Modulation of chemical carcinogen-induced unscheduled DNA synthesis by dehydroepiandrosterone (DHEA) in the primary rat hepatocytes.

Modulation of unscheduled DNA synthesis by dehydroepiandrosterone (DHEA) after exposure to various chemical carcinogens was investigated in the primary rat hepatocytes. Unscheduled DNA synthesis was induced by treatment of such direct acting carcinogens as methyl methanesulfonate (MMS) and ethyl methanesulfonate (EMS) or procarcinogens including benzo(a)pyrene (BaP) and 7,12-dimethylbenz(a)anthracene (DMBA). Unscheduled DNA synthesis was determined by measuring [methyl-3H]thymidine radioactivity incorporated into nuclear DNA of hepatocytes treated with carcinogens in the presence or absence of DHEA. Hydroxyurea (5x10(-3) M) was added to growth medium to selectively suppress normal replication. DHEA at concentrations ranging from 1x10(-6) M to 5x10(-4) M did not significantly inhibit unscheduled DNA synthesis induced by either MMS (1x10(-4) M) or EMS (1x10(-2) M). In contrast, DHEA significantly inhibited unscheduled DNA synthesis induced by BaP (6.5x10(-5) M) and DMBA (2x10(-5) M). DHEA-induced hepatotoxicity in rats was examined using lactate dehydrogenase (LDH) release as an indicator of cytotoxicity. DHEA exhibit no significant increase in LDH release compared with the solvent control at 18 h. These data suggest that nontoxic concentration of DHEA does not affect the DNA excision repair process, but it probably influence the enzymatic system responsible for the metabolic activation of procarcinogens and thereby decreases the amount of the effective DNA adducts formed by the ultimate reactive carcinogenic species.

Inhibition by ginsenosides Rb1 and Rg1 of methamphetamine-induced hyperactivity, conditioned place preference and postsynaptic dopamine receptor supersensitivity in mice.

The ginsenosides Rb1 and Rg1, the major components of ginseng saponin, inhibited not only methamphetamine-induced hyperactivity but also conditioned place preference (CPP) in mice following a single or repeated administration. Dopamine (DA) receptor supersensitivity, which developed in methamphetamine-induced CPP mice, was also inhibited by both Rb1 and Rg1. Therefore, the present results suggest that Rb1 and Rg1 may be the active components of ginseng saponin in the modulation of methamphetamine-induced dopaminergic behaviors such as hyperactivity and CPP, supporting our previous conclusion that ginseng saponin might modulate methamphetamine-induced dysfunction at both the pre- and postsynaptic DA receptors.

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.

Blockade by naloxone of cocaine-induced hyperactivity, reverse tolerance and conditioned place preference in mice.

Cocaine-induced hyperactivity was inhibited by a single administration of naloxone (2 and 5 mg/kg, i.p.), an opioid receptor antagonist, and naloxone administered prior to and during the chronic injection of cocaine attenuated the development of both cocaine-induced reverse tolerance and conditioned place preference (CPP). Dopamine (DA) receptor supersensitivity which developed in cocaine-induced reverse tolerant or CPP mice, was also inhibited by naloxone. Furthermore, naloxone reduced an apomorphine-induced striatal dopaminergic action, climbing behavior. Therefore, the present studies suggest that cocaine-induced dopaminergic behaviors, such as hyperactivity, reverse tolerance and CPP, may be commonly produced via activation of an opioid receptor. The development of DA receptor supersensitivity may be a possible common mechanism of cocaine-induced reverse tolerance and CPP, since cocaine-induced changes in sensitivity to apomorphine, as well as apomorphine-induced climbing behavior in mice, were both inhibited by naloxone.

Blockade by ginseng total saponin of methamphetamine-induced hyperactivity and conditioned place preference in mice.

Ginseng total saponin (GTS) inhibited methamphetamine-induced hyperactivity and conditioned place preference (CPP). Dopamine (DA) receptor supersensitivity was developed in methamphetamine-induced CPP mice and it was inhibited by GTS. GTS also inhibited apomorphine-induced climbing behavior, showing the antidopaminergic activity of GTS. These results suggest that GTS inhibition of the methamphetamine-induced hyperactivity and CPP may be closely related with the inhibition of dopaminergic activation induced by methamphetamine.

Blockade by ginseng total saponin of the development of methamphetamine reverse tolerance and dopamine receptor supersensitivity in mice.

Repeated administration of methamphetamine (2 mg/kg) developed reverse tolerance to the ambulation-accelerating effect. Intraperitoneal administration of ginseng total saponin (GTS, 200 mg/kg of body weight) prior to and during chronic administration of methamphetamine inhibited the development of reverse tolerance. Dopamine receptor supersensitivity was also developed in reverse tolerant mice which had received the same methamphetamine. The development of dopamine receptor supersensitivity was evidenced by the enhanced hypothermic response to apomorphine (1 mg/kg) and the enhanced ambulatory activity of apomorphine (4 mg/kg). GTS also prevented the development of dopamine receptor supersensitivity induced by the chronic administration of methamphetamine. These results show that GTS may be useful for the prevention of and therapy for the adverse action of methamphetamine. It is concluded that the development of reverse tolerance to methamphetamine may be associated with the enhanced dopamine receptor supersensitivity since both phenomena were blocked by GTS.

Interactions of ginsenosides with ligand-bindings of GABA(A) and GABA(B) receptors.

1. Total saponin fraction decreased the affinity of specific [3H]muscimol binding without changes in Bmax. Ginsenoside Rb1 Rb2, Rc, Re, Rf and Rg1 inhibited the specific [3H]muscimol binding to the high-affinity site. 2. Total saponin fraction increased the affinity of specific [3H]flunitrazepam binding. Ginsenoside Re and Rf enhanced specific [3H]flunitrazepam binding. 3. Total saponin fraction decreased the affinity of specific [35S]TBPS binding without changes in Bmax. Ginsenosides did not affect specific or non-specific [35S]TBPS binding. 4. Total saponin fraction decreased the affinity of specific [3H]baclofen binding without changes in Bmax. Ginsenoside Rc inhibited specific [3H]baclofen binding.

Antagonism of U-50,488H-induced antinociception by ginseng total saponins is dependent on serotonergic mechanisms.

Morphine-induced antinociception was prevented by pretreatment with ginseng total saponins in the tail-pinch and tail-flick tests carried out in mice. The antinociceptive effect of U-50,488H, a selective kappa-opioid receptor agonist, was prevented by naloxone, a nonselective opioid receptor antagonist, in the tail-pinch but not in the tail-flick test. However, U-50,488H-induced antinociception was prevented by ginseng total saponins in the tail-flick but not in the tail-pinch test. These results indicate that nonopioid mechanisms are involved in the antagonism of U-50,488H-induced antinociception by ginseng total saponins. In addition, the antagonism of U-50,488H-induced antinociception in mice pretreated with ginseng total saponins was abolished by pretreatment with a serotonin precursor, 5-hydroxytryptophan, but not by a noradrenaline precursor, L-dihydroxyphenylalanine, in the tail-flick test. Therefore, it appears that the antagonism of U-50,488H-induced antinociception by ginseng total saponins is dependent on serotonergic mechanisms.