Abstract
Although cognitive dysfunction is considered one of the more debilitating symptoms of schizophrenia, there is a fundamental gap in our knowledge of how the primary pharmacologic treatments of this disease, first- and second-generation antipsychotics (FGAs and SGAs, respectively), affect cognition, particularly over extended periods of time. Moreover, it has been known for decades that chronic treatment with FGAs can lead to imbalances in cholinergic function in the striatum that result in movement disorders; however, there is a growing body of evidence to suggest that both FGAs and SGAs can lead to cholinergic alterations in brain areas more traditionally considered as memory-related, such as cortical and hippocampal regions. Data from our laboratories in rodents indicate that some SGAs (if administered for sufficient periods of time) can be associated with impairments in memory-related task performance as well as alterations in the cholinergic enzyme choline acetyltransferase, the vesicular acetylcholine transporter, and nicotinic (α7) and muscarinic (M2) acetylcholine receptors. Given the well documented importance of central cholinergic function to information processing and cognitive function, it is important that the mechanisms for such chronic antipsychotic effects be identified. In this review, two potential mechanisms for long-term antipsychotic-related cholinergic alterations in the central nervous system are discussed: 1) antipsychotic antagonist activity at dopaminergic-D2 receptors on cholinergic neurons and 2) antipsychotic effects on neurotrophins that support cholinergic neurons, such as nerve growth factor and brain derived growth factor. Novel strategies to optimize the therapeutics of schizophrenia and maintain cognitive function via adjunctive cholinergic compounds and antipsychotic crossover approaches are also discussed.
Footnotes
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This work was supported by the National Institute of Mental Health (Grant MH 066233 to A.V.T.). We have also provided consultation or performed research (relevant to this article) either contractually or in collaboration with a several pharmaceutical companies, including Abbott Laboratories, Janssen Pharmaceutica, Lilly, Memory Pharmaceuticals, Merck, Pfizer, Roche Palo Alto, and Targacept, Inc.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.106047.
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ABBREVIATIONS: FGA, first-generation antipsychotic; SGA, second-generation antipsychotic; AUC, area under the curve; AChE, acetylcholinesterase; BDNF, brain-derived growth factor; ChAT, choline acetyltransferase; ELISA, enzyme-linked immunosorbent assay; mAChR, muscarinic acetylcholine receptor; NGF, nerve growth factor; nAChR, nicotinic acetylcholine receptor; TD, tardive dyskinesia; VAChT, vesicular acetylcholine transporter.
- Received August 6, 2006.
- Accepted September 7, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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