Uncovering the Biochemical Basis of Depression

In the future, researchers hope to develop an antidepressant targeting the acetylcholine receptors in the human brain. Image courtesy of Wikipedia.

A staggering 40 percent of individuals afflicted with depression do not react to popular antidepressants, which are usually selective serotonin reuptake inhibitors (SSRIs). Although depressive episodes have been primarily attributed to serotonin deficiencies, researchers at the Yale School of Medicine recently discovered that other systems are likely at work.

“The acetylcholine system could also play a role in depression,” said Marina Picciotto, the Charles B. G. Murphy Professor of Psychiatry and Professor of Neurobiology and of Pharmacology, and senior author of a new study, published in the Proceedings of the National Academy of Sciences in February. First author Yann Mineur is an Associate Research Scientist in Psychiatry at the Yale School of Medicine.

Dr. Marina Picciotto, senior author of the study and a Charles B. G. Murphy Professor of Psychiatry and Professor of Neurobiology and of Pharmacology. Image courtesy of Yale University.

The Picciotto Laboratory had examined the acetylcholine system before, particularly in connection with smoking. Their work focused on the nicotinic acetylcholine receptors, which are the primary sensors for the neurotransmitter acetylcholine. Generally, these receptors can be found at the neuromuscular junction, where they mediate communication between nerves and muscles. However, in the brain, the acetylcholine system is much broader and more complex – for instance, acetylcholine may either activate or inhibit cognitive processes based on its location within the brain.

Nicotinic acetylcholine receptors activate during smoking, and there is a known connection between smoking and depression. Professor Picciotto explained, “human smokers who have had a previous episode of depression find it much harder to quit smoking, while those with no previous history of depression may encounter their first episode after quitting.” Withdrawal from smoking can account for a change in mood, since changes in the activation of nicotinic receptors can generate a chemical imbalance ideal for depressive episodes.

Structure of the acetylcholine molecule. Image courtesy of Wikipedia.

In order to further understand how nicotinic acetylcholine receptors affect mood in humans, the researchers developed a model for depression with genetically-altered mice. They found that regardless of nicotine exposure, mice were less depressed when a blocker for acetylcholine was present. Researchers thus inferred that the presence of this neurotransmitter may play an integral role for depression in mice.

Research in the 1970s showed an analogous result in human subjects, which uncovered a relationship between acetylcholine and depression.

Vincent van Gogh’s Sorrowing Old Man, a 1980 painting that depicts depression. Image courtesy of Wikipedia.

The existing knowledge about tobacco, acetylcholine, and depression provided the motivation for the researchers to directly investigate the connection between acetylcholine and depression.

To explore this theory, the researchers generated a stressful environment for the subjects, where mice with varying levels of acetylcholine were placed in a pool of water from which they could not escape. Normally, in similar situations, mice have a positive reaction to stress and continuously search for an exit. However, with higher levels of acetylcholine and greater depression-like symptoms, mice displayed just enough motivation to keep their noses out of the water.

Brain scans depicting significant reduction in neurotransmitter activity in brains with depression. Image courtesy of the Mayo Foundation for Medical Education and Research.

As a follow-up experiment, researchers then used a top-down approach by observing the effect of common SSRI antidepressants on mice with depressive symptoms. These mice began to recuperate and react more normally – that is, they actively sought to escape the stressful environment.

Additionally, the researchers determined that the major region of the brain undergoing changes resulting in symptoms of depression was the hippocampus, which is associated with motivation and emotions in both mice and humans. By increasing the amount of acetylcholine in just the hippocampus, scientists could observe effects throughout the body. This finding in particular gives researchers a potential area of the brain in which to manipulate the genes involved in depression.

Individuals who smoke cigarettes are more likely to develop depression. Image courtesy of the University of Pennsylvania Perelman School of Medicine.

Mineur and Picciotto then collaborated with colleagues in the Yale Department of Psychiatry on a study where individuals with varying degrees of depression were given a tracer that competed with acetylcholine for the nicotinic acetylcholine receptors. As expected, people with chronic depression had the most tracer still present at the end of the trial, meaning that either there was more competition for the receptors due to higher concentrations of acetylcholine, or that these individuals had a decreased number of acetylcholine receptors to begin with. The researchers disproved the latter notion by examining post-mortem cortical tissue from the Canadian brain bank. Brains from very depressed individuals had normal numbers of receptors compared to brains from people with no history of depression, implying that depressed individuals tend to have higher concentrations of acetylcholine.

The implications of this research are vast, though the pathways involved in motivation and mood regulation are just starting to be understood. But by pinpointing the exact biochemical system involved during the development of depression, researchers might be able to provide more viable cures than the currently used SSRIs. “We’re interested in how stress regulates activity of neurons and whether we can alter that using genetic techniques or other manipulations in the mouse,” Professor Picciotto said. In the near future, researchers hope to test an antidepressant targeting acetylcholine receptors in the human brain.