The Hedlund Lab

Research

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. In order to characterize the function of this receptor in the mammalian brain, we have generated a mouse strain where the 5-HT₇ receptor has been inactivated. Together with selective antagonist the mouse strain has provided us with the necessary tools for an extensive analysis of 5-HT₇ receptor function.

Receptor Distribution

Using a combination of 5-HT₇ receptor knockout mice, unselective radioligands, and selective antagonists we have been able to map the distribution of 5-HT₇ binding sites in great detail.

Areas with a high density of 5-HT₇ receptors are shown in the figure below. The figure also indicates how these regions correspond the the hypothesized functions of the receptor.

Thermoregulation

It has long been known that 5-HT is involved in thermoregulation, generally inducing hypothermia. We have now been able to establish that the 5-HT₇ receptor, together with the 5-HT_1A receptor, plays a crucial role in mediating this effect. It seems that the 5-HT₇ receptor is important for fine tuning body temperature homeostasis.

Current research investigates the involvement of 5-HT₇ receptors in the thermic response to MDMA ("Ecstasy").

Learning and Memory

We have established a role for the 5-HT₇ receptor in hippocampus-dependent learning. Mice lacking the receptor show a selective impairment in contextual fear conditioning. There is also a diminished ability to induce LTP in the hippocampus in these mice.

Depression and Sleep

The forced swim test and the tail suspension test are two behavioral models for depression. In both of these tests, inactivation or pharmacological blockade of the 5-HT₇ receptor leads to a response consistent with being more "anti-depressed".

In sleep recordings it has also been possible to demonstrate changes in the EEG consistent with being "anti-depressed" following inactivation or blockade of the 5-HT₇ receptor.

Taken together this makes the 5-HT₇ receptor a very strong candidate as a target for the treatment of depression. Ongoing work in the lab aims to further characterize the molecular and neurochemical mechanisms involved in the "anti-depressed" response.

Other Neuropsychiatric Disorders

We are currently investigating the possible involvement of the 5-HT₇ receptor in additional psychiatric disorders. Studies in progress use models for schizophrenia, obsessive-compulsive disorder, and drugs of abuse.