A genetic rat model of cholinergic hypersensitivity: implications for chemical intolerance, chronic fatigue, and asthma.
The fact that only some individuals exposed to environmental chemicals develop chemical intolerance raises the possibility that genetic factors could be contributing factors. The present communication summarizes evidence from a genetic animal model of cholinergic supersensitivity that suggests that an abnormal cholinergic system could be one predisposing genetic factor. The Flinders Sensitive Line (FSL) rats were established by selective breeding for increased responses to an organophosphate. It was subsequently found that these FSL rats were also more sensitive to direct-acting muscarinic agonists and had elevated muscarinic receptors compared to the selectively bred parallel group, the Flinders Resistant Line (FRL) rats, or randomly bred control rats. Increased sensitivity to cholinergic agents has also been observed in several human populations, including individuals suffering from chemical intolerance. Indeed, the FSL rats exhibit certain behavioral characteristics such as abnormal sleep, activity, and appetite that are similar to those reported in these human populations. In addition, the FSL rats have been reported to exhibit increased sensitivity to a variety of other chemical agents. Peripheral tissues, such as intestinal and airway smooth muscle, appear to be more sensitive to both cholinergic agonists and an antigen, ovalbumin. Hypothermia, a centrally mediated response, is more pronounced in the FSL rats after nicotine and alcohol, as well as agents that are selective for the dopaminergic and serotonergic systems. In some cases, the increased sensitivity has been detected in the absence of any changes in the receptors with which the drugs interact (dopamine receptors), while receptor changes have been seen in other cases (nicotine receptors). Therefore, there may be multiple mechanisms underlying the multiple chemical sensitivity-chemical intolerance of the FSL rats. An elucidation of these mechanisms may provide useful clues to those involved in chemical intolerance in humans.
Overstreet
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DH
Department of Psychiatry and Center for Alcohol Studies, University of North Carolina at Chapel Hill, 27599-7178, USA. dhover@med.unc.edu
Djuric
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D000109:Acetylcholine / Q000502:physiology*; D000485:Allergens / Q000276:immunology / Q000633:toxicity; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D018678:Cholinergic Agents / Q000494:pharmacology / Q000633:toxicity*; D002799:Cholinergic Fibers / Q000187:drug effects / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000633:toxicity; D004195:Disease Models, Animal; D004785:Environmental Pollutants / Q000009:adverse effects / Q000494:pharmacology; D015673:Fatigue Syndrome, Chronic / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced / Q000503:physiopathology; D008954:Models, Biological; D018777:Multiple Chemical Sensitivity / Q000235:genetics* / Q000503:physiopathology; D018721:Muscarinic Agonists / Q000494:pharmacology / Q000633:toxicity; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000633:toxicity; D010047:Ovalbumin / Q000276:immunology / Q000633:toxicity; D010575:Pesticides / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000502:physiology; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000502:physiology; D015290:Second Messenger Systems / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000494:pharmacology / Q000633:toxicity; D012893:Sleep Wake Disorders / Q000139:chemically induced / Q000503:physiopathology; D015854:Up-Regulation
D000485:Allergens; D018678:Cholinergic Agents; D002800:Cholinesterase Inhibitors; D004785:Environmental Pollutants; D018721:Muscarinic Agonists; D018722:Nicotinic Agonists; D010575:Pesticides; D011954:Receptors, Dopamine; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D017366:Serotonin Receptor Agonists; D010047:Ovalbumin; D000109:Acetylcholine