Mice exhibited a marked suppression of motor activity when placed into the same environment in which they had previously received electric foot shocks. Apomorphine-HCl (0.1-10 mg/kg) produced a dose-dependent reduction of the conditioned suppression of activity, but did not increase activity in non-shocked mice. Diazepam (0.2, 1, and 5 mg/kg), meprobamate (25 and 50 mg/kg), and chlorpromazine-HCl (2 and 5 mg/kg) did not reduce conditioned suppression. Thus, the conditioned suppression caused by a quick conditioning technique does not produce similar results to those using the conditioned emotional response involving suppression of operant lever-pressing behavior.

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Among various unsaturated fatty acids which were examined in this experiment, trans-2-tridecenoic acid was found to be a potent inhibitor on gastric secretion in rats (i.p. or i.d.). Therefore, the effects of trans-2-tridecenoic acid on several experimental ulcerations in rats were examined. At the dose of 10 mg/kg, trans-2-tridecenoic acid significantly decreased the ulcer index in pylorus-ligated rats; aspirin-, phenylbutazone-, histamine- and stress-induced ulcerations were also significantly inhibited at the dose of 25 mg/kg. Finally, effects of trans-2-tridecenoic acid on hexosamine and sialic acid contents in the gastric mucous were examined. In intact or phenylbutazone-induced ulcerated rats, trans-2-tridecenoic acid increased the sialic acid levels in the gastric mucous at the dose of 25 mg/kg. The decreased hexosamine content in the gastric mucous by phenylbutazone treatment was recovered by the administration of trans-2-tridecenoic acid.

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The metabolism of dibucaine was studied in the rat, rabbit and man. A total of ten basic metabolites other than dibucaine were detected in the urine samples of three species by thin-layer chromatography (TLC) and gas chromatography (GC), and structures of these metabolites were identified by comparison of the properties given by TLC, GC and gas chromatography-mass spectrometry (GC-MS) with those of authentic compounds. Four of these metabolites were new metabolites which were found in the rabbit or human urine ; two were identified as the 2', 3'-dihydroxybutoxy product (M-6, diol) and its N-deethyl product (M-2), and others were identified as the 2'-hydroxyethoxy product (M-8, alcohol) and its N-deethyl product (M-3). One of the two hydroxyl groups on M-5 was at 6-position on the quinoline ring, while another was assumed to be at 3'-position on the O-alkyl side chain. There were apparent species differences with regard to the major metabolites found in each species ; i.e. M-10 and M-5 in rat, M-6 and M-4 in rabbit, and M-8 and M-4 in man. Small amounts of the conjugated basic metabolites were observed in the urine of all three species. The new metabolic pathways to the diols (M-2 and M-6) or the alcohols (M-3 and M-8) were also discussed.

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The effects of dietary cholesterol and sitosterol on the activity of the hepatic steroid 12α-hydroxylase, gallbladder bile acid composition, and serum and liver cholesterol concentrations were studied in female hamsters. The 12α-hydroxylase activity was inhibited by 63% in cholesterol-fed animals and by 30% in sitosterol-fed animals. Cholesterol feeding increased percentages of chenodeoxycholic and lithocholic acids in gallbladder bile with reciprocal decrease of cholic acid, while sitosterol feeding had no significant effect on bile acid composition. Cholesterol feeding increased levels of serum and liver cholesterol, on the contrary, sitosterol decreased both concentrations. A positive correlation between the 12α-hydroxylase activity and the ratio of cholic acid plus its metabolites to chenodeoxycholic acid plus its metabolite was also observed. These results support the proposal that steroid 12α-hydroxylase is a major factor in determining the relative proportion of cholic acid and chenodeoxycholic acid synthesized in the liver and indicate that cholesterol feeding increased percentage of chenodeoxycholic acid by inhibiting the activity of steroid 12α-hydroxylase.

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9α, 10α-Epoxyhexahydrocannabinol (9α, 10α-EHHC) was found to be formed from Δ⁹-tetrahydrocannabinol (Δ⁹-THC) by liver microsomes of mice pretreated with phenobarbital. Further, pharmacological effects of 9α, 10α-EHHC in mice were compared with those of Δ⁹-THC using catalepsy, hypothermia, pentobarbital-induced sleep prolongation and anticonvulsant activity against pentylenetetrazol as indices. 9α, 10α-EHHC was approximately equipotent with Δ⁹-THC in the pharmacological indices except for catalepsy. The cataleptogenic effect of the epoxide was about 4 times as potent as the parent compound. From these results, it is suggested that 9α, 10α-EHHC can contribute to the pharmacological effects of Δ⁹-THC as an active metabolite.

