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Stroke The Role of Fluoxetine and Selective Serotonin Re-uptake Inhibitors in Motor Recovery Following Acute Ischemic Stroke François Chollet, MD, PhD, 1 Jean Tardy, MD, PhD, 2 Jérémie Pariente, MD, PhD, 3 Isabelle Loubinoux, PhD 4 and Jean-François Albucher, MD 2 1. Professor; 2. Physician Neurologist; 3. Assistant Professor; 4. Researcher in Neuroscience, Department of Neurology, Purpan University Hospital, INSERM U825, Paul Sabatier University Toulouse III, Toulouse, France Abstract Until now, recombinant tissue plasminogen activator thrombolysis within the first hours after a stroke has been recognised as the only validated treatment able to improve the spontaneous—and most of the time incomplete—recovery of neurologic functions after stroke. However, we have learnt from research over the last decade, in part based on the considerable improvement in neuroimaging techniques, that spontaneous recovery of neurologic functions was associated with a large intracerebral re-organization of the damaged human brain. The question of whether lesioned-brain plasticity can be modulated by external factors such as pharmacologic agents is now addressed, with the aim of improving recovery and reducing the final disability of patients. We review the preclinical and clinical arguments for a direct action of selective serotonin re-uptake inhibitors in promoting recovery after stroke in humans. Keywords Stroke, recovery, fluoxetine, brain plasticity, motor function, monoaminergic drugs Disclosure: The authors have no conflicts of interest to declare. Received: September 2, 2011 Accepted: November 21, 2011 Citation: US Neurology, 2012;8(1):37–41 Correspondence: François Chollet, MD, PhD, Department of Neurology, Purpan University Hospital and Paul Sabatier University, Place Baylac, 31059 Toulouse, France. E: francois.chollet@inserm.fr Recovery of neurologic functions after a stroke has long been a puzzling question for clinicians and scientists. On the one hand, clinicians knew from their own practice that partial recovery was very often observed after a stroke and on the other hand, it was well known that neurons, when destroyed after ischemia, were not restored despite some very localized neurogenesis. In the past two decades, we have learnt from modern neuroimaging techniques, mainly positron emission tomography (PET) scanning and magnetic resonance imaging (MRI), that the human brain is able to spontaneously re-organize after a stroke and that brain re-organization can be considered as a rational biologic basis for recovery of neurologic functions. The question of whether lesioned-brain plasticity can be modulated by external factors such as pharmacologic agents is now addressed with the aim of improving recovery and reducing the final disability of patients. Preclinical studies, mainly using small animal models, have shown that monoaminergic drugs can modify functional recovery. This is particularly the case for noradrenergic drugs, which have been shown to improve functional recovery, while neuroleptics have been shown to impair it. From this approach, selective serotonin re-uptake inhibitors (SSRIs) were tested and their suspected positive action in the recovery process was recently proved in the Fluoxetine for motor recovery after acute ischaemic stroke (FLAME) trial. © TOUCH BRIEFINGS 2012 Preclinical Arguments for Direct Action of Monoaminergic Drugs on the Damaged Brain Studies in laboratory animals clearly show that the rate and extent of functional recovery after focal brain injury can be modulated by drugs affecting certain neurotransmitters in the central nervous system (CNS). Several lines of evidence suggest that motor recovery after injury to the cerebral cortex can be modulated through the effects of norepinephrine on the CNS. For example, in rats, central infusion of norepinephrine hastens locomotor recovery after a unilateral sensorimotor cortex lesion. In contrast, the administration of DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine], a neurotoxin that leads to the depletion of norepinephrine in the CNS, has the opposite effect and delays the recovery process. In addition, bilateral or unilateral selective lesions of the locus ceruleus, the major source of noradrenergic projection fibres to the cerebral cortex and cerebellum, also impair motor recovery after a subsequent unilateral cortical lesion. Dopaminergic agents also act in damaged brains. They may influence recovery from neglect caused by prefrontal cortical injury. Apomorphine, a dopamine agonist, reduces the severity of experimentally induced neglect, and spiroperidol, a dopamine receptor antagonist, reinstates neglect in recovered animals. Concurrent administration of dopamine-blocking drugs such as haloperidol also blocks amphetamine-promoted recovery and haloperidol, as well as 37