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



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 VMAT2(lox/lox) mice with DBHcre, SERTcre and DATcre mice, respectively. We conducted a complete neurochemical and behavioural characterization of VMAT2-HET animals in each system.



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.



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.



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.
From the Department of Psychiatry, Douglas Mental Health research center, McGill University, Montreal, Que., Canada (Isingrini, Perret, Rainer, Sagueby, Moquin, Gratton, Giros); and ISERM, UMRS 1130; CNRS, UMR 8246; Sorbonne University UPMC, Neuroscience Paris-Seine, F-75005, Paris, France (Giros).
Elsa
E
Isingrini
From the Department of Psychiatry, Douglas Mental Health research center, McGill University, Montreal, Que., Canada (Isingrini, Perret, Rainer, Sagueby, Moquin, Gratton, Giros); and ISERM, UMRS 1130; CNRS, UMR 8246; Sorbonne University UPMC, Neuroscience Paris-Seine, F-75005, Paris, France (Giros).
Lea
L
Perret
From the Department of Psychiatry, Douglas Mental Health research center, McGill University, Montreal, Que., Canada (Isingrini, Perret, Rainer, Sagueby, Moquin, Gratton, Giros); and ISERM, UMRS 1130; CNRS, UMR 8246; Sorbonne University UPMC, Neuroscience Paris-Seine, F-75005, Paris, France (Giros).
Quentin
Q
Rainer
From the Department of Psychiatry, Douglas Mental Health research center, McGill University, Montreal, Que., Canada (Isingrini, Perret, Rainer, Sagueby, Moquin, Gratton, Giros); and ISERM, UMRS 1130; CNRS, UMR 8246; Sorbonne University UPMC, Neuroscience Paris-Seine, F-75005, Paris, France (Giros).
Sara
S
Sagueby
From the Department of Psychiatry, Douglas Mental Health research center, McGill University, Montreal, Que., Canada (Isingrini, Perret, Rainer, Sagueby, Moquin, Gratton, Giros); and ISERM, UMRS 1130; CNRS, UMR 8246; Sorbonne University UPMC, Neuroscience Paris-Seine, F-75005, Paris, France (Giros).
Luc
L
Moquin
From the Department of Psychiatry, Douglas Mental Health research center, McGill University, Montreal, Que., Canada (Isingrini, Perret, Rainer, Sagueby, Moquin, Gratton, Giros); and ISERM, UMRS 1130; CNRS, UMR 8246; Sorbonne University UPMC, Neuroscience Paris-Seine, F-75005, Paris, France (Giros).
Alain
A
Gratton
From the Department of Psychiatry, Douglas Mental Health research center, McGill University, Montreal, Que., Canada (Isingrini, Perret, Rainer, Sagueby, Moquin, Gratton, Giros); and ISERM, UMRS 1130; CNRS, UMR 8246; Sorbonne University UPMC, Neuroscience Paris-Seine, F-75005, Paris, France (Giros).
Bruno
B
Giros
D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000235:genetics / Q000378:metabolism; D004644:Emotions / Q000187:drug effects / Q000502:physiology*; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D010641:Phenotype; D012201:Reward; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000378:metabolism
D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493453:Slc18a2 protein, mouse; C493231:Slc6a4 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D012701:Serotonin; D004299:Dopamine beta-Hydroxylase; D004298:Dopamine; D009638:Norepinephrine