Tomorrow's Health, Today's Research

Dr. Raad Nashmi

Associate Professor, Department of Biology
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Phone: (250) 721-6169
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Research area: neurobiology, synaptic transmission, nicotinic receptors, nicotine addiction

Research Profile:

Why nicotine is addictive, yet good for the brain

Nicotine, the main pharmacological component of tobacco, is a paradox. The addictive nature of nicotine, which reinforces tobacco smoking, inflicts a heavy toll on the world population, resulting in 4 million deaths annually. Yet, nicotine alone, excluding the other harmful components of tobacco, has great therapeutic potential for the treatment of many nervous system disorders including Parkinson's disease, Alzheimer's disease, schizophrenia, epilepsy, pain, and can also enhance cognitive performance. Neuroscientist Dr. Raad Nashmi recently discovered a novel mechanistic pathway for nicotine addiction, which also helps explain nicotine’s benefits for those prone to Parkinson’s.

Mice and humans show similar responses to nicotine and we can see the paradox of nicotine in mice. If you give a mouse a small dose of nicotine, it will act sedated; give it a larger dose, it will run around. If you get the dose exactly right it will perform better than normal at mazes and show other signs of improved cognitive prowess. Nicotine will also dull pain. These symptoms might sound familiar to smokers, who will also add to the list the feelings of peace and contentment after a smoke. All these effects have the same starting point in humans and mice: once nicotine reaches the nervous system, it binds to nicotinic acetylcholine receptors inside and on the cell surface of several types of neurons.

Nashmi studies nicotine addiction by looking at a group of receptors called nicotinic acetylcholine receptors, which normally receive the neurotransmitter acetylcholine, but are also happy to bind nicotine, which is how nicotine delivers its hit.

Nashmi wants to know what these receptors do normally, and how they are affected by nicotine addiction. Finding answers to these questions could have multiple applications, including: how can you help people quit smoking? But perhaps more surprisingly, Nashmi’s work is more likely to lead to nicotine-based drugs that could help people better perceive, reason and remember, perhaps helping those with Alzheimer’s. There is even evidence that nicotine prevents Parkinson’s disease. Too bad about that little problem of addiction.

To understand nicotine addiction, it helps to understand acetylcholine. Acetylcholine has multiple roles in the nervous system, and its receptors are wide spread. Receptors are found in muscles, for instance, where acetylcholine causes contractions. Luckily, muscle nicotinic acetylcholine receptors are 400 fold less sensitive to nicotine than nicotinic receptors in the brain, or else smoking would likely result in fatal muscle contractions. In several regions of the brain, acetylcholine modulates neural communication, causing neurons to become more excitable. Acetylcholine is involved in countless neural pathways, including the pleasure reward system. When a person is exposed to nicotine, nicotine binds in acetylcholine’s place, mimicking the presence of acetylcholine.

One of the ongoing challenges of acetylcholine and nicotine research is getting a clear picture of where the nicotinic acetylcholine receptors are. It is well-known that humans respond to chronic exposure to nicotine by increasing the number of nicotinic receptors. So far, it hasn’t been clear which specific neurons and where on these neurons the new receptors show up. Ideally, neuroscientists would like to pinpoint the location down to the neuron sub-type. If researchers could tell where these receptors are, they could start to piece together the exact mechanisms for nicotine’s effects.

Previous methods to find receptors (radioactively labeled nicotinic ligands) were limited in that the spatial resolution was low ­-- limited to identifying brain regions. To counter this problem, Nashmi and his team created a strain of mice that express nicotinic acetylcholine receptors tagged with a fluorescent protein. In one recent study, this allowed them to accurately pinpoint the change in number and location of the receptors in various regions, cell types and subcellular neuronal structures of the brain, as mice became addicted to nicotine. Curiously, they found an increase in nicotinic receptors in an unexpected type of neuron, those that produce the neurotransmitter GABA (γ-aminobutyric acid) in the substantia nigra (Nashmi et al 2007 Journal of Neuroscience).

This finding is important for several reasons. For one, GABA affects neurons that release dopamine, slowing these neurons down. While Nashmi knew that nicotine had to affect dopamine function in some fashion (because all addictive drugs interfere with the dopamine pleasure-reward system), nobody has yet seen an addictive drug affect dopamine producing cells via GABA. Thus, it is a new insight into addiction mechanisms.

Nicotine’s involvement with GABA-producing cells in the substantia nigra also gives clues to another continuing mystery: why are smokers less likely to get Parkinson’s? Nashmi was interested in looking in this region of the brain because the loss of dopamine-producing neurons in the substantia nigra causes Parkinson’s disease.

 Nashmi reasons that, if chronic nicotine exposure leads to increased GABA levels, that will slow down firing of dopamine-releasing neurons. Perhaps this dampening effect reduces stress to these neurons, keeping them healthy longer.

Looking ahead, Nashmi’s recombinant DNA approach to understanding nicotinic acetylcholine receptors has proven so powerful he is collaborating with several researchers who want to use his mice system to answer various other questions.

Something Nashmi has not tackled yet, but might in the future, is how to help people overcome nicotine addiction. Nashmi is curious to know how long it takes after a person quits smoking for their neurotransmitter receptors to go back to normal baseline. He suspects that it depends on the neuron; receptors levels may return quickly to baseline for some neuron subtypes, in others, you may see long lasting changes, meaning, unfortunately, some cravings will never go away.