Potential Root Cause of Depression Discovered by NARSAD Grantee
From The Quarterly, Spring 2013
Marina Picciotto, Ph.D., leading a team of researchers at Yale University, has made an exciting discovery in the search for the biological causes of depression and anxiety. Their discovery points to the importance of a signaling system in the brain that was not previously believed to be central in causing depression.
For decades, many scientists have favored a theory of depression that stresses the impact of abnormally low levels of a signal-carrying chemical, called serotonin. The new research by Dr. Picciotto’s team shifts attention to a different signaling chemical, or neurotransmitter, called acetylcholine.
Millions of depressed people take anti-depressant drugs called SSRIs—an acronym for selective serotonin re-uptake inhibitors.
Prozac®, Paxil®, Celexa®, Zoloft® and other SSRI medications act to keep message-carrying serotonin molecules from being rapidly reabsorbed by nerve cells.
By allowing serotonin to float for longer periods of time in the tiny spaces between nerve cells, called synapses, scientists have theorized the SSRI drugs promote signaling by compensating for abnormally low serotonin levels.
Dr. Picciotto’s new research, published in Proceedings of the National Academy of Sciences in February, turns attention to fluctuations in levels of the neurotransmitter acetylcholine and the larger chemical signaling system it is part of, called the cholinergic system.
“Serotonin may be treating the problem,” Dr. Picciotto says, “but acetylcholine disruption may be a primary cause of depression. If we can treat the root cause, perhaps we can get a better response from the patient.”
Her team’s experiments demonstrate that abnormally high levels of acetylcholine in the brain can cause depression and anxiety symptoms in mice.
In the brains of non-depressed mice—and people—an enzyme called acetyl- cholinesterase (AChE) is produced to lower acetylcholine levels.
The team showed that when depressed mice were given Prozac®, AChE levels were raised, and abnormally high levels of acetylcholine were thus brought under control. This adds a new dimension to understanding how and why SSRI anti-depressants can alleviate depression.
Yet many depressed people do not get a therapeutic benefit from Prozac® or other SSRI medications. Dr.
Picciotto’s research suggests this may be because the root problem is not, after all, low levels of serotonin, but rather, high levels of acetylcholine.
By experimentally blocking the “ports,” called receptors, where acetylcholine molecules “dock” with nerve cells in the brain, the team was able to reverse depression in mice.
In still other experiments, the Yale team showed how interruptions in acetylcholine signaling in the brain area called the hippocampus—important in memory and mood—promotes depression and anxiety in mice.
While the relation between the serotonin and acetylcholine signaling systems is not yet fully clear, this new research opens a new possibility to treat the cause of depression and not just its symptoms.
With the new hypothesis that it is the disruption of acetylcholine, and not serotonin, that sets depression in motion, further research studies can be undertaken to determine if medications that target acetylcholine rather than serotonin, are more effective in treating depression.
Marina Picciotto, Ph.D.Charles B. G. Murphy Professor of Psychiatry,Professor of Neurobiology and Pharmacology,Assistant Chair for Basic Science Research, Psychiatry,Yale University;
1996 NARSAD Young Investigator Grantee,
2004 NARSAD Independent Investigator Grantee
Content Background: The Effects of Acetylcholine
intestines: contraction (diarrhea, vomit)tear ducts: secretion (lacrimation or tears)heart: decreased heart ratebladder: contraction (urination)lungs: (bronchii) constrictioneyes: pupil constriction (miosis)salivary glands: secretion (salivation)muscles: contractionsweat glands: secretion (sweat)
brain: stimulate (vomit)
The location of acetylcholine1 neurons and receptors2 can be mapped with respect to the organization of the nervous system (Figure 7). Acetylcholine neurons are plentiful in the central nervous system, which includes the brain and the spinal cord.
The peripheral nervous system includes neurons that connect the brain and spinal cord to muscles, organs and skin to send sensory and motor information.
The peripheral nervous system is sub-divided into 1) the somatic motor system, in which skeletal muscles receive information from the spinal cord via motor nerves to cause movement (mostly voluntary) and 2) the autonomic nervous system, in which smooth muscles and other organs receive information from the brain and spinal cord to control organ function (mostly involuntary). Last, the autonomic nervous system is sub-divided into the parasympathetic nervous system3 (PSNS), which is active all of the time, and the sympathetic nervous system4 (SNS), which is active especially during times of stress, fear and emergencies. Acetylcholine neurons are present in all parts of the peripheral nervous system. In the somatic nervous system5, motor nerves release acetylcholine onto skeletal muscle. In the autonomic nervous system, there are 2 types of neurons that contribute to the PSNS and the SNS. The first type of neuron leaves the spinal cord, en route to a cluster of neurons called a ganglion6. In the ganglia, the acetylcholine neurons release acetylcholine onto the second type of neuron. This second type of neuron travels to its final destination (e.g., organs, glands, smooth muscle) and it either releases acetylcholine in the PSNS or it releases another neurotransmitter, norepinephrine7 in the SNS. These 2 nervous systems usually work in opposition to each other. For example, in the lungs, the PSNS causes bronchiole constriction and the SNS causes bronchiole dilation; the PSNS stimulates salivation and the SNS inhibits salivation. In each place where acetylcholine is released, acetylcholine receptors are present on the corresponding target (Figure 7).
