Scientific Report 2005

Molecular Biology

The 5-HT₇ Receptor as a Target in Depression and Schizophrenia

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

Serotonin (5-HT) is produced by a small group of nuclei in the brain stem that send their projections to a vast number of receptive fields. The family of receptors for 5-HT is the most diverse family that binds a single ligand; it has at least 14 members. One of these is the 5-HT₇ receptor, which we previously discovered. In earlier studies, we showed that this receptor mediates resetting of circadian rhythms by the hypothalamus. Despite vast differences in amino acid sequence between the 5-HT₇ receptor and the 5-HT_1A receptor, the 2 share considerable pharmacology and have been implicated in some of the same functions. 5-HT_1A is more abundant than 5-HT₇, but the areas of the brain that express the 2 receptors overlap considerably.

We produced mutant mice in which the gene for the 5-HT₇ receptor was inactivated. Studies with these mice and SB-266970, a 5-HT₇-selective antagonist, indicated that this receptor mediates serotonin-induced hypothermia and is important for fine tuning of temperature homeostasis.

Sleep, circadian rhythm, and mood are related phenomena. 5-HT₇-selective antagonists increase REM sleep latency and decrease the cumulative duration of REM sleep, patterns the opposite of those found in patients with clinical depression. Several antidepressants activate 5-HT₇ neurons in the circadian control area of the hypothalamus, and chronic treatment with antidepressants diminishes both activation and 5-HT₇ binding there. We examined sleep parameters in the mutant mice in which the gene for the 5-HT₇ receptor was inactivated. We found that they spent less time than normal mice in REM sleep. This pattern is the opposite of that found in humans with depression.

Two models of behavioral despair, the forced swim test and the tail suspension test, make rats and mice immobile. This immobility, or helplessness, is likened to depression in humans because a high correlation exists between the ability of antidepressant drugs to reverse immobility in rodents and to be effective clinically in humans. Furthermore, mice selectively bred to have increased helplessness in these behavioral despair tests resemble patients with clinical depression. The mice have decreased REM latency and more cumulative REM sleep, elevated levels of corticosterone, a decreased 5-HT metabolism index, and altered serotonin-induced hypothermia. We examined unmedicated 5-HT₇ mutant mice in these tests and found that the mice remained significantly more mobile than unmedicated normal mice during both the forced swim and the tail suspension tests. Normal mice medicated with the 5-HT₇-selective antagonist SB-266970 mimicked the mobility of unmedicated mutant mice, whereas the selective antagonist had no effect on the mobility of mutant mice. A selective serotonin reuptake inhibitor increased mobility in both types of mice (albeit at a lower concentration in the mutant mice), suggesting that the inhibitor worked through an independent mechanism.

These results are consistent with the notion that the 5-HT₇ mutant mice have characteristics of a partially “antidepressed” state: they spend less time in REM sleep, have reduced immobility in the forced swim and tail suspension tests, and have decreases in serotonin-induced hypothermia. Normal mice medicated with 5-HT₇-selective antagonists resemble unmedicated 5-HT₇ mutant mice in these measures. These findings suggest that 5-HT₇-selective antagonists might be sufficient treatment for some aspects of clinical depression.

Several antipsychotic drugs have high affinity for the 5-HT₇ receptor. We examined the role of 5-HT₇ receptors in an animal model of schizophrenia: phencyclidine-induced disruption of prepulse inhibition of the acoustic startle reflex. In untreated mice, we found no difference between mice in which the gene for the 5-HT₇ receptor was inactivated and wild-type mice in startle response or in prepulse inhibition regardless of prepulse intensity, interstimulus interval, or pulse intensity. SB-269970 had no effect on prepulse inhibition. The disruption of prepulse inhibition produced by phencyclidine in wild-type mice did not occur in the mutant mice. Similarly, the effect of phencyclidine on prepulse inhibition was reduced by SB-269970 in wild-type mice. The results indicate a specific role for the 5-HT₇ receptor in the glutamatergic prepulse inhibition model of schizophrenia.

Publications

de Lecea, L., Sutcliffe, J.G. Hypocretin as a wakefulness regulatory peptide. In: The Orexin/Hypocretin System: Physiology and Pathophysiology. Nishino, S., Sakurai, T. (Eds.). Humana Press, Totowa, NJ, 2005, p. 143. A volume in the series Contemporary Clinical Neuroscience.

de Lecea, L., Sutcliffe, J.G. (Eds.). The Hypocretins: Integrators of Physiological Functions. Plenum Press, New York, 2005.

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, in press.

Hedlund, P.B., Sutcliffe, J.G. Functional, molecular and pharmacological advances in 5-HT₇ receptor research. Trends Pharmacol. Sci. 25:481, 2004.

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, in press.

Sutcliffe, J.G., de Lecea, L. The hypocretin/orexin system. In: Handbook of Contemporary Neuropharmacology. Sibley, D. (Ed.). Wiley & Sons, Hoboken, NJ, in press.

Sutcliffe, J.G., de Lecea, L. Hypocretins/orexins in brain function. In: Handbook of Neurochemistry and Molecular Neurobiology. Lim, R. (Ed.). Springer, New York, in press.

Sutcliffe J.G., de Lecea, L. Not asleep, not quite awake. Nat. Med. 10:673, 2004.

Ziolkowska, B., Gieryk, A., Bilecki, W., Wawrzczak-Bargiela, A., Wedzony, K., Chocyk, A., Danielson, P.E., Thomas, E.A., Hilbush, B.S., Sutcliffe, J.G., Przewlocki, R. Regulation of α-synuclein expression in limbic and motor brain regions of morphine-treated mice. J. Neurosci. 25:4996, 2005.