Selective genetic disruption of dopaminergic,serotonergic and noradrenergic neurotransmission: Insights into motor,emotional and addictive behaviour

Background: the monoaminergic transmitters dopamine (da),noradrenaline (ne) and serotonin (5-ht) modulate cerebral functions via their extensive effects in the brain. investigating their roles has led to the creation of vesicular monoaminergic transporter-2 (vmat2) knockout (ko) mice. while this mutation results in postnatal death,vmat2-heterozygous (het) mice are viable and show a complex behavioural phenotype. however,the simultaneous alteration of the 3 systems prevents investigations into their individual functions. methods: to assess the specific role of ne,5-ht and da,we genetically disrupted their neurotransmission by creating conditional vmat2-ko mice with targeted recombination. these specific recombinations were obtained by breeding vmat2lox/lox mice with dbhcre,sertcre and datcre mice,respectively. we conducted a complete neurochemical and behavioural characterization of vmat2-het animals in each system. results: conditional vmat2-ko mice revealed an absence of vmat2 expression,and a specific decrease in the whole brain levels of each monoamine. although ne- and 5-ht-depleted mice are viable into adulthood,da depletion results in postnatal death before weaning. interestingly,alteration of the da transmission fully accounted for the increased amphetamine response formerly observed in the vmat2-het mice,whereas alteration of the 5-ht system was solely responsible for the increase in cocaine response. limitations: we used vmat2-het mice that displayed a mild phenotype. because the vmat2-ko in da neurons is lethal,it precluded a straightforward comparison of the full kos in the 3 systems. conclusion: given the intermingled functions of ne,5-ht and da in regulating cognitive and affective functions,this model will enhance understanding of their respective roles in the pathophysiology of psychiatric disorders. © 2016 joule inc. or its licensors.