1 a neurotransmitter stored in vesicles of nerve terminals; it is found in neurons within the central nervous system, the somatic nervous system, the parasympathetic nervous system and the sympathetic nervous system.
2 a protein to which hormones, neurotransmitters and drugs bind.
They are usually located on cell membranes and elicit a function once bound.
3 part of the autonomic nervous system which controls everyday functions of organs and tissues. It consists of 2 types of neurons, pre-ganglionic and post-ganglionic. Both types release acetylcholine.
4 part of the autonomic nervous system which controls the functions of organs and tissues especially during times of stress, fear and emergencies. It consists of 2 types of neurons, pre-ganglionic and post-ganglionic. The pre-ganglionic neurons release acetylcholine and the post-ganglionic neurons release norepineprine.
5 part of the peripheral nervous system that controls movement. Motor nerves leave the spinal cord and innervate skeletal muscles. The motor nerves release acetylcholine to make muscles contract.
6 a bundle of nerve cell bodies, often referred to as the “post-ganglionic neuron”.
In the both the PSNS and SNS, the pre-ganglionic neurons release acetylcholine; the post-ganglionic neurons release either acetylcholine (PSNS) or norepinephrine (SNS).
7 a neurotransmitter (chemical messenger) in the catecholamine family that medicates chemical communication in the sympathetic nervous system.
It is responsible for the physiologic response to a stressful challenge (the ‘flight or fight’ response).
Figure 7 Organization of the nervous system including the central, autonomic (PSNS and SNS) and somatic subdivisions. Act, acetylcholine; NE, norepinephrine; AChR, acetylcholine receptor; NER, norepinephrine receptor.
How Acetylcholine Functions in the Body
PASIEKA / Science Photo Library / Getty Images
Acetylcholine is one of the most abundant neurotransmitters in the human body, often abbreviated ACh. It is in found in both the central nervous system (CNS) and the peripheral nervous system (PNS). It is one of the body's most important neurotransmitters, which are chemicals used to transmit signals from one cell to another.
The name acetylcholine is derived from its structure. It is a chemical compound made up of acetic acid and choline. Cholinergic synapses are those in which transmission is mediated by acetylcholine.
Why is acetylcholine so important in the body? It serves a number of critical functions, many of which can be impaired by diseases or drugs that influence the function of this neurotransmitter.
- Acetylcholine can be found in all motor neurons, where it stimulates muscles to contract.
From the movements of the stomach and heart to the blink of an eyelash, all of the body's movements involve the actions of this important neurotransmitter.
- It is also found in many brain neurons and plays an important role in mental processes such as memory and cognition. Severe depletion of acetylcholine is associated with Alzheimer's disease.
Acetylcholine is not only the most common chemical messenger, but it was also the very first neurotransmitter to be identified.
It was discovered by Henry Hallett Dale in 1914, and its existence was later confirmed by Otto Loewi. Both individuals were awarded the Nobel Prize in Physiology/Medicine in 1936 for their discovery.
In the peripheral nervous system, this neurotransmitter is a major part of the somatic nervous system and works to activate muscles. Within this system, it plays an excitatory role leading to the activation of muscles.
Within the autonomic system, acetylcholine controls a number of functions by acting on preganglionic neurons in the sympathetic and parasympathetic systems. It is also the neurotransmitter released at all parasympathetic innervated organs, promoting contraction of smooth muscles, dilation of blood vessels, increased body secretions and a slower heart rate.
Because acetylcholine plays an important role in muscle actions, drugs that influence this neurotransmitter can cause various degrees of movement disruption or even paralysis.
For example, the brain might send out a signal to move the right arm. The signal is carried by nerve fibers to the neuromuscular junctions. The signal is transmitted across this junction by the acetylcholine neurotransmitter, triggering the desired response in those specific muscles.
Acetylcholine also acts at various sites within the central nervous system where it can function as a neurotransmitter and as a neuromodulator. It plays a role in motivation, arousal, attention, learning, and memory ACH is also involved in promoting REM sleep.
Critical cholinergic pathway deterioration in the CNS has been associated with the onset of Alzheimer's disease.
Drugs and substances that interrupt acetylcholine function can have negative effects on the body and can even lead to death. Examples of such substances include some types of pesticides and nerve gasses.
The venom of a black widow spider acts by causing the release of acetylcholine. When a person is bitten by a black widow, their acetylcholine levels rise dramatically, leading to severe muscle contractions, spasms, paralysis, and even death.
Acetylcholine is a critical neurotransmitter that plays an important role in the normal function of the brain and body. Disruptions in the release and function of this neurotransmitter can result in significant problems in areas such as memory and movement.
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