A single neurotoxic dose of methamphetamine induces a long-lasting depressive-like behaviour in mice.
Methamphetamine (METH) triggers a disruption of the monoaminergic system and METH abuse leads to negative emotional states including depressive symptoms during drug withdrawal. However, it is currently unknown if the acute toxic dosage of METH also causes a long-lasting depressive phenotype and persistent monoaminergic deficits. Thus, we now assessed the depressive-like behaviour in mice at early and long-term periods following a single high METH dose (30 mg/kg, i.p.). METH did not alter the motor function and procedural memory of mice as assessed by swimming speed and escape latency to find the platform in a cued version of the water maze task. However, METH significantly increased the immobility time in the tail suspension test at 3 and 49 days post-administration. This depressive-like profile induced by METH was accompanied by a marked depletion of frontostriatal dopaminergic and serotonergic neurotransmission, indicated by a reduction in the levels of dopamine, DOPAC and HVA, tyrosine hydroxylase and serotonin, observed at both 3 and 49 days post-administration. In parallel, another neurochemical feature of depression--astroglial dysfunction--was unaffected in the cortex and the striatal levels of the astrocytic protein marker, glial fibrillary acidic protein, were only transiently increased at 3 days. These findings demonstrate for the first time that a single high dose of METH induces long-lasting depressive-like behaviour in mice associated with a persistent disruption of frontostriatal dopaminergic and serotonergic homoeostasis.
Laboratory of Pharmacology and Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, Subunit 1 - Polo 3, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.
Carlos D
CD
Silva
Ana F
AF
Neves
Ana I
AI
Dias
Hugo J
HJ
Freitas
Sheena M
SM
Mendes
Inês
I
Pita
Sofia D
SD
Viana
Paulo A
PA
de Oliveira
Rodrigo A
RA
Cunha
Carlos A
CA
Fontes Ribeiro
Rui D
RD
Prediger
Frederico C
FC
Pereira
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D003866:Depressive Disorder / Q000139:chemically induced* / Q000503:physiopathology*; D004298:Dopamine / Q000378:metabolism; D004924:Escape Reaction / Q000187:drug effects / Q000502:physiology; D005625:Frontal Lobe / Q000187:drug effects / Q000503:physiopathology; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D020258:Neurotoxicity Syndromes / Q000503:physiopathology*; D012701:Serotonin / Q000378:metabolism; D013550:Swimming / Q000502:physiology; D013997:Time Factors
D012701:Serotonin; D008694:Methamphetamine; D004298:Dopamine