Scientific Report 2006

Molecular Biology

The 5-HT₇ Receptor in Neuropsychiatric Disorders

P.B. Hedlund, P.E. Danielson, S. Huitrón-Reséndiz, S.J. Henriksen, S. Semenova, M.A. Geyer, A. Markou, J.G. Sutcliffe

Interest in the serotonin 5-HT₇ receptor as a putative target in neuropsychiatric disorders has been growing continually. The interest was prompted by the finding that several classes of drugs used to treat disorders such as depression and schizophrenia have high affinity for the 5-HT₇ receptor. We have established evidence that supports a role for this receptor in depression, obsessive-compulsive disorder, and schizophrenia.

Depression

The forced swim test and the tail suspension test are animal models of behavioral despair that have high value for predicting the antidepressant efficacy of drugs. The tests can also be used to characterize animals in which genes have been deleted. Using both of these tests, we showed that mice lacking the 5-HT₇ receptor have a behavioral profile similar to that of mice treated with antidepressants. We replicated these findings by using a compound that acts as a selective antagonist at the 5-HT₇ receptor. Thus, both blockade and inactivation of the 5-HT₇ receptor yield the same result.

Sleep disturbances are common in depression. Increased amounts of REM sleep are a frequent finding. Compared with mice that have the 5-HT₇ receptor mice lacking the receptor spend less time in REM sleep without alteration of other sleep parameters, further establishing the antidepressant-like profile of the animals that lack the receptor.

Taken together our results suggest an important role for the 5-HT₇ receptor in depression, and antagonists to this receptor should be evaluated as a treatment for depression.

Obsessive-Compulsive Disorder

Obsessive-compulsive disorder is related to depression, at least to the extent that antidepressants are commonly used to treat both disorders. In an animal model of obsessive-compulsive disorder (marble burying), we showed that blockade or inactivation of the 5-HT₇ receptor results in less compulsive behavior. Thus, the 5-HT₇ receptor might be of interest as a putative target for treatment of obsessive-compulsive disorder.

Schizophrenia

Prepulse inhibition (PPI) of the acoustic startle reflex is a well-characterized animal model of schizophrenia. The model is especially relevant because similar responses can be observed in patients with schizophrenia. We showed that PPI per se is not altered in mice lacking the 5-HT₇ receptor, but that when PPI is disrupted by phencyclidine, the mice are significantly less affected than are mice that have the receptor. Phencyclidine-induced disruption involves a glutamatergic component of PPI that is relevant for the action of atypical antipsychotics such as clozapine. Clozapine is a drug with relatively high affinity for the 5-HT₇ receptor.

Publications

Hedlund, P.B., Huitrón-Reséndiz, S., Henriksen, S.J., Sutcliffe, J.G. 5-HT₇ receptor inhibition and inactivation induce antidepressantlike behavior and sleep pattern. Biol. Psychiatry 58:831, 2005.

Hedlund, P.B., Sutcliffe, J.G. 5-HT₇ receptors as favorable pharmacological targets for drug discovery. In: The Serotonin Receptors: From Molecular Pharmacology to Human Therapeutics. Roth, B.L. (Ed.). Humana Press, Totowa, NJ, 2006, p. 517.

Hedlund, P.B., von Euler, G. Z-analysis: a new approach to analyze stimulation curves with intrinsic basal stimulation. Biochem. Pharmacol. 70:170, 2005.