By David N. Leff
Why do people afflicted with schizophrenia ¿have the highest prevalence of smoking that is found for any grouping of the population?¿ That statistic comes from neuroscientist John Dani, at Baylor College of Medicine, in Houston.
Schizophrenia draws up a dire litany of signs and symptoms, but nicotine addiction is not on the list of its psychoses. That bill of particulars cites, among many other features of the disease, abnormalities in perception, hallucinations and delusions, withdrawal from interest in other people and the outside world, and excessive focusing on one¿s own mental life.
¿The current statistical prevalence of schizophrenia,¿ observed research psychiatrist Fu-Ming Zhou, an instructor in Dani¿s lab at Baylor, ¿is about 1 percent. It¿s universal in different parts of the world, and across the spectrum of various socio-economic, gender and ethnic subjects.¿
Zhou described how a clinical psychiatrist diagnoses schizophrenia in a patient who presents with some suspicion of the disease. ¿It¿s generally based on the clinical symptoms,¿ he told BioWorld Today. ¿Usually, the person has some kind of weird behavior ¿ such as disoriented thoughts. That¿s the major part of the symptoms. These tend to get worse over time, marked especially by a decline in the patient¿s social and emotional capability.
¿Schizophrenia usually begins in early adulthood, at around 20 years of age, and then progresses,¿ Zhou went on. ¿There is a quite significant genetic contribution to the disease ¿ about 30 percent from inheritance. It clearly has multigenic gene linkage. There are some gene studies, especially in Northern European countries, which point strongly to a genetic contribution.¿
Zhou is first author of a paper in the December issue of Nature Neuroscience, dated December 2001. Dani is its senior author. The article¿s title: ¿Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum.¿
¿Our main finding,¿ Zhou said, ¿shows that there is some internal regulation of dopamine release in the brain. Those regulators are the nicotinic cholinergic receptors. This, I believe, was not described earlier, before our experiments. Also, I suggest that smoking probably is bad in this regard, because nicotine significantly disrupts this internal regulation.¿
Q: Why Do Addicts Smoke? A: Acetylcholine
¿Nicotine causes desensitization of these nicotinic receptors in the brain,¿ Zhou explained. ¿The brain also has a chemical neurotransmitter called acetylcholine [ACh], which can activate these nicotinic receptors. But ACh is broken down rapidly by an enzyme, acetylcholinesterase, that¿s sitting next to this ACh molecule. In contrast, nicotine cannot be degraded quickly. So when a person smokes, nicotine goes into the brain, where it hangs around for a very long time ¿ hours, or even more than hours. The nicotinic receptors in the brain are then desensitized ¿ made nonfunctional.¿
Dani elaborated: ¿Acetylcholine may be one reason why addicts smoke ¿ and could be key to developing new approaches for treatment of schizophrenia. ACh may play a role in release of dopamine, and is thought to be important in learning, movement and reinforcing rewarding behavior ¿ as in smoking. When dopamine neurons fire in the midbrain,¿ Dani pointed out, ¿the dopamine is released onto targets in the forebrain, including striatum and nucleus accumbens.¿
His metaphor for this process: ¿It¿s like turning on a garden hose behind the house to water plants in front. As our paper reports, we found that there is a valve¿ that controls the hose at the other end. When the faucet is on, the water does not flow out of the hose unless the valve is also open ¿ meaning it controls dopamine release in the brain target.¿
The co-authors took healthy, normal mice, removed their brains, sliced their striatal tissue thin, and inserted electrochemical microprobes to measure dopamine release. They showed that if the nicotinic ACh receptors were blocked, dopamine output fell by 80 percent ¿ demonstrating that ACh can indeed control dopamine release.
¿This sheds new light on tobacco addiction,¿ Zhou noted, ¿revealing that not only does nicotine activate dopamine neurons in the midbrain, but also regulates its release. Classically, drugs of addiction, such as cocaine, amphetamines and nicotine, boost dopamine by turning on its source in the brain. Our work shows that there is a very potent control at the other end, in the target.¿
Parkinson¿s disease (PD) tells a contrarian story.
¿PD is usually caused by a loss or lack of dopamine,¿ Zhou pointed out. ¿So somehow it¿s in the opposite direction to schizophrenia. It¿s not clear how our work can be directly related to PD. But it¿s my suggestion that it¿s not good for PD patients to smoke, because if they do, they have a good chance to further reduce dopamine levels, which are already low in these people.¿
Mice First, Therapeutic Drugs Next ¿ Maybe
¿Quite a few studies recently reported that schizophrenia patients have a higher than normal dopamine level in their brain,¿ Zhou observed. ¿Our paper shows that nicotine decreases that level. So a schizophrenic smoker can probably knock down dopamine levels in his or her brain. That might make the patient feel a little bit better, and could be a factor than contributes to the higher smoking rate in schizophrenics.¿
Dani¿s lab is now gearing up from probing murine brain slices in vitro to in vivo histochemical and behavioral studies of living mice. ¿We¿re going to implant multiple recording electrodes in the brain, and give the mice a dose of nicotine,¿ Zhou said. ¿Then we¿ll see how nicotine changes the firing of these neurons. At the same time, we will try to correlate the behavior of the animals with the neuronal activity. We haven¿t published anything on that. We started to set up the system just a few months ago, and are now getting ready to do the experiments.¿
At some future point, he suggested, ¿new therapeutic drugs may emerge from this work. There is a possibility to enhance the activity of these nicotinic receptors. Then, we probably could increase the release of dopamine. One of my colleagues is doing that in Dani¿s lab. He has seen some quite exciting preliminary results. A few pharmaceutical companies, I understand, are also testing these compounds independently. They are focused more on clinical aspects, and we¿re trying to explore the underlying mechanism.¿