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The developmental change of the intrinsic clearance (Cl_int) and the hepatic clearance (Cl_H) for the glucuronidated p-phenylbenzoic acid (PPBA) by uridine 5'-phosphoglucronic acid-glucuronyltransferase (UDPGT) in liver of rat fetus was investigated. The UDPGT activity was stimulated by 225% by Brij 58 which is a detergent. The Cl_int increased with the day of gestation, remarkably between the 19th and 21st day of gestation, showing nearly the same developmental profile as the V_max. The Cl_int in a whole liver on the 21st day of gestation was 246-fold and 7.0-fold higher than those on the 15th and 19th day of gestation, respectively. The Cl_H showed the similar developmental profile to the Cl_int. The Cl_H on the 21st day of gestation was 48.7 times and 6.7 times those on the 17th and 19 the day of gestation, respectively. The Cl_H on the 20th and 21st day of gestation was about 30% of the corresponding values of the fetal tissue clearance (Cl_f) from the in vivo data using isolated fetuses. The similarity between the Cl_H/Cl_f ratio and the PPBA glucuronide/biliary excretion ratio indicated that the Cl_H from the in vitro data corresponded with that in the in vivo condition.

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The nature of the falling phase of the synaptic current was studied in more detail at the crayfish neuromuscular junction and fundamental data relating to focally recorded excitatory junctional potentials (e.j.p.s) was complemented. The decay of extracellular e.j.p.s at the crayfish neuromuscular junction was almost exponential. The decay time constant of extracellular e.j.p.s varied considerably from one e.j.p. to another, the mean of the decay time constant being about 1 ms at the normal resting potential at a bath temperature of 22°C. There was no detectable correlation between the decay time constant and the amplitude of extracellular e.j.p.s which were induced by a single stimulation of the excitatory axon. Prolonged application of glutamate hardly affected the decay time constant of extracellular e.j.p.s. The significance of the study on the crayfish neuromuscular system was discussed.

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The glucuronidation of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), cannabidiol (CBD) and cannabinol (CBN) in rat liver microsomes was studied. The enzyme activities for the cannabinoids were 26.3 (Δ⁹-THC), 52.9 (CBD) and 104.8 (CBN) pmol/min/mg protein. The apparent K_m values of UDP-glucuronyltransferase for the cannabinoids were 0.29 (Δ⁹-THC), 0.18 (CBD) and 2.78 (CBN) mM, while V_max were 40.3 (Δ⁹-THC), 104.9 (CBD) and 593.3 (CBN) pmol/min/mg protein. Following treatment of rats with 3-methylcholanthrene, the enzyme activities for Δ⁹-THC, CBD and CBN were increased 132, 43 and 1198%, respectively, whereas the corresponding increases in microsomes from phenobarbital-treated rats were 127, 13 and 97%, respectively. The cannabinoid glucuronidation was activated 2 to 3 folds by the addition of UDP-N-acetylglucosamine, but not activated by the addition of Triton X-100 in vitro. The properties of cannabinoid UDP-glucuronyltransferase were discussed from the above results.

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A solid phase immunoassay for the determination of adriamycin has been developed. Specific antibody against adriamycin was raised in rabbits after coupling adriamycin to bovine serum albumin. β-D-Galactosidase labelled adriamycin was prepared by m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS) as a coupling reagent. This assay system followed the double antibody solid phase method for the B/F separation of antibodybound and free adriamycin. By this method, from 0.5 to 100 ng of adriamycin could be detected. Using this assay system, drug levels were determined in serum of mice, following administration of adriamycin in a single dose of 15 mg/kg i.p., the peak appearing at 20 min after administration. The change of serum levels was found to be biphasic, and the half-life of β-phase was about 5 h.

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A nonlinear least squares program based on first-order simultaneous differential equations, MULTI (RUNGE), for personal computers was developed. Four algorithms, i.e.the classical Gauss-Newton method, the damping Gauss-Newton method, the modified Marquardt method and the simplex method can be used for the nonlinear curve fitting in MULTI (RUNGE). The differential equations and the initial conditions which are voluntarily defined by the user are numerically solved by the Runge-Kutta-Gill method and the numerically integrated solutions are fitted to the observed data points by the iterative least squares algorithms. MULTI (RUNGE) can be executed on many personal computers without any modification, because this program is written in the Microsoft minimum BASIC commands alone. The dimensions of differential equations, the number of parameters to evaluate and the number of experimental data points are restricted only by the available memory in computers and by the computing time.

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