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Research Focus

Molecular Targets for Neuropsychiatric Disorders


The aim of our research is to identify new targets for the treatment of neuropsychiatric disorders, especially depression. Depression is a very common disorder with a life-time prevalence of close to 20%. Although efficient treatment is available in many cases, there are still a significant number of patients who do not respond to treatment or experience unwanted side effects. With currently available drugs there is also usually a significant delay in the onset of symptom relief.

Currently our work is focused on the serotonin 5-HT7 receptor. This receptor shows many characteristics that makes it interesting in depression. Blockade or inactivation of the 5-HT7 receptor leads to changes consistent with being in a more "anti-depressed" state.

Ongoing work also suggests that the 5-HT7 receptor is of importance for physiological and pathophysiological phenomena related to schizophrenia, obsessive-compulsive disorder, and drugs of abuse.

Education

M.D., Karolinska Institutet, Stockholm, Sweden, 1989
Ph.D., Neuroscience, Karolinska Institutet, Stockholm, Sweden, 1994

Selected References

Hedlund, P. B., P. E. Danielson, E. A. Thomas, K. Slanina, M. J. Carson, and J. G. Sutcliffe (2002) No hypothermic response to serotonin in 5-HT7 receptor knockout mice. Proc. Natl. Acad. Sci., 100:1375-1380

Bonaventure, P., D. Nepomuceno, L. Hein, J. G. Sutcliffe, T. Lovenberg, and P. B. Hedlund (2004) Radioligand binding analysis of knockout mice reveals 5-hydroxytryptamine7 receptor distribution and uncovers 8-hydroxy-[N-n-dipropyl-N-(3'-iodo-2'propenyl)amino]tetraline interaction with α2 adrenergic receptors. Neuroscience, 124:901-911

Roberts, A. J., T. Krucker, C. L. Levy, K. A. Slanina, J. G. Sutcliffe, and P. B. Hedlund (2004) Mice lacking 5-HT7 receptors show specific impairments in contextual learning. Eur. J. Neurosci., 19:1913-1922

Hedlund, P. B., S. Huitron-Resendiz, S. J. Henriksen, and J. G. Sutcliffe (2005) 5-HT7 receptor knockout mice exhibit antidepressed-like behavior and sleep pattern. Biol. Psychiatry, 58:831-837

Semenova, S., M. A. Geyer, J. G. Sutcliffe, A. Markou, and P. B. Hedlund (2008) Inactivation of the 5-HT7 receptor partially blocks PCP-induced disruption of prepulse inhibition. Biol. Psychiatry, 63:98-105.

Sarkisyan, G. and P. B. Hedlund (2009) The 5-HT7 receptor is involved in allocentric spatial memory information processing. Behav. Brain Res., 202:26-31.

Abbas, A., P. B. Hedlund, X. P. Huang, T. B. Tran, H. Y. Meltzer, and B. L. Roth (2009) Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo. Psychopharmacology, 205:119-128.

Hedlund, P. B. (2009) The 5-HT₇ receptor and disorders of the nervous system: an overview. Psychopharmacology, 206:345-354.

Sarkisyan, G., A. J. Roberts, and P. B. Hedlund (2010) The 5-HT₇ receptor as a mediator and modulator of antidepressant-like behavior. Behav. Brain Res., 209:99-108.

Hedlund, P. B., M. Leopoldo, S. Caccia, G. Sarkisyan, C. Fracasso, G. Martelli, E. Lacivita, F. Berardi, and R. Perrone (2010) LP-211 is a brain penetrant selective agonist for the serotonin 5-HT₇ receptor. Neurosci. Lett., 481:12-16.

Leopoldo, M., E. Lacivita, F. Berardi, R. Perrone, and P. B. Hedlund (2010) Serotonin 5-HT₇ receptor agents: structure-activity relationships and potential therapeutic applications in central nervous system disorders. Pharmacol. Ther., 129:120–148.

Sutcliffe, J. G., P. B. Hedlund, E. A. Thomas, F. E. Bloom, and B. S. Hilbush (2011) Peripheral reduction of β-amyloid is sufficient to reduce brain Aβ: implications for Alzheimer's disease. J. Neurosci. Res., 89:808–814.

Roberts, A. J. and P. B. Hedlund (2012) The 5-HT₇ receptor in learning and memory. Importance of the hippocampus. Hippocampus, 22:762–771.

Lacivita, E., D. Patarnello, N. Stroth, A. Caroli, M. Niso, M. Contino, P. De Giorgio, P. Di Pilato, N. A. Colabufo, F. Berardi, R. Perrone, P. Svenningsson, P. B. Hedlund, and M. Leopoldo (2012) Investigations on the 1-(2-biphenyl)piperazine motif. Identification of new potent and selective ligands for the serotonin7 (5-HT₇) receptor with agonist or antagonist action in vitro or ex vivo. J. Med. Chem., 55:6375–6380.