Serotonin 5HT 1A receptor availability and pathological crying after stroke Introduction The purpose of rehabilitation is to facilitate preser- vation and restoration of brain function in stroke patients. Clinical outcome scales are used to assess rehabilitation in stroke studies, but they are crude measurements and justify a search for more precise measures that can guide future research. Animal and human studies indicate a modulating effect on motor activity of pharmacological treatment with antidepressants or psychostimulants (1–4). This evidence of an effect on motor function after stroke was not confirmed in two double-blind randomized, placebo-controlled human trials com- pleted to date (5, 6) The negative results may be explained by methodological uncertainties invol- ving patient heterogeneity (age, infarct size and location, concomitant brain atrophy), as well as the small numbers of subjects included in the trials. The role of neurotransmitters in stroke is complex and further insight into the functional changes mediated by neurotransmitters is needed. An alternative strategy is therefore to identify surrogate markers of neurotransmission of brain plasticity prior to the onset of large-scale clinical studies. Serotonin plays a major role in the development of brain and its functions in the adult (7) and therefore may be important to the plasticity also of lesioned brain tissue. Activation of the 5HT 1A receptor has revealed neuroprotective effects. Thus, treatment with 5HT 1A agonist reduced the size of infarcts in stroke models (8), and application of 5HT 1A receptor agonists and 5HT 2A antagonists has reduced loss of neuronal and dendritic cells, whereas treatment with a 5HT 1A antagonist had the opposite effect (9–11). However, the first random- ized placebo controlled trial in stroke patients with the 5HT 1A agonist, Repinotan, did not show any significant effect of treatment (12). Of the 14 subtypes of serotonin receptors, the 5HT 1A receptor is of special interest, because it has dual roles as presynaptic autoreceptor in the raphe nuclei in the brainstem, regulating the firing rate of the serotonergic neurons, and as post-synaptic receptor in hippocampus and neocortical tissues mediating the serotonergic neurotransmission (13). Acta Neurol Scand 2007: 116: 83–90 DOI: 10.1111/j.1600-0404.2007.00869.x Copyright Ó 2007 The Authors Journal compilation Ó 2007 Blackwell Munksgaard ACTA NEUROLOGICA SCANDINAVICA Møller M, Andersen G, Gjedde A. Serotonin 5HT 1A receptor availability and pathological crying after stroke. Acta Neurol Scand 2007: 116: 83–90. Ó 2007 The Authors Journal compilation Ó 2007 Blackwell Munksgaard. Objectives – Post-stroke depression and pathological crying (PC) implicate an imbalance of serotonergic neurotransmission. We claim that PC follows serotonin depletion that raises the binding potential (p B ) of the 5-HT 1A receptor antagonist [carbonyl– 11 C]WAY-100635, which is reversible by selective serotonin re-uptake inhibitor (SSRI) treatment. Materials and Methods – We PET scanned patients with acute stroke and PC and age-matched control subjects. Maps of receptor availability were generated from the images of eight cortical regions and raphe nuclei. Results – The maps showed highest binding in limbic areas and raphe nuclei, while binding in basal ganglia and cerebellum was negligible. Baseline binding potentials of patients were lower than that of control subjects (3.7  0.6 vs 4.2  0.2). Treatment with SSRI markedly reduced free receptor sites, whereas placebo administration led to a global increase. Discussion – The study is the first suggestion of changes of serotonergic neurotransmission in the early phase of stroke and the modulation of these changes with SSRI treatment. M. Møller 1,2 , G. Andersen 3 , A. Gjedde 1,2 1 Center of Functionally Integrative Neuroscience, Aarhus University, Denmark; 2 PET-Centre Aarhus University, Denmark; 3 Department of Neurology, Aarhus University Hospital, Denmark Key words: positron emission tomography; stroke; pathological crying; serotonin receptor; selective serotonin re-uptake inhibitor Mette Møller, PET Centre, Aarhus University Hospital, 8000 Aarhus C, Denmark. Tel.: +45 8949 4095 Fax: +45 8949 4400 e-mail: moller@pet.auh.dk Accepted for publication February 21, 2007 83