1980 Master of Research training in Molecular and Cellular Genetics, CGM-CNRS, Gif-sur-Yvette
1980-1983 Ph.D. in Molecular and Cellular Genetics, ICGM, Paris
1983-1988 Postdoctoral researcher, ICGM, Paris
1983-1988 Postdoctoral researcher, CNRS UPR 9065, Collège de France, Paris
1989-1998 CR1 INSERM tenured research position, CNRS UPR 9065, Collège de France, Paris
1999-2008 INSERM U513, Créteil, Head of team : Organic cation transporters in central nervous system
2008-2012 UMRS952/UMR7224, Université Pierre et Marie Curie, Paris - Team Physiopathology of Psychiatric Diseases
Low-affinity monoamine transporters of the CNS
In the central nervous system, monoaminergic pathways are implicated in major physiological and behavioral functions like locomotor activity, attention and mood. Alterations of these pathways are found in neuropsychiatric disorders such as schizophrenia, Parkinson’s disease, depression and drug addiction. Until recently, the high-affinity reuptake transporters were considered the principal elements responsible for the clearance of monoamines in these pathways, by ensuring the rapid reuptake of the released transmitters into the presynaptic terminals. In agreement, number of potent psychoactive compounds, like drugs of abuse and antidepressants, target these transporters - namely, the dopamine, serotonin or noradrenaline transporters. Lately, however, other categories of transporters have drawn attention, which also have the capacity to transport aminergic neurotransmitters, albeit with low affinity. These last years, my group has gathered using multidisciplinary approaches evidence on the role in the brain of two families of low-affinity monoamine transporters, organic cation transporters (OCT) and plasma monoamine transporter (PMAT)1.
The team showed that OCTs can interact with diverse categories of psychoactive compounds, like drugs of abuse, antidepressants, antipsychotics and various adrenoceptor ligands, modifying our conception of the mechanisms of action of these drugs in central nervous system, and of their potential impact on the pharmacokinetics of other therapeutic agents transported by OCTs2-4. We established that a member of the OCT family, OCT3, is highly expressed in circumventricular organs and other osmoregulatory regions of the brain. In agreement, mice deficient for OCT3 show changes in the neural and behavioral responses to environmentally-induced variations in osmolarity5.
Mouse mutants for OCTs show altered monoamine neurotransmission in the brain and mood-related behaviors, suggesting a “ back-up ” role in monoamine clearance for these transporters6, 7. Recently, the team showed that one OCT member, OCT2, is notably enriched in the limbic system, which plays a major role in the response to stress or threats and mood disorders. Based on OCT2 properties established in vitro, we speculated that this transporter could participate in monoamine uptake in the limbic system, broadly innervated by monoaminergic fibers. Taken together our experiments indicate that OCT2 is an important actor in norepinephrine and serotonin clearance in vivo in projection regions. This can have significant effects on norepinephrine and/or serotonin signaling in conditions of monoamine spillover, in the presence of antidepressants, but also in areas of lesser high-affinity transporter density, at distance from the aminergic varicosities7.
Our studies demonstrate that OCT2 is indeed implicated in mood-related behaviors. Prolonged stress is believed to be a precipitating factor for depression in humans, and was shown to induce in rodents depression-like behaviors. Contrarily to acute behavior despair tests such as the forced swim test, chronic corticosterone exposure in rodents constitutes a depression model with relatively good face-validity, since it induces a panel of persistent behavioral anomalies mimicking distinct aspects of this disorder. The team showed in this chronic depression model that OCT2 is required for the antidepressant venlafaxine to exert its full effects, indicating that this transporter is a crucial element of long-term antidepressant action7. In addition, OCT2 knockout mice show a marked increase in secreted corticosterone levels following acute stress. This last observation suggests that in humans genetic polymorphisms influencing OCT2 transport activity, or long-term administration of drugs interacting with this transporter (such as antidiabetics or cytostatics) may have important consequences on the hormonal response to stress, enhancing vulnerability to traumatic events or to repeated stressful situations, therefore predisposing to depression.
Collectively, our work reveals a previously unsuspected role of OCTs in monoamine homeostasis, identifying them as novel therapeutic targets for the treatment of mood disorders. Ongoing projects aim to further decipher the neurochemical and cellular mechanisms underlying their role in antidepressant efficacy and the response to stress. Since antidepressants traditionally used to treat major depression, dysthymia and anxiety disorders, like serotonin and norepinephrine reuptake inhibitors, do not provide positive treatment outcomes for all patients, a main concern on the long term is to identify agents that could improve antidepressant action by targeting OCTs.
1 Vialou, V., Balasse, L., Dumas, S., Giros, B. and Gautron, S. Neurochemical characterization of pathways expressing plasma membrane monoamine transporter in the rat brain. Neuroscience (2007) 144, 616-622.
2 Amphoux A., Vialou V., Drescher, E., Bruss M., Mannoury La Cour C., Rochat C., Millan M., Giros B., Bonisch H. and Gautron S. Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacol. (2006) 50, 941-952.
3 Amphoux A, Millan MJ, Cordi A, Bönisch H, Vialou V, Mannoury la Cour C, Dupuis DS, Giros B, Gautron S. Inhibitory and facilitory actions of isocyanine derivatives at human and rat organic cation transporters 1, 2 and 3: a comparison to human alpha1- and alpha2-adrenoceptor subtypes. Eur J Pharmacol. (2010) 634,1-9.
4 Haenisch B., Drescher E, Thiemer L., Xin H., Giros B., Gautron S., Bönisch H. Interaction of antidepressant and antipsychotic drugs with the human organic cation transporters hOCT1, hOCT2, and hOCT3. N-S Arch. Pharmacol. (2012) 385: 1017-23.
5 Vialou V, Amphoux A, Zwart R, Giros B and Gautron S. Organic cation transporter 3 (Slc22a3) is implicated in salt-intake regulation. J. Neurosci. (2004) 24, 2846-2851.
6 Vialou V, Balasse L, Callebert J, Launay JM, Giros B, Gautron S. Altered aminergic neurotransmission in the brain of organic cation transporter 3-deficient mice. J. Neurochem. (2008) 106,1471-82.
7 Bacq A., Balasse L., Biala G., Guiard B.P., Gardier A.M., Schinkel A., Louis F., Vialou V., Martres M-P., Chevarin C., Hamon M., Giros B. and Gautron S. Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response. Molecular Psychiatry (2012) 17: 926-939.