QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.106047v1 jpet.106.106047v2 320/3/961    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Terry, A. V. Articles by Mahadik, S. P. Search for Related Content PubMed PubMed Citation Articles by Terry, A. V., Jr. Articles by Mahadik, S. P. Pubmed/NCBI databases Medline Plus Health Information Schizophrenia

PERSPECTIVES IN PHARMACOLOGY

Time-Dependent Cognitive Deficits Associated with First and Second Generation Antipsychotics: Cholinergic Dysregulation as a Potential Mechanism

Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia (A.V.T.); Small Animal Behavior Core, Medical College of Georgia, Augusta, Georgia (A.V.T.); Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta, Georgia (S.P.M.); and Medical Research Service Line, Veterans Administration Medical Center, Augusta, Georgia (S.P.M.)

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 (₇) 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.

Address correspondence to: Dr. Alvin V. Terry, Jr., Professor of Pharmacology and Toxicology, Director, Small Animal Behavior Core, CJ-1020, Medical College of Georgia, 1120 Fifteenth Street, Augusta, Georgia 30912-2450. E-mail: aterry{at}mail.mcg.edu