Integrating the Neurobiology of Schizophrenia, Volume 78 (International Review of Neurobiology) by Anissa Abi-Dargham & Olivier Guillin

Author:Anissa Abi-Dargham & Olivier Guillin
Language: eng
Format: mobi
ISBN: 9780123737373
Publisher: Academic Press
Published: 2007-03-12T22:00:00+00:00

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MARTIN AND FREEDMAN

Reduced 7 subunit levels have been noted in frontal lobe regions (Guan et al., 1999),

including the dorsolateral prefrontal cortex (Martin-Ruiz et al., 2003). Reduced

levels of mRNA are also seen in peripheral blood lymphocytes (Perl et al., 2003).

The relatives of persons with schizophrenia also have poor P50 auditory

gating (Clementz et al., 1998; Ross et al., 1999; Siegal et al., 1984), consistent with

a genetically determined trait (Waldo et al., 1991). An initial genome scan using

poor P50 auditory gating as a phenotype gave only suggestive results at several

chromosomes (Coon et al., 1993). Following the identification of genetic markers

specific to the 7 nicotinic acetylcholine receptor gene (CHRNA-7) at 15q13–14

(Chini et al., 1994), P50 auditory gating was linked to the chromosome 15q14

locus of CHRNA-7 (Freedman et al., 1997). Families from the NIMH Schizo-

phrenia Genetics Initiative database have since been utilized to find linkage to the

diagnosis of schizophrenia itself (Leonard et al., 1998). Since that time, replica-

tions of these findings have occurred in North American families of African

descent (Kaufmann et al., 1998) and European descent (Tsuang et al., 2001),

German families (Sto¨ber et al., 2000), South African families (Riley et al., 2000),

Azorean families (Xu et al., 2001), Taiwanese families (Liu et al., 2001) and

Canadian families (De Luca et al., 2004). Other studies, including those that have

looked specifically at this region, have not found linkage (Curtis et al., 1999;

Neves-Pereira et al., 1998).

Although no amino acid-coding region polymorphisms have been identified,

multiple single nucleotide polymorphisms in the promoter region of CHRNA-7

as well as a partial duplication of the CHRNA-7 gene have been characterized

(Gault et al., 1998). Certain alleles are more frequently present in people with

schizophrenia and their family members (Houy et al., 2004; Leonard et al., 2002).

Furthermore, as some of these alleles are associated with both decreased promoter

region activity in vitro and impaired P50 auditory gating, they represent functional

polymorphisms that may be related to brain inhibitory pathway failure (Leonard

et al., 2002).

III. The Prototypic a7 Nicotinic Agonist, Nicotine, and Schizophrenia

The frequency of tobacco smoking is elevated in people with schizophrenia in

both inpatient (De Leon et al., 1995; Llerena et al., 2003) and outpatient settings

(Diwan et al., 1998; Hughes et al., 1986). They are heavier smokers (De Leon et al.,

1995; Kelly and McCreadie, 1999; Lasser et al., 2000; Masterson and O’Shea,

1984) and they extract more nicotine per cigarette smoked than the general

population (Olincy et al., 1997; Strand and Nyba¨ck, 2005 but see Bozikas et al.,

2005). In addition to the health implications of smoking (Go V et al., 2005), the

burden of this heavy use includes spending 27% of an already limited income on

SCHIZOPHRENIA AND THE 7 NICOTINIC RECEPTOR

229

the purchase of cigarettes (Steinberg et al., 2005). Their motivation to quit

smoking is low (Addington et al., 1997; Ziedonis and George, 1997), and the

smoking cessation rate is lower than the rates of other mentally ill populations

(Diwan et al., 1998) and the general population (Kelly and McCreadie, 1999).

Fortunately, interventions targeted specifically for persons with schizophrenia are

being developed (Steinberg et al., 2004; Ziedonis et al., 2003). Successful interventions

have utilized cognitive behavioral therapy and sustained release bupropion (Evins

et al.

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