Neuronal Nicotinic Receptor Agonists

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The incidence of smoking is high in patients with schizophrenia, a rate at least three times higher than the general population. In fact, nicotine appears to produce a modest transient improvement in cognitive and sensory deficits in these patients. It has been suggested that smoking in schizophrenia represents an attempt to self-medicate.39 However, these views must be interpreted with caution. Overall, schizophrenic patients have a high degree of comorbid abuse of a variety of substances including nicotine, alcohol, cannabis, cocaine, and amphetamine. Importantly, the rate of substance abuse is higher than in the general population for all of these substances in spite of the fact that such abuse is associated with poorer outcomes, exacerbation of positive symptoms, increased hospitalization, and increased frequency of homelessness. This increased propensity to abuse a variety of substances regardless of consequences suggests that there may be a disregulation of reward systems in schizophrenics. Alternatively, high levels of D2 receptor occupancy by atypical antipsychotics may blunt DA-mediated reward and lead to an enhanced abuse drive. In support of this, a correlation exists between D2 receptor occupancy by antipsychotics and the number of cigarettes smoked by schizophrenics.72

Genetic linkage studies have shown that polymorphisms in the NNR gene are associated with schizophrenia, being linked to deficiency in the normal inhibition of the P50 auditory-evoked response,39 an electrographic index of auditory sensory gating that correlates with the PPI deficit observed in patients with schizophrenia. Deficits in sensory gating, therefore, may contribute to cognitive symptoms and perceptual disturbances and activation of nicotinic receptors may be a viable drug target for treating the sensory gating deficits of patients with schizophrenia.73

Clozapine but not haloperidol can improve sensory gating deficits in mice through a nicotinic mechanism. a7 NNR agonists, e.g., GTS-21 15, AZD-0328 73, SSR-180711 74, and W-56203 75, are currently being targeted for the treatment of schizophrenia. It remains to be determined whether these kinds of agents will broadly impact cognitive deficits in patients with schizophrenia, simply improve sensory gating, or be of no utility. Long-term use of nicotinic agonists also may be precluded because this class of receptors is susceptible to rapid tachyphylaxis.

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