Cochlear pathology induced by aminoglycoside ototoxicity during postnatal maturation in cats.

Cochlear pathology resulting from neonatal administration of the aminoglycoside antibiotic, neomycin sulfate, was studied in young kittens at 15-24 days postnatal. Hearing thresholds showed severe to profound hearing loss in all but one animal. Scanning electron microscopy demonstrated that initial hair cell degeneration occurred in the extreme base (hook region) of the cochlea and sequentially progressed to the basal, middle, then the apical coil of the cochlea. The first row of outer hair cells degenerated first, followed by row 2, then row 3; the last cells to degenerate in a given region were the inner hair cells. This pattern of hair cell degeneration is similar to that seen in adults with neomycin ototoxicity. In contrast, the spiral ganglion exhibited a different pattern of degeneration with initial cell loss occurring in the middle of the cochlea, about 40-60% from the base (approximately 2.8-8 kHz). Thus, neuronal degeneration apparently is not secondary to sensory cell loss, but rather comprises an independent process in these neonatal animals. Taken together, the findings suggest that the spiral ganglion cell loss in the middle cochlear turn results from increased aminoglycoside sensitivity associated with an earlier initial onset of function in these neurons as compared to other cochlear regions.

Peripheral plasma levels of progesterone, oestradiol-17 beta, oestrone, testosterone, androstenedione and chorionic gonadotrophin during pregnancy in the marmoset monkey, Callithrix jacchus.

Concentrations of LH/CG, androstenedione and testosterone rose in early pregnancy to maximum values at 6--10 weeks. Thereafter LH/CG levels declined and androstenedione and testosterone levels remained at plateau values or declined until term. Progesterone, oestradiol-17 beta and oestrone increased after ovulation and remained high throughout pregnancy. At 12 weeks, when LH/CG levels were falling, progesterone and oestradiol rose well above the luteal-phase levels which were maintained for the first 12 weeks. Progesterone declined in the 2 weeks before birth, while oestradiol and oestrone remained high. Pregnancies of an unknown stage were dated by reference to a graph of uterine diameter, measured by abdominal palpation, in animals at known times after conception. Measurement of progesterone concentrations during the conception cycle gave more accurate dating and showed that the gestation length was 144 days.

The assessment of neurotoxicity using the cockroach nerve cord.

The acute central nervous system toxicity of chemicals may be detected and analysed with relative ease in the isolated abdominal ventral nerve cord of the American cockroach. Stable electrophysiological measurements of axonal and both inhibitory and excitatory synaptic transmission can be made for several hours with extracellular electrodes using a mannitol-gap technique. Dose-response curves can be obtained for the effects of the chemicals. These can be analysed in terms of site of action, be it on the axons, the presynaptic nerve terminal, the postsynaptic receptors or the termination of neurotransmitter action. Possible non-specific sites are also considered.

Ultrastructural changes induced by p-benzoquinone in the terminal abdominal ganglion of the cockroach.

The morphology of the sixty abdominal ganglion, associated connectives and cercal nerves was examined using an electron microscope after acute treatment of the isolated tissue with 0.5 mM p-benzoquinone. A high incidence of mitochondrial damage was observed in all three regions of the tissue. This may be due to a metabolic inhibitory action or a pro-oxidant action of p-benzoquinone.

The toxicity of p-benzoquinone on the central nervous system of the cockroach.

The behavioural symptoms of acute-p-benzoquinone intoxication in the cockroach were shown to be an initial excitation followed by rigid paralysis. p-Benzoquinone produced a depolarization of the postsynaptic membrane of the giant neurones in the 6th abdominal ganglion of the cockroach which was accompanied by an increase in the electrically evoked excitatory postsynaptic potential. The frequency and amplitude of unitary postsynaptic potentials also increased. These effects may be due to inhibition of active cation transport, as illustrated here on the frog isolated skin.

Warfarin and the grey squirrel.

The anticoagulant warfarin [3-(alpha-acetonylbenzyl)-4-hydroxycoumarin] has been used for controlling the grey squirrel Sciurus carolinensis in Great Britain. Before legislation was passed to allow for its use in Ireland, it was felt that more information on its effectiveness was required. Since the small mammal population of Ireland is low, any toxic effects on the native mammal population could greatly deplete the wildlife in Ireland. No accurate assessment of the toxicity of warfarin for the squirrel appears in the literature. The squirrel were dosed with warfarin at four different concentrations, 6.0, 1.25, 0.5, 0.01 mg per kg of body weight, by stomach tube, in order to find the least effective dose. The prothrombin times (PT) were monitored as an assessment of the action of the drug. The control prothrombin time and the standard deviation of the mean was 13.83 +/- 3.64. Animals that were treated with warfarin showed an elevated PT even at the lowest dose by the 7th day of treatment. The PT was found to be in excess of 30 s and this was statistically significant, p = 0.05. Within the group receiving 0.5 mg/kg one animal showed a very significant initial rise in PT, but after 22 days of daily dosing, the PT decreased to within the normal range of the controls. Despite continuous dosing for a total of 26 days, it remained within this range.

Effects of methylglyoxal on central and peripheral cholinergic responses.

Methylglyoxal (MG) has been shown to have a depolarizing effect on the giant interneurones of the isolated 6th abdominal ganglion of the cock-roach. This effect of MG was inhibited by concentrations of nicotine, d-tubocurarine and physostigmine which blocked transmission at the cholinergic cercal nerve-giant interneurone synapse. MG (5 X 10(-5) to 5 X 10(-4) M) produced concentration-dependent contractures of the isolated frog rectus abdominis muscle which were inhibited by d-tubocurarine (10(-4) M) and physostigmine (10(-6) M). MG enhanced the action of acetylcholine and inhibited KCl-evoked contractures whereas it had no effect on the response to carbachol. It is concluded that MG appears to act as a cholinomimetic in both the peripheral and central nervous systems.

The effects of methylglyoxal on central synaptic transmission in the isolated nerve cord of the cockroach. (Periplaneta americana L).

Methylglyoxal (10(-5) to 1.5 X 10(-4) M) was found to have excitatory effects on synaptic transmission in the isolated 6th abdominal ganglion of the cockroach. There was a concentration-dependent depolarization of the giant interneurones which was accompanied by an increase in the amplitude and duration of electrically evoked excitatory postsynaptic potentials. The frequency of spontaneous activity was