Nicotine in tobacco, tetrahydrocannabinol (Δ9-THC) in marijuana and morphine in opium are well known as drugs associated with dependence or addiction. Endogenous active substances that mimic the effects of the natural drugs and their respective receptors have been found in the mammalian central nervous system (CNS). Such active substances and receptors include acetylcholine (ACh) and the nicotinic ACh receptor (nAChR) for nicotine, anandamide and CB1 for Δ9-THC, and endomorphins (1and2) and the μ(OP3) opioid receptor for morphine, respectively. Considerable progress has been made in studies on neurotoxicity, in terms of the habituation, dependence and withdrawal phenomena associated with these drugs and with respect to correlations with endogenous active substances and their receptors. In this article we shall review recent findings related to the neurotoxicity of tobacco, marijuana and opium, and their toxic ingredients, nicotine, Δ9-THC and morphine in relation to their respective endogenous agents and receptors in the CNS.
A view that 14 stages of rat spermatogenic cycle could be arranged into 4 groups, viz., conventional stages I-VI, VII-VIII, IX-XI and XII-XIV, according to the features of elongated spermatids was previously presented. A novel morphometry of seminiferous epithelia based on these 4 groups was also proposed. In the present study, utility of the proposed morphometry in the histopathological evaluations of testicular toxicities was monitored in comparison with the conventional one. After administrating adriamycin, ethylene glycol monomethyl ether or 1, 3-dinitrobenzene to rats, the viability of their germ cells was estimated by the proposed morphometry and the conventional one employed stages II-III, V, VII, X and XII. In every case, the evaluating results of the proposed morphometry were similar to those of the conventional one. Thus, it was verified that the proposed morphometry was identical with the conventional one in respect of reliable detection of the testicular toxicities. In addition, in situ terminal dUTP nick end labeling indicated that death of spermatogonia, pachytene spermatocytes or round spermatids induced by the above 3 toxic cornpounds was exclusively apoptotic death. In conclusion, the proposed morphometry would be useful as a practical tool in the evaluation of testicular toxicities.
The effects of the 77 kDa Ju-myo protein, isolated from Drosophila melanogaster, on the development of glutathione S-transferase placental form (GST-P) positive foci in the male F344 rat liver were evaluated using a medium-term bioassay system. No modifying potential was evident in terms of the numbers or areas of GSTP positive foci. Ju-myo protein did not exert any influence on cell proliferation, as reflected by ornithine decarboxylase (ODC) or spermidine/spermine N1-acetyltransferase (SAT) activity and BrdU labeling. These results demonstrated that Ju-myo protein is unlikely to have inhibitory or promoting effects on rat liver carcinogenesis.
The toxicity of the lowest viscosity grade of hydroxiprorpyl methylcellulose (HPMC) that is currently commercially available was investigated by means of a three-month repeated oral administration study in male and female Crj:CD (SD) IGS rats at doses of 505, 1, 020 and 2, 100 mg/kg/day. Body weights of males and females in the 2, 100 mg/kg group were lower than those of the control group on and after day 28 of administration, but the differences were not statistically significant. The degree of suppression of body weight gain in males was higher than that in females. This tendency was similar to the results in other toxicity studies of HPMC that have been reported. Males in the 2, 100 mg/kg group showed a tendency (not significant) for decreased food consumption and urine volume. Examinations of general signs, hematology, blood chemistry, ophthalmology, absolute and relative organ weights, autopsy and Phistopathology revealed only a few, apparently coincidental, statistically significant differences from the control, and no evidence of any dose-dependent changes was found. It was concluded that the lowest viscosity grade of HPMC showed extremely lo1w toxicity under the conditions of this study, as has been found for higher viscosity grades.
Effects of ER-40133, an inhibitor of angiotensin converting enzyme (ACE), on weight gain and sodium and potassium balance were studied in growing SD male rats. Thirty-two animals (seven weeks of age) were divided into two groups; one received a standard diet containing 0.227% sodium and the other a low (0.0657%) sodium diet. They were divided into four subgroups; one control group and three treated groups receiving 3, 10 or 30 mg/kg of ER-40133, by gavage, once a day for five consecutive days. Body weight gain (average of the standard and low sodium diet groups) was -32% in the 3 mg/kg group, -74% in 10 mg/kg group and -99% in 30 mg/kg group, when compared with the control group. There was a highly linear correlation between suppression of body weight gain and reduction in sodium and potassium retention for both groups of animals given the standard and low sodium diet. The reduced sodium retention, the primary effect of ACE inhibitors, accounted for about 30% of suppressed weight gain, and the reduced potassium retention, the secondary effect of sodium deficiency, could account for the rest about 70% of weight suppression by ER-40133.
