Developmental exposure to 3,4-methylenedioxymethamphetamine results in downregulation of neurogenesis in the adult mouse hippocampus.

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a powerful releaser of 5-HT and chronic use of this drug can cause depletion of monoamines. Recently, concerns about the risk of adult brain damage due to fetal exposure to MDMA have been raised. We investigated whether developmental MDMA exposure affected adult neurogenesis in C57 black/6 mice. MDMA (1.25 or 20 mg/kg, p.o.) or vehicle was administered daily to the mother from prenatal 6th day to postnatal 21st day. When the offspring were 11 weeks old, they were injected with 5-bromo-2'-deoxyuridine (BrdU) (120 mg/kg, i.p.) once a day for 4 days. After 24 h or 28 days, the animals were killed to count the BrdU-positive cells in the dentate gyrus. At 24 h after the last BrdU injection, the number of BrdU-positive cells in the offspring developmentally exposed to MDMA was significantly lower than that of the control group. At 28 days post-BrdU labeling, BrdU-positive cells in the dentate gyrus of female offspring with developmental exposure to high dose MDMA were significantly fewer compared with the control group. In addition, most BrdU-positive cells were co-labeled with the mature neuronal marker, neuronal nuclei, while a few BrdU-labeled cells were merged with an astrocyte marker. Our results suggest that developmental exposure to MDMA can result in decreases in the proliferation and survival of mature newborn cells in the adult dentate gyrus.

NMDA receptor antagonists inhibit apomorphine-induced climbing behavior not only in intact mice but also in reserpine-treated mice.

The present study showed that the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, MK-801 {(+)-5-methyl-10,11-dihydroxy-5H-dibenzo-[a,d]-cyclohepten-5,10-im ine hydrogen maleate}, ketamine, dextrorphan and dextromethorphan attenuated apomorphine-induced climbing behavior in reserpine-treated mice. In addition, the competitive NMDA receptor antagonists, D(-)-2-amino-5-phosphonopentanoic acid (AP-5) and D(-)-3-(2-carboxypipera-zine-4-yl)-propyl-1-phosphonic acid (CPP), also inhibited the apomorphine-induced climbing behavior in reserpine-treated mice as well as in intact mice. Previous work in our laboratory had shown that the noncompetitive NMDA receptor antagonists, MK-801, ketamine, dextrorphan and dextromethorphan cause a pronounced inhibition of apomorphine-induced cage climbing behavior in intact mice, suggesting the involvement of NMDA receptors in the glutamatergic modulation of dopaminergic function at the postsynaptic dopamine (DA) receptors. Therefore, the present results strongly support our previous conclusion that the NMDA receptors play important roles in the glutamatergic modulation of dopaminergic function at the postsynaptic DA receptors.

Psychostimulant-like effects of p-fluoroamphetamine in the rat.

The present study was undertaken to compare the pharmacological properties of p-fluoroamphetamine with those of amphetamine and of other halogenated amphetamines, using several in vivo and in vitro tests. These included substitution testing in (+)-amphetamine (1 mg/kg, 5.4 mu mol/kg, i.p.)-, (+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine [(+)-MBDB] (1.75 mg/kg, 7.8 mu mol/kg, i.p.)-, and 5-methoxy-6-methyl-2-aminoindan (MMAI) (1.71 mg/kg, 8 mu mol/kg, i.p.)-trained rats, [3H]5-HT and [3H]dopamine uptake inhibition in whole brain synaptosomes, and changes in striatal extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) as measured by in vivo microdialysis in freely moving rats. In drug discrimination substitution tests, p-fluoroamphetamine fully mimicked (+)-amphetamine (ED50 0.43 mg/kg, 2.11 mu mol/kg), whereas 'no substitution' was observed in rats trained to discriminate the serotonin (5-hydroxytryptamine, 5-HT)-releasing agents (+)-MBDB or MMAI from saline. p-Chloroamphetamine did not substitute for amphetamine but fully substituted for the (+)-MBDB and MMAI cues (ED50 0.17 mg/kg, 0.82 mu mol/kg, and 0.14 mg/kg, 0.69 mu mol/kg, respectively). p-Fluoroamphetamine, in comparison with p-chloroamphetamine and p-iodoamphetamine, showed much stronger inhibition of [3H]dopamine than [3H]5-HT uptake into rat brain synaptosomes but was less selective than amphetamine. p-Fluoroamphetamine (7.0 mg/kg, i.p.), 1 h after administration, strongly elevated (849% of baseline) extracellular dopamine in rat striatum measured using in vivo microdialysis. Amphetamine (2 mg/kg, i.p.) increased extracellular dopamine in rat striatum with a maximum at the same time as did p-fluoroamphetamine, but the latter gave a smaller increase. The data presented suggest that p-fluoroamphetamine resembles amphetamie more than it does the 5-HT-releasing type amphetamines.

Inhibition by noncompetitive NMDA receptor antagonists of apomorphine-induced climbing behavior in mice.

