Catherine A Schweppe1,2, Caitlin Burzynski1, Subramaniam Jayanthi3, Bruce Ladenheim3, Jean Lud Cadet3, Eliot L Gardner1, Zheng-Xiong Xi1, Henriette van Praag4,5, Amy Hauck Newman1, Thomas M Keck6,7. 1. Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, Baltimore, 333 Cassell Drive, Baltimore, MD, 21224, USA. 2. Department of Neurology, University of California Los Angeles, 635 Charles E Young Drive South, Los Angeles, CA, 90095, USA. 3. Molecular Neuropsychiatry Research Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, Baltimore, 333 Cassell Drive, Baltimore, MD, 21224, USA. 4. Neuroplasticity and Behavior Unit, Laboratory of Neurosciences, National Institute on Aging - Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA. 5. Department of Biomedical Science, Charles E. Schmidt College of Medicine, and Brain Institute, Florida Atlantic University, Jupiter, FL, 33458, USA. 6. Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, Baltimore, 333 Cassell Drive, Baltimore, MD, 21224, USA. keckt@rowan.edu. 7. Department of Chemistry & Biochemistry, Department of Molecular & Cellular Biosciences, College of Science and Mathematics, Rowan University, 201 Mullica Hill Road, Glassboro, NJ, 08028, USA. keckt@rowan.edu.
Abstract
RATIONALE: Abuse of the psychostimulant methamphetamine (METH) can cause long-lasting damage to brain monoaminergic systems and is associated with profound mental health problems for users, including lasting cognitive impairments. Animal models of METH exposure have been useful in dissecting the molecular effects of the drug on cognition, but many studies use acute, non-contingent "binge" administrations of METH which do not adequately approximate human METH use. Long-term METH exposure via long-access (LgA) self-administration paradigms has been proposed to more closely reflect human use and induce cognitive impairments. OBJECTIVE: To better understand the role of contingency and patterns of exposure in METH-induced cognitive impairments, we analyzed behavioral and neurochemical outcomes in adult male rats, comparing non-contingent "binge" METH administration with contingent (LgA) METH self-administration and non-contingent yoked partners. RESULTS: Binge METH (40 mg/kg, i.p., over 1 day) dramatically altered striatal and hippocampal dopamine, DOPAC, 5-HT, 5-HIAA, BDNF, and TrkB 75 days after drug exposure. In contrast, 6-h LgA METH self-administration (cumulative 24.8-48.9 mg METH, i.v., over 16 days) altered hippocampal BDNF in both contingent and yoked animals but reduced striatal 5-HIAA in only contingent animals. Neurochemical alterations following binge METH administration were not accompanied by cognitive deficits in Morris water maze, novel object recognition, or Y-maze tests. However, contingent LgA METH self-administration resulted in impaired spatial memory in the water maze. CONCLUSIONS: Overall, substantial differences in neurochemical markers between METH exposure and self-administration paradigms did not consistently translate to deficits in cognitive tasks, highlighting the complexity of correlating METH-induced neurochemical changes with cognitive outcomes.
RATIONALE: Abuse of the psychostimulant methamphetamine (METH) can cause long-lasting damage to brain monoaminergic systems and is associated with profound mental health problems for users, including lasting cognitive impairments. Animal models of METH exposure have been useful in dissecting the molecular effects of the drug on cognition, but many studies use acute, non-contingent "binge" administrations of METH which do not adequately approximate humanMETH use. Long-term METH exposure via long-access (LgA) self-administration paradigms has been proposed to more closely reflect human use and induce cognitive impairments. OBJECTIVE: To better understand the role of contingency and patterns of exposure in METH-induced cognitive impairments, we analyzed behavioral and neurochemical outcomes in adult male rats, comparing non-contingent "binge" METH administration with contingent (LgA) METH self-administration and non-contingent yoked partners. RESULTS: Binge METH (40 mg/kg, i.p., over 1 day) dramatically altered striatal and hippocampal dopamine, DOPAC, 5-HT, 5-HIAA, BDNF, and TrkB 75 days after drug exposure. In contrast, 6-h LgA METH self-administration (cumulative 24.8-48.9 mg METH, i.v., over 16 days) altered hippocampal BDNF in both contingent and yoked animals but reduced striatal 5-HIAA in only contingent animals. Neurochemical alterations following binge METH administration were not accompanied by cognitive deficits in Morris water maze, novel object recognition, or Y-maze tests. However, contingent LgA METH self-administration resulted in impaired spatial memory in the water maze. CONCLUSIONS: Overall, substantial differences in neurochemical markers between METH exposure and self-administration paradigms did not consistently translate to deficits in cognitive tasks, highlighting the complexity of correlating METH-induced neurochemical changes with cognitive outcomes.
Entities:
Keywords:
Cognitive performance; Methamphetamine; Neurotoxicity; Self-administration; Spatial working memory
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