In this study, effects of nicotine on locomotor sensitization to methamphetamine in mice were investigated to assess whether nicotine modified induction and expression of psychotoxic action of methamphetamine. Although nicotine (0.03-1 mg/kg s.c.) had no effect at first administration, 5-time nicotine administrations at 3-day intervals progressively developed a significant locomotor stimulant effect, and caused an enhanced sensitivity (cross-sensitization) to methamphetamine (2 mg/kg s.c.). Five-time administrations of methamphetamine (2 mg/kg) at 3-day intervals produced not only a locomotor sensitization to methamphetamine itself, but also a cross-sensitization to nicotine (0.1-1 mg/kg). Nicotine (0.03-1 mg/kg) did not affect the locomotor stimulant effect of methamphetamine (2 mg/kg) in the drug-naive mice. However, nicotine acted dose-dependently to reduce the progressive enhancement of the locomotor stimulant effect of methamphetamine during 5-time Repeated administrations. Mice treated with coadministration of methamphetamine with nicotine (1 mg/kg) showed less sensitization to metharnphetamine than mice treated with methamphetamine alone. In addition, nicotine (1 mg/kg) inhibited the locomotor stimulant effect of methamphetamine in mice sensitized to methamphetamine. These results suggest that methamphetamine and nicotine produce a symmetrical cross-sensitization, although nicotine may act to inhibit the induction and expression of locomotor sensitization to methamphetamine in mice.
In this study, morphological examination and computer-assisted sperm analysis (CASA) of epididymal spermatozoa in non-treated Crj:CD(SD)IGS rats were performed, and the relationship between the data obtained and the retention of step 19 spermatids in Stage IX to XI seminiferous tubules was examined. Retention of step 10 spermatids in Stage IX to XI seminiferous tubules was observed in all 50 untreated males, and the incidence ranged from 3.3% to 100%. Eighteen animals showed a high incidence of retention (74.7±14.2%, HIR for short), and the others showed a low incidence (24.9±11.0%, LIR for short). Although the incidence of retention in Stage X and XI seminiferous tubules was very low in LIR males, it was high in HIR males (1.8±3.0% vs 58.6±23.2%). Morphological abnormlalities of sperms in the caudal region of the epididymis, mainly amorphous head and no head, were more frequently observed in HIR males than in LIR males (36.2±28.5% vs 1.8±1.2%). Sperm analysis also revealed some differences between HIR and LIR males: sperm motility in HIR males was severely lower than that in LIR males, and sperm velocity, beat/cross frequency and amplitude of lateral head displacement in HIR males were lower than the corresponding va1ues in LIR males. In summation, retention of step 19 spermatids frequently occurred in the non-treated Crj:CD(SD)IGS males, and a relationship between the retention of these spermatids and sperm abnormalities, such as morphologically abnormal sperms, low motility and other items revealed by sperm analysis (CASA), was suggested.
To investigate the role of nitric oxide (NO) in hepatitis-induced endotoxemia, we injected mice intraperitoneally with 250 mg/kg galactosamine (GalN) and 1 mg/kg lipopolysaccharide (LPS) separately and in combination. NO synthesis increased in a dose-dependent manner with LPS. NO generation at 5 hr after administration of LPS was greater than that at 24 hr. Enhancement of NO generation was demonstrated in mice administered GalN and LPS in combination. A nitrosyl-heme signal in l0, 000 g supernatant of liver homogenate, due to cytochrome P450 (P450) combining with NO, NO-P450, was detected at more than ten hr and even more after administration of LPS by electron spin resonance (ESR) measurements at 77°K. The strongest NO-P450 signal and most extreme elevation of aspartate oxoglutarate aminotransferase (AST), alanine oxoglutarate aminotransferase (ALT), and lactate dehydrogenase (LDH) in serum and of lysosomal enzyme activity in plasma were observetd in the GalN+LPS group. Their potency was greater than in the 10 mg/kg LPS group, which was even greater than in the LPS 1mg/kg group. The aniline hydroxylase activity was inversely proportional to NO-P450 signal intensity. It appears that NO might contribute to LPS-induced hepatic damage in GalN-sensitized mice through degeneration and inactivation of liver microsomal enzymes by binding P450 active sites.