Invited reviewCholinergic contributions to the cognitive symptoms of schizophrenia and the viability of cholinergic treatments
Introduction
There is wide agreement in psychiatric practice and the literature that treatment with dopamine D2 receptor antagonists benefits the positive symptoms of a majority of patients with schizophrenia (Agid et al., 2006, Kapur et al., 2005, Kapur and Mamo, 2003, Kinon et al., 2010a, Kinon et al., 2010b). However, the cognitive impairments, which are present in all patients, albeit at highly variable degrees of severity (Fioravanti et al., 2005, Heinrichs and Zakzanis, 1998), and which greatly limit the patient’s ability to interact with the world and engage in a productive life (e.g., Green, 1996), are only minimally or not at all improved by antipsychotic drug treatment (for review see van Os and Kapur, 2009).
Treatments targeted at the cholinergic system are currently intensely studied candidates for addressing the cognitive deficits that remain after antipsychotic treatment and in remission. We will argue in this review that much of the current reasoning about cholinergic neuropsychopharmacology is based on a back-translation of the hypothesized mechanisms of acetylcholinesterase inhibitor treatments. Perhaps even more importantly, current drug development and theoretical work often treats the cholinergic system in a rather generic and static way, and does not consider the situational or temporal dynamics of its involvement in cognitive function. As will be discussed below, it is very likely that acetylcholine plays a role in the attention deficits of schizophrenia. However, we believe that a real and detailed understanding of what that role might be is still at the earliest stages. If drug development is to be effective, there is a strong need for truly mechanistic research that takes the complexities and interactions of the cholinergic system’s functions in attention into account, and details which aspects are dysfunctional in both the active and remitted states of the disease (Sarter et al., 2009a).
For more than two decades, basic neuroscience research in animals as well as psychopharmacological studies in humans, including studies employing pharmaco-fMRI approaches, have confirmed that forebrain cholinergic systems, specifically the cortical cholinergic input system, are a major and indeed necessary modulator of the brain’s fronto-parietal attention system (e.g., Deco and Thiele, 2009, Giocomo and Hasselmo, 2007, Hahn et al., 2007, Hasselmo and Sarter, 2010, Sarter et al., 2005). Cholinergic treatment approaches for the cognitive symptoms of schizophrenia have often started from a static hypothesis predicting a role for both abnormally low and high levels of cholinergic neurotransmission in the expression of cognitive symptoms (e.g., Money et al., 2010, Stip et al., 2005, Tandon and Greden, 1989). Recent research has begun to describe the multiple time scales that characterize the cholinergic mediation of attentional processes and capacities (Parikh et al., 2007, Parikh and Sarter, 2008) and thereby indicate new challenges and opportunities for the development of cholinergic therapies of attentional impairments. We begin with a review of the current literature, before giving a more detailed description of these new findings and their potential implications.
Section snippets
Attentional symptoms in schizophrenia and role of cholinergic systems
Among the domains of cognitive functions impaired in schizophrenia, considerable research has focused on the ability to sustain attention, specifically in situations which require that internal representations are employed in order to maintain attentional orienting toward the target location, target type, and/or the timing of targets (e.g., Gold et al., 2007, Grillon et al., 1990, Jazbec et al., 2007, Nuechterlein et al., 2009). Several reasons justify such a focus. Chronic impairments in the
Basic methodological and conceptual issues
In this section we will focus on evidence indicating how the forebrain cholinergic system, specifically the cortical cholinergic input system, mediates attentional performance and describe the implications of evidence from animal models of schizophrenia for the generation of hypotheses about the role of the cholinergic systems in schizophrenia’s cognitive symptoms. An initial clarification of two important methodological and conceptual issues will assist in illuminating a complex array of
Specific cholinergic treatment strategies
In this section, we consider the implications of the dynamic and demand-dependent aspects of the cholinergic system’s involvement in attention for the major classes of cholinergically-targeted treatments that are either in use or under active development. For each, we describe the demonstrated or likely effectiveness in terms of the circuitry model described above, and indicate what evidence may further establish and refine their clinical utility.
Conclusions
Efforts to find and develop treatments for the cognitive symptoms of schizophrenia remain intensely focused on drugs acting at cholinergic mechanisms (e.g., Conn et al., 2009, Leach et al., 2010, Lieberman et al., 2008, Money et al., 2010). As discussed above, such a focus seems well-justified based on basic neuroscientific and, specifically with respect to nAChR agonists and psychopharmacological research in animal models and healthy humans. However, the nature of cholinergic dysregulation in
Acknowledgements
The research described in this manuscript has been supported by NIH grants MH080332, MH080426, MH086530 (MS), MH086701 and MH086701 (SFT) and NSF grant 0726285 (CL).
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