Schizophrenia and the α7 Nicotinic Acetylcholine Receptor
Introduction
In addition to the more obvious symptoms of hallucinations and delusions, people with schizophrenia frequently suffer from cognitive symptoms such as the inability to focus attention. This results in a “flooding” with extraneous sensory stimuli which overwhelms the person's ability to think coherently (Venables, 1992). Poor cognitive functioning contributes to both poor role‐functioning and high costs of care through its association with activities of daily living, productivity, rate of inpatient hospitalization and outpatient utilization, independence, trainability/education levels, employability, and the lost productivity of family members spent caring for their ill relatives (reviewed in Sevy and Davidson, 1995). Cognitive impairment also contributes to poor medication adherence (Jeste et al., 2003) and limits the efficacy of rehabilitative therapies (reviewed in Sharma and Antonova, 2003). Cognitive deficits improve slightly with current antipsychotic medications, but they are not normalized and therefore remain a target for new treatment efforts (Weickert et al., 2003). Given increasing evidence for a role of the nicotinic cholinergic system's role in the cognitive symptoms of schizophrenia, the α7 nicotinic acetylcholine receptor has been proposed as a candidate for the development of medications specifically targeting cognitive deficits in schizophrenia (Martin et al., 2004). This chapter will review the neurobiological findings that led to the development of this promising new drug treatment for schizophrenia as well as new evidence for the beneficial effect of an α7 nicotinic receptor agonist on cognitive impairment in schizophrenia.
Section snippets
Neurobiological and Neurogenetic Evidence for a Link Between the α7 Nicotinic Acetylcholine Receptor and Schizophrenia
Sensory gating, measured using the P50 auditory‐evoked response, is impaired in persons with schizophrenia (Adler et al., 1985). The P50 auditory‐evoked response occurs 40–75 ms following an auditory stimulus. When a second auditory stimulus is presented in close proximity (500 ms), the P50 auditory‐evoked response to the second stimulus is diminished, which is evidence for the activity of an inhibitory process. This impairment has been replicated in multiple independent laboratories (Boutros 1991
The Prototypic α7 Nicotinic Agonist, Nicotine, and Schizophrenia
The frequency of tobacco smoking is elevated in people with schizophrenia in both inpatient (De 1995, Llerena 2003) and outpatient settings (Diwan 1998, Hughes 1986). They are heavier smokers (De 1995, Kelly 1999, Lasser 2000, Masterson 1984) and they extract more nicotine per cigarette smoked than the general population (Olincy 1997, Strand 2005 but see Bozikas et al., 2005). In addition to the health implications of smoking (Goff et al., 2005), the burden of this heavy use includes spending
The Search for an α7 Nicotinic Acetylcholine Receptor Agonist
Two compounds in current clinical use may have direct effects on α7 nicotinic receptors. The anticholinesterase inhibitor galantamine, which has additional modulatory effects on the α7 nicotinic receptor, has been reported to be beneficial for schizophrenia in a case study (Rosse and Deutsch, 2002). Tropisetron, a 5‐HT3 antagonist marketed outside the United States as an antinausea drug, also has efficacy as an α7 nicotinic receptor agonist (Macor 2001, Papke 2005). Tropisetron increases the
The Phase 1 Study of DMXBA in Schizophrenia
On the basis of the success of preclinical trials of α7 agonists in animal models of learning and memory and the safety of these drugs, DMXBA was initially evaluated in normal subjects with a planned development for the treatment of dementia of the Alzheimer's type. DMXBA was found to significantly improve simple reaction time, correct detection during digit vigilance, both word and picture recognition memory, and both immediate and delayed word recall. Additionally, DMXBA improved subject
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