In the present study, pseudoginsenoside-F11 (PF11), a saponin that existed in American ginseng, was studied on its protective effect on methamphetamine (MA)-induced behavioral and neurochemical toxicities in mice. MA was intraperitoneally administered at the dose of 10mg/kg four times at 2-h intervals, and PF11 was orally administered at the doses of 4 and 8mg/kg two times at 4-h intervals, 60 min prior to MA administration. The results showed that PF11 did not significantly influence, but greatly ameliorated, the anxiety-like behavior induced by MA in the light-dark box task. In the forced swimming task, PF11 significantly shortened the prolonged immobility time induced by MA. In the appetitively motivated T-maze task, PF11 greatly shortened MA-induced prolonged latency and decreased the error counts. Similar results were also observed in the Morris water maze task. PF11 significantly shortened the escape latency prolonged by MA. There were significant decreases in the contents of dopamine (DA), 3, 4-dihydroxyphenacetic acid (DOPAC), homovanillic acid (HVA), and 5- hydroxyindoacetic acid (5-HIAA) in the brain of MA-treated mice. PF11 could partially, but significantly, antagonize MA-induced decreases of DA. The above results demonstrate that PF11 is effective in protection of MA-induced neurotoxicity and also suggest that natural products, such as ginseng, might be potential candidates for the prevention and treatment of the neurological disorders induced by MA abuse.

Opiate abuse causes adaptive changes in several processes of synaptic transmission in which the glutamatergic system appears a critical element involved in opiate tolerance and dependence, but the underlying mechanisms remain unclear. In the present study, we found that glutamate uptake in hippocampal synaptosomes was significantly increased (by 70% in chronic morphine-treated rats) during the morphine withdrawal period, likely attributable to an increase in the number of functional glutamate transporters. Immunoblot analysis showed that expression of GLT1 (glutamate transporter subtype 1) was identified to be upregulated in synaptosomes but not in total tissues, suggesting a redistribution of glutamate transporter expression. Moreover, the increase in glutamate uptake was reproduced in cultured neurons during morphine withdrawal, and the increase of uptake in neurons could be blocked by dihydrokainate, a specific inhibitor of GLT1. Cell surface biotinylation and immunoblot analysis showed that morphine withdrawal produced an increase in GLT1 expression rather than EAAC1 (excitatory amino acids carrier 1), a neuronal subtype, at the cultured neuronal cell surface, whereas no significant change was observed in that of cultured astrocytes. Electron microscopy also revealed that GLT1 expression was markedly increased in the nerve terminals of hippocampus and associated with the plasma membrane in vivo. These results suggest that GLT1 in hippocampal neurons can be induced to translocate to the nerve terminals and express on the cell surface duringmorphine withdrawal. The translocation of GLT1 at synapses during morphine withdrawal provides a neuronal mechanism for modulation of excitatory neurotransmission during opiate abuse.

Previous studies have shown that acute systemic administration of ethanol induced ascorbic acid release in the striatum. However, the pharmacological implications of ethanol-induced striatal ascorbic acid release are unclear. In the present study, ethanol-induced extracellular changes of ascorbic acid and hydroxyl radical levels were detected in rat striatum by using brain microdialysis coupled to high-performance liquid chromatography with electrochemical detection. It was found that both in male and female rats, ethanol (3.0g/kg, i.p.) increased striatal ascorbic acid release in the first 60 min after ethanol administration. Meanwhile, the extracellular hydroxyl radical levels, detected as 2, 3- and 2, 5-DHBA, were significantly decreased. However, when the ascorbic acid levels returned to the baseline, hydroxyl radical levels rebounded. Administration of DL-fenfluramine (20mg/kg, i.p.) had no effect on the basal levels of ascorbic acid and hydroxyl radical, but significantly blocked ethanol-induced ascorbic acid release and increased hydroxyl radical levels significantly. Exogenous administration of ascorbic acid (20mg/kg, s.c.) increased the extracellular levels of ascorbic acid in the striatum, and inhibited the increase of 2, 3- and 2, 5-DHBA in DL-fenfluramine plus ethanol group. These results provide first evidence that release of endogenous ascorbic acid in the striatum plays an important role in preventing oxidative stress by trapping hydroxyl radical in the central nervous system.

The effect of oleamide on apoptosis was investigated by using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide reduction assay, DNA staining assay with propidiumiodide and caspase-3 activity analyses. The present results showed that oleamide significantly attenuated the cell death and nuclear condensation of cultured rat cerebellar granule neurons induced by K+ deprivation in a dose-dependent manner. The oleamide actions were well parallel with the attenuation of caspase-3 activity in the process of apoptotic death. Moreover, neither elaidic acid nor stearic acid, two fatty acids structurally related to oleamide without the Δ9-cis double bond, had similar effects on the cell death, suggesting the selectively structural features of oleamide required for this action. These data provided the first evidence of a protective effect of oleamide against apoptosis in a structurally specific manner.

Accumulating evidence has indicated that there might exist some correlation between opiate reward and certain kinds of learning and memory processes. The present study attempted to investigate the correlation between individual differences in morphine reward and capacities in spatial learning and spontaneous alternation. In the present studies, good-response (GR) and poor-response (PR) mice were respectively selected according to their performance in a spatial learning test involving the Morris water maze or in a spontaneous alternation task using the Y-maze. In a place preference conditioning procedure, morphine (3.0 mg/kg) produced significant conditioned place preference (CPP) in both GR and PR mice selected by using either the Morris water maze or the Y-maze. The PR mice selected with the Morris water maze showed significantly more CPP induced by morphine than the GR mice. However, no detectable difference was observed in morphine-induced CPP between the GR and PR mice selected with the Y-maze. These results suggested that the variation in morphine-induced CPP in mice is somehow differentially related to that of spatial learning but unlikely to that of spontaneous alternation.