Hippocampal brain amines in methotrexate-induced learning and memory deficit

• Published in: Canadian journal of physiology and pharmacology 2002-11, Vol.80 (11), p.1076-1084
• Main Authors: Madhyastha, Sampath, Somayaji, S N, Rao, M S, Nalini, K, Bairy, K Laxminarayana
• Format: Article
• Language: English
• Subjects: Amines; Animals; Avoidance Learning - drug effects; Avoidance Learning - physiology; Biogenic Amines - metabolism; Biological and medical sciences; Brain; Conditioning (Psychology) - drug effects; Conditioning (Psychology) - physiology; Drug toxicity and drugs side effects treatment; Drugs; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Male; Medical sciences; Memory Disorders - chemically induced; Memory Disorders - metabolism; Memory Disorders - pathology; Methotrexate - toxicity; Pharmacology. Drug treatments; Physiological aspects; Rats; Rats, Wistar; Toxicity: nervous system and muscle
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/y02-135

Intrathecal methotrexate in children with leukemia is known to cause seizures, dementia, leukoencephalo pathy, and cognitive dysfunction after long-term treatment. To investigate the cognitive dysfunction, male Wistar rats were given multiple intracerebroventricular injections of methotrexate. Its effect on behaviour was tested in the two-compartment conditioned avoidance task and dark–bright arena test. Levels of brain amines in the hippocampal region of the brain were estimated by HPLC. The qualitative and quantitative histopathological changes in the different regions of the hippocampus were studied by cresyl violet staining. Multiple injections (1 or 2 mg/kg) produced convulsions and learning and memory impairment but did not induce anxiolytic activity. They also reduced concentrations of all three brain amines (norepinephrine, dopamine, and serotonin) and the serotonin metabolite 5-hydroxyindoleacetic acid. The CA4 region of the hippocampus was severely affected by intraventricular methotrexate. Disruption of brain monoamines has been proposed as a cause of brain dysfunction from this chemotherapy, and that disruption may in turn involve cytotoxic effects of methotrexate on brain tissue. The outcomes of this study may have therapeutic implications in the management of cancer conditions, particularly in childhood lymphoblastic leukemia.Key words: methotrexate, hippocampus, norepinephrine, dopamine, serotonin, learning and memory.