Nicotinic receptor essential for cognition and mental health

The ability to maintain mental representations of ourselves and the world — the fundamental building block of human cognition — arises from the firing of highly evolved neuronal circuits, a process that is weakened in schizophrenia. In a new study, researchers at Yale University School of Medicine pinpoint key molecular actions of proteins that allow the creation of mental representations necessary for higher cognition that are genetically altered in schizophrenia. The study was released July 1 in the Proceedings of the National Academy of Sciences.

Working memory, the mind’s mental sketch pad, depends upon the proper functioning of a network of pyramid-shaped brain cells in the prefrontal cortex, the seat of higher order thinking in humans. To keep information in the conscious mind, these pyramidal cells must stimulate each other through a special group of receptors. The Yale team discovered this stimulation requires the neurotransmitter acetylcholine to activate a specific protein in the nicotinic family of receptors — the alpha7 nicotinic receptor.

Acetycholine is released when we are awake — but not in deep sleep. These receptors allow prefrontal circuits to come “online” when we awaken, allowing us to perform complex mental tasks. This process is enhanced by caffeine in coffee, which increases acetylcholine release. As their name suggests, nicotinic alpha-7 receptors are also activated by nicotine, which may may help to explain why smoking can focus attention and calm behavior, functions of the prefrontal cortex.

The results also intrigued researchers because alpha7 nicotinic receptors are genetically altered in schizophrenia, a disease marked by disorganized thinking. “Prefrontal networks allow us to form and hold coherent thoughts, a process that is impaired in schizophrenia,” said Amy Arnsten, professor of neurobiology, investigator for Kavli Institute, and one of the senior authors of the paper. “A great majority of schizophrenics smoke, which makes sense because stimulation of the nicotinic alpha7 receptors would strengthen mental representations and lessen thought disorder.”

Arnsten said that new medications that stimulate alpha-7 nicotinic receptors may hold promise for treating cognitive disorders.

Publication of the PNAS paper comes on the eve of the 10^th anniversary of the death of  Yale neurobiologist Patricia Goldman-Rakic, who was hit by a car in Hamden Ct. on July 31, 2003. Goldman-Rakic first identified the central role of prefrontal cortical circuits in working memory.

“Patricia’s work has provided the neural foundation for current studies of molecular influences on cognition and their disruption in cognitive disorders,” said Arnsten. “Our ability to apply a scientific approach to perplexing disorders such as schizophrenia is due to her groundbreaking research.”

Researchers Find Why Nicotine in Cigarettes May Relieve Anxiety in Smokers

Preclinical data suggests inactivation of a specific sub-class of nicotinic receptors may be an effective strategy to help smokers quit without feeling anxious, according to Virginia Commonwealth University researchers.

These findings could one day point researchers to the development of novel therapies to help smokers quit without feeling anxious.

Smokers use cigarettes for many reasons, but many report that they smoke to relieve anxiety, despite the health danger of cigarette smoking. Researchers are now working to understand the underlying neurochemical pathways that support smoking behavior.

In a study, published online this week in PLoS ONE, researchers observed that low doses of nicotine and a nicotinic receptor blocker had similar effects to reduce anxiety-like behavior in an animal model. They found that inactivation of beta2 subunit, a specific sub-class of nicotinic receptors that bind nicotine, appears to reduce anxiety. This is different from the mechanism that regulates nicotine reward and likely occurs in a separate brain area.

“This work is unique because it suggests that nicotine may be acting through inactivation, rather than activation, of the high affinity nicotinic receptors,” said Darlene Brunzell, Ph.D., assistant professor in the Department of Pharmacology and Toxicology in the VCU School of Medicine.

“Nicotine acts like a key that unlocks nicotine receptors in the brain. Usually that key opens the receptor, but at other times nicotine is like a key that has gotten broken inside of the lock. Our findings suggest that low-dose nicotine may block a specific subtype of receptor from opening that is important for regulating anxiety behavior,” she said, adding that anxiety is a major reason why people relapse to smoking.