It is helpful at this point to review briefly the disorders where nicotinic physiology and pharmacology seem relevant as a prelude to the methodological issues arising when conducting nicotinic studies in normal volunteers and patient populations. These disorders can be divided into groups based on the strength of the link to nicotinic receptor functioning.
There are two disorders for which there is an identified nicotinic pathology: autosomal dominant frontal lobe epilepsy (ADNFLE) and schizophrenia. In schizophrenia there is impairment in auditory sensory gating that may be related to the difficulty that these patients have in filtering extraneous sensory information.5 Normal subjects presented with a pair of auditory tones produce a smaller P50 (evoked potential at 50 ms) brain wave response to the second tone; the subjects partially inhibit or gate their electrophysiological response to the second tone. In patients with schizophrenia and their first-degree relatives, an inhibitional failure exists whereby these patients produce nearly identical P50 responses to both tones.5 Studies have found that nicotine administration temporarily corrects this gating deficit in patients with schizophrenia. This has been linked to a polymorphism at chromosome 15, which is the locus of the alpha7 nicotinic receptor.67
ADNFLE has been found to result from a missense mutation in the alpha4 subunit gene,8 resulting in a mutated alpha 4-beta2 nicotinic receptor unit. This is hypothesized to lead to the expression of brief seizures via effects on reduced receptor function, resulting in lower levels of GABA and glycine that may be triggered by these genetic mutations.5
Another classification of disorders can be considered to be those disorders where known nicotinic pathology is associated with the presence of the disease state. This includes Alzheimer's disease (AD) and Parkinson's disease (PD). Several researchers have shown that, in AD a significant loss of cortical nicotinic receptor binding in patients occurs, compared to age-matched controls.911 Nordberg12 demonstrated that there is a correlation between the level of cognitive dysfunction in AD and the loss of nicotinic receptor binding in temporal and frontal cortices and in the hippocampus using positron emission tomography (PET). This link is further supported by the finding13 that the anticholinesterase tacrine, which produces mild cognitive improvements, increases nicotinic receptor binding along with increasing cerebral blood flow. Cholinesterase inhibitors have been the primary pharmacologic treatment strategy for AD, showing moderate effects in reducing symptoms and slowing progression of the disease.1415 It is presumed that this therapy is partially effective through effects on the nicotinic receptor system.5 Nicotine and nicotinic agonists have been studied in patients with AD and have significant positive effects on learning memory1617 and attentional functioning.18 The nicotinic antagonist mecamylamine has been shown to cause impairment in learning and memory in normal volunteers and patients with PD and AD, with the patient groups showing increased sensitivity to nicotinic blockade, which correlates with the presumed level of nicotinic receptor loss.19
The primary pathology of PD is the loss of dopaminergic neurons in the sub-stantia nigra. There is a complex relationship between the dopaminergic and nicotinic receptor systems. Nicotine stimulates dopamine release in several areas of the brain, including the striatum and substantia nigra,20 and administration of a nicotinic antagonist has been shown to inhibit dopamine release from the striatal and mesolim-bic structures.21 Patients with PD often develop cognitive impairments that may be related to nicotinic receptor loss.19 Whitehouse and colleagues22 demonstrated that the loss of nicotinic receptors in PD correlates with the degree of dementia seen in the patient. Kelton and colleagues23 administered nicotine to non-demented patients with PD and found short-term, measurable cognitive and motor benefits, which included positive effects on attention, arousal, and processing speed. These effects were inhibited when pretreatment with the nicotinic antagonist mecamylamine was administered.
In PD and AD, epidemiological studies have found tobacco smoking to be associated with reduced incidence of these diagnoses.24 This finding, together with the finding that a loss of high-affinity nicotine binding in both AD and PD occurs, has lead researchers to hypothesize that the consequences of nicotinic cholinergic transmission may be neuroprotective.21
A third classification of disorders related to nicotinic function is those where there is no known loss or genetic alteration of nicotinic receptors, but there is evidence that stimulating nicotinic receptors may have therapeutic value. These disorders include ADHD, anxiety and depression, and Tourette's syndrome.
Attention deficit hyperactivity disorder (ADHD) is a clinical syndrome usually diagnosed in childhood. While to date no firm evidence of nicotinic system dysfunction in this disorder exists, current pharmacological treatments are psychostimulants, which are presumably effective via their interactions with dopamine. The primary deficits of this disorder involving attention are affected by nicotine administration in other clinical populations.25 Pilot studies administering nicotine to patients with ADHD have shown improvements in clinical global impressions (CGI) of symptoms, and on attentional tasks.26
There is evidence that anxiety and depression may be linked to nicotinic functioning. Nicotine has anxiolytic effects in humans and animals,17 27 which can be blocked by administration of mecamylamine.28 Major depression is associated with increased rates of cigarette smoking, and a greater difficulty in quitting smoking.29 Transdermal nicotine administration improves the mood of nonsmoking depressed patients.30 Treatments for depression that directly impact nicotinic receptor functioning have yet to be investigated.
Tourette's syndrome (TS) is a neurological disorder characterized by motor and vocal tics, often accompanied by hyperactivity, anxiety, fear, and symptoms of obsessive-compulsive disorder. Studies have demonstrated that nicotine administration (via transdermal patch or nicotine gum) can potentiate the action of traditional neuroleptics and is effective in managing the symptoms of TS.3132 These effects are fairly long lasting, with improvements in symptoms being reported up to four weeks after two days of nicotine exposure.33 It is hypothesized that this effect is related to the regulation of dopamine resulting from the desensitization of nicotinic receptors through chronic nicotine exposure. Novel nicotinic agents with a larger therapeutic index, as well as fewer side effects, offer promise for the treatment of this disorder.5
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