Methamphetamine-induced striatal dopamine release, behavior changes and neurotoxicity in BALB/c mice.
The behaviors associated with the neurotoxic effects of methamphetamine were evaluated in BALB/c mice. Hyperthermia and behavioral observations were measured 60 min after each subcutaneous injection of methamphetamine (4x4 or 8 mg/kg) or saline, each given 2 h apart. The behavioral observations included stereotyped behaviors, incidence of hemorrhage in breast, salivation and self-injurious behavior (SIB). Repeated administration of methamphetamine produced these behavioral changes and hyperthermia, but resulted in hypothermia by the final injection (8 mg/kg). In addition, the methamphetamine treatment induced a long-lasting dopamine depletion of similar magnitude in the 4 and 8 mg/kg-treated animals. In a time course study striatal monoamine levels were measured 60 min after each injection of these doses. The first and second injections of methamphetamine (8 mg/kg) produced a drastic increase in striatal 3-methoxytyramine; this failed to occur after the third or fourth injection of the same dose. In contrast, 4 mg/kg of methamphetamine also produced an increase in 3-methoxytyramine after the second and third injections of the drug and, in this case, these were maintained for the duration of the treatment. Striatal 3, 4-dihydroxyphenylacetic acid levels also drastically decreased following both doses of methamphetamine, suggesting inhibition of monoamine oxidase in striatum. Moreover, a single injection of methamphetamine increased striatal 2,3-dihydroxybenzoic acid formation. These results suggest that the incidence of hyperthermia, SIB and striatal dopamine neurotoxicity are closely linked to striatal dopamine release and inhibition of monoamine oxidase produced by methamphetamine in BALB/c mice.
Kita
T
T
Department of Pharmacology, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8521, Nara, Japan. tkita@nmu-gw.cc.naramed-u.ac.jp
Matsunari
Y
Y
Saraya
T
T
Shimada
K
K
O'Hara
K
K
Kubo
K
K
Wagner
G C
GC
Nakashima
T
T
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis / Q000378:metabolism; D019969:Amphetamine-Related Disorders / Q000209:etiology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001831:Body Temperature / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000031:analogs & derivatives / Q000032:analysis / Q000172:deficiency / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006719:Homovanillic Acid / Q000032:analysis / Q000378:metabolism; D062385:Hydroxybenzoates / Q000032:analysis / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D020156:Salicylic Acid / Q000008:administration & dosage / Q000032:analysis; D016728:Self-Injurious Behavior / Q000139:chemically induced; D013045:Species Specificity
D062385:Hydroxybenzoates; D015102:3,4-Dihydroxyphenylacetic Acid; D008694:Methamphetamine; C009135:2,3-dihydroxybenzoic acid; C001746:3-methoxytyramine; D020156:Salicylic Acid; D004298:Dopamine; D006719:Homovanillic Acid