UJIKE Hiroshi Okayama University Medical School Hospital, Department of Neuropsychiatry, Assis, 医学部附属病院, 助手 (90213420)
FUJIWARA Yutaka Okayama University Medical School Hospital, Department of Neuropsychiatry, Assis, 医学部附属病院, 助手 (50173498)
|Budget Amount *help
¥2,000,000 (Direct Cost : ¥2,000,000)
Fiscal Year 1992 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 1991 : ¥1,100,000 (Direct Cost : ¥1,100,000)
Abuse of psychostimulants such as amphetamine (AMP) or methamphetamine (MAP) can produce psychosis, which resembles paranoid schizophrenia. Similarly, subchronic administration of AMP or MAP to experimental animals induces behavioral sensitization, in which augmented behavioral responses can be induced by administration of challenge doses of these drugs after cessation of subchronic treatment. The present study was conducted to investigate the mechanism of behavioral sensitization, and consists of two experiments.
1. The effect of manipulation of Na^+ gradient between the intracellular and extracellular media on striatal dopamine (DA) efflux under steady-state conditions after subchronic MAP treatment was investigated. Rats were injected with 4 mg/kg MAP or saline once daily for 14 days. Seven days after the last injection, ouabain, a selective inhibitor of the Na^+, K^+-ATPase, was infused locally through a semi-permeable probe in the striatum. Ouabain induced a significantly greater i
ncrease of the DA concentrations in the striatal perfusate in the subchronic MAP than the control group. Reserpine pretreatment did not affect the enhanced ouabain-induced DA efflux in the subchronic MAP than in the MAP group. In contrast, -methyl-p-tyrosine pretreatment abolished the ouabain-induced efflux of DA in both groups. These results suggest that subchronic MAP treatment facilitates the efflux of newly synthesized DA, which is induced by the ouabain-induced decrease of the Na^+ gradient between intracellular and extracellular media.
2. Experimental rats aged 7, 14, 21, 28, 56 postnatal days (PNDs) were pretreated twice daily with 2 mg/kg MAP for 3 days followed by 4 mg/kg for 3 days. Matched control rats were given equivalent volumes of saline according to the same schedule. The MAP challenge, given 21 days after the last pretreatment, induced significantly greater increases in extracellular DA levels in the MAP-pretreated rats compared with control rats only when MAP pretreatment was initiated on PNDs 21, 28 and 56, but not in younger rats. Correspondingly, MAP-induced stereotyped behavior was enhanced significantly only when MAP pretreatment was started on PNDs 21, 28 and 56, but not PNDs 7 and 14. These results suggest that MAP-induced behavioral sensitization and the underlying ability to release DA is established on or around PND 21. Less