PI: Sophie Gautron
One of our axes of
research aims to identify novel processes
underlying
the emergence of depression and the action of antidepressants, and to develop
new therapeutic strategies.
In the brain, the
high-affinity monoamine transporters are critical for the rapid reuptake of
neurotransmitters released into the presynaptic terminals. Consequently, several
drugs of abuse and antidepressants target these
transporters, specifically, dopamine, serotonin or noradrenaline transporters. Our
team is studying atypical monoamine transporters, such as the organic cation
transporters (OCTs), using multiple approaches. Our previous
studies have revealed OCTs as important determinants of aminergic tonus
in the
brain and of mood-related behaviors, thereby identifying them as novel
potential pharmacological targets for the management of depressive
disorders. Two OCT subtypes, OCT2 and OCT3 specifically, have been
proposed to act as a low-affinity
monoamine clearance system,
complementing the high-affinity transporters in the brain. There is also
substantial evidence that these atypical
transporters subserve major central functions, controlling
anxiety, response to stress and long-term antidepressant action.
Mood
disorders represent widespread and invalidating disorders, with up to 16% of
the world population affected by various symptoms of the depression spectrum.
However, antidepressants traditionally used to treat major depression disorder,
like serotonin and norepinephrine reuptake inhibitors, show important shortcomings such as slow action onset and
limited efficacy in nearly a third of patients. Thus, there is at
present a pressing need for novel well-tolerated antidepressants.
Our preclinical studies using a validated
experimental model of chronic depression demonstrated that in mice the
transporter OCT2 is essential for long-term efficacy of standard
antidepressants. Ongoing studies aim to characterize the causes of resistance to
antidepressant treatment in preclinical models, and to identify genetic and
physiological markers of resistant depression in humans, in connection with OCT
activity.
We recently demonstrated
proof-of-concept that OCTs are relevant therapeutic targets for depression by developing an OCT ligand with high antidepressant potential (Patent WO2019012150A1). In a preclinical depression model, this molecule shows rapid positive
effects on several behaviors related to depression, with improved action on
anhedonia and anxiety as compared to the classical antidepressant fluoxetine. The high therapeutic relevance of these findings
is being exploited to develop new, more effective, and safe classes of
antidepressants.
The causes for
individual variability in antidepressant response are in large part
undetermined. Identifying biological and environmental risk factors for
antidepressant resistance may help to distinguish subsets of depressed patients
and influence treatment outcome. We are
currently exploring the interactions between dietary status and OCT
activity. Moreover, a number of common medications such as antidiabetics, and
antineoplastic and antiviral agents interact with OCT, which could have
important repercussions on antidepressant efficacy. Our findings emphasize the
importance of these potential risk factors for individual resistance to
antidepressant treatment.
Selected references
- Orrico-Sanchez A, Chausset-Boissarie L, Alves De
Sousa R, Coutens B, Rezai Amin S, Vialou V, Louis F, Hessani A, Dansette PM, Zornoza
T, Gruszczynski C, Giros B, Guiard BP, Acher F, Pietrancosta N, Gautron S (2020) Antidepressant
efficacy of a selective organic cation transporter blocker in a mouse model of
depression. Mol Psychiatry 25, 1245-1259
- Couroussé
T, Bacq A, Belzung C, Guiard B, Balasse L, Louis F, Le Guisquet AM, Gardier A,
Schinkel A, Giros B, Gautron S (2015) Brain organic cation transporter 2
controls response and vulnerability to stress and GSK3ß signaling. Mol Psychiatry 20,
889-900
- Bacq
A, Balasse L, Biala G, Guiard BP, Gardier AM, Schinkel A, Louis F, Vialou V,
Martres MP, Chevarin C, Hamon M, Giros B, Gautron S (2012) Organic cation
transporter 2 controls brain norepinephrine and serotonin clearance and
antidepressant response. Mol Psychiatry
17, 926-939