The N-methyl-D-aspartate (NMDA) subtype of glutamate receptors is an important mediator of several forms of neural and behavioral plasticity. In the present study, we examined the potential role of NMDA receptors in the glutamatergic modulation of dopaminergic function at the postsynaptic dopamine receptor by determining the effects of NMDA antagonists on apomorphine-induced climbing behavior in mice. The noncompetitive NMDA receptor antagonists, MK-801, ketamine, dextrorphan, and dextromethorphan attenuated the apomorphine-induced climbing behavior at does well below those that produce untoward side effects. These results suggest that the NMDA receptors play important roles in the glutamatergic modulation of dopaminergic function at the postsynaptic dopamine receptors that mediate the apomorphine-induced climbing behavior in mice.

Reinforcing effects of certain serotonin-releasing amphetamine derivatives.

The present study was designed to characterize further the rewarding and aversive properties of 3,4-methylenedioxymethamphetamine (MDMA), the alpha-ethyl homologue of MDMA (MBDB), fenfluramine, and the selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan (MMAI) using the conditioned place preference paradigm (CPP). Extracellular dopamine (DA) and its metabolite DOPAC were also measured in the nucleus accumbens after systemic drug administration, using in vivo microdialysis in freely moving rats. MDMA produced a positive dose-dependent effect in the CPP test, which was maximal at doses of 5 and 10 mg/kg. MBDB also induced a positive CPP, with a maximum effect at 10 mg/kg. The conditioning effect of MBDB was more than 2.5-fold weaker compared with MDMA. Fenfluramine evoked place aversion at doses of 4, 6, and 10 mg/kg. This effect of fenfluramine was independent of dose. MMAI at doses of 1.25, 2.5, and 5 mg/kg produced no significant effect on place conditioning. At doses of 10 and 20 mg/kg, MMAI produced an effect similar to fenfluramine: Place aversion was independent of dose. In the microdialysis experiments, MDMA significantly elevated extracellular DA and induced a decrease of DOPAC in the nucleus accumbens. Thus, activation of dopaminergic systems may be responsible for the rewarding properties of MDMA-like drugs. In contrast to the effects seen with MDMA, no difference in extracellular DA or DOPAC was seen after injection of MBDB, fenfluramine, or MMAI, even though MBDB weakly induced a place preference. The mechanism responsible for the development of place aversion by fenfluramine or MMAI is unknown at this time and requires further study.

Effects of ginseng total saponin on morphine-induced hyperactivity and conditioned place preference in mice.

A single or repeated administration of morphine in mice produced hyperactivity, conditioned place preference (CPP) and postsynaptic dopamine (DA) receptor supersensitivity. The hyperactivity induced by morphine was evidenced by measuring the enhanced ambulatory activity using a tilting-type ambulometer. CPP effects were evaluated assessing the increased time spent by the mice to morphine and the inhibition of CPP by the decreased time spent by the mice in the white compartment. Postsynaptic DA receptor supersensitivity in mice displaying a morphine-induced CPP was evidenced by the enhanced response in ambulatory activity to the DA agonist, apomorphine (2 mg/kg, s.c.). The intraperitoneal injection of ginseng total saponin (GTS) from the root of Panax ginseng C.A. Meyer (Araliaceae), prior to and during the morphine treatment in mice inhibited morphine-induced hyperactivity and CPP. GTS inhibited the development of postsynaptic DA receptor supersensitivity. A single dose administration of GTS also inhibited apomorphine-induced climbing behavior, showing the antidopaminergic action of GTS at the postsynaptic DA receptor. These results suggest that the development of morphine-induced CPP may be associated with the enhanced DA receptor sensitivity and that GTS inhibition of the morphine-induced hyperactivity and CPP may be closely related with the inhibition of dopaminergic activation induced by morphine.

Protective effects of acetylbergenin against carbon tetrachloride-induced hepatotoxicity in rats.

The present study was undertaken to investigate whether or not the hepatoprotective activity of acetylbergenin was superior to bergenin in carbon tetrachloride (CCl4)-intoxicated rat. Acetylbergenin was synthesized by acetylating bergenin, which was isolated from Mallotus japonicus. The hepatoprotective effects of acetylbergenin were examined against CCl4-induced liver damage in rats by means of serum and liver biochemical indices. Acetylbergenin was administered orally once daily for 7 successive days, then a 0.5 ml/kg mixture of CCl4 in olive oil (1:1) was intraperitoneally injected at 12 h and 36 h after the final administration of acetylbergenin. Pretreatment with acetylbergenin reduced the elevated serum enzymatic activities of alanine/aspartate aminotransferase, sorbitol dehydrogenase and gamma-glutamyltransferase in a dose dependent fashion. Acetylbergenin also prevented the elevation of hepatic malondialdehyde formation and depletion of glutathione content dose dependently in CCl4-intoxicated rats. In addition, the decreased activities of glutathione S-transferase and glutathione reductase were restored to almost normal levels. The results of this study strongly suggest that acetylbergenin has potent hepatoprotective activity against CCl4-induced hepatic damage in rats by glutathione-mediated detoxification as well as having free radical scavenging activity. In addition, acetylbergenin doses of 50 mg/kg showed almost the same levels of hepatoprotective activity as 100 mg/kg of bergenin, indicating that lipophilic acetylbergenin is more active against the antihepatotoxic effects of CCl4 than those of the much less lipophilic bergenin.