice with a vector expressing eGFP only, b2 knock-out mice (b2KO) with the eGFP-only vector, and b2KO mice with a bicistronic vector reintroducing b2 and eGFP into the VTA as described before (Maskos et al., 2005). Our results suggest that the neurochemical effects of varenicline as measured by using microdialysis in awake, freely moving mice are mainly mediated via b2* nAChR subunits localized in the VTA. (Reperant et al., Neuropharmacology)