Sukehiro Chiba

Reinforcing effects of the enkephalin analogs, EK-209 and EK-399, in rats

The reinforcing effects of two enkephalin analogs, Tyr-D-Ala-Gly-MePhe-NHNHCOCH2CH3.AcOH (EK-209) and Tyr-D-Met(O)-Gly-EtPhe-NHNHCOCH3.AcOH (EK-399), were assessed by means of a self-administration technique with rats. The animals were trained to self-administer an intravenous dose of morphine by a lever-press response. A test drug was substituted for morphine after the rats had initiated and maintained its self-administration. When codeine, fentanyl, pentazocine or EK-209 was available, most of the rats increased the number of self-administrations as the unit dose of these drugs was decreased. When levallorphan or EK-399 was available, most of the rats did not increase responding; only one of 4 rats slightly increased the number of self-administrations as the unit dose of EK-399 was decreased. These results indicate that EK-209, like codeine, fentanyl, and pentazocine, possesses a reinforcing effect, whereas EK-399, like levallorphan, has a very weak effect, suggesting that the latter compound possesses low abuse liability.

Effects of Aminoglycoside Antibiotics on the Auditory Brainstem Response and Post Rotatory Nystagmus in Rats

Effects of three aminoglycoside antibiotics, amikacin (AMK), tobramycin (TOB), and gentamicin (GM), on the auditory and vestibular functions were assessed in rats, the most frequently used species in toxicity studies. Chronic electrodes for auditory brainstem response (ABR) recording were implanted on the epidural surface, and those for post rotatory nystagmus (PRN) were implanted at the nictitating membrane and the outer canthus. AMK, TOB, and GM were given intramuscularly twice daily for 3-4 weeks at a daily dose of 350, 150, and 100 mg/kg, respectively. The amplitude of each wave of the ABR was decreased or disappeared in the groups treated with AMK, TOB, and GM. In the PRN, the duration of the nystagmus was decreased in the TOB group and completely lost in the GM group. No abnormality was observed in the PRN in the AMK group. These results were similar to those reported in the ototoxicity studies of these drugs in guinea pigs and indicate that ototoxicity can be evaluated in rats as successfully as in guinea pigs by this procedure.

Retinotoxic effects of diaminodiphenoxybutane in rats

The effects of diaminodiphenoxybutane (DAPB) on visual function in rats were studied using behavioral, electrophysiological and histological techniques. A light-dark discrimination test was conducted by an operant behavioral method. DAPB did not modify intensity detection threshold at an intravenous dose of 35 mg/kg, but elevated it at doses of 50 and 70 mg/kg. Secondly, DAPB did not produce any changes in either electroretinogram (ERG) or visually evoked potential (VEP) at the dose of 35 mg/kg, but a marked decrease in the amplitude of the ERG a- and b-waves appeared after the doses of 50 and 70 mg/kg. The latency of the VEP first wave was also prolonged dose-dependently. Finally, retinal lesions were revealed in rats receiving 70 mg/kg. These results indicate that DAPB has a toxic effect on the retina in rats.

Discriminative stimulus effects of enkephalin analogs, EK-209 and EK-399, in rats

The discriminative stimulus effects of two enkephalin analogs, Tyr-D-Ala-Gly-MePhe-NHNHCOCH2CH3.AcOH (EK-209) and Tyr-D-Met(O)-Gly-EtPhe-NHNHCOCH3.AcOH (EK-399), were assessed in a drug discrimination experiment with rats. The animals were trained to discriminate between the effect of morphine (3 mg/kg s.c.) and saline in a two-lever choice, water reinforced procedure. After the discrimination training had been completed, the animals were used in stimulus generalization tests. A test drug was administered subcutaneously before the test session, and the animals were allowed to select the morphine or saline lever. The animals completely generalized to the effects of codeine, fentanyl and EK-209, but did not generalize completely to the effect of ethylketocyclazocine. After receiving an injection of pentazocine, levallorphan, N-allynormetazocine, or EK-399, the animals pressed the morphine lever, but did not generalize completely to the effects of these drugs. These results suggest that the discriminative stimulus effect of EK-209 is similar to that of morphine, whereas the effect of EK-399 may be different from that of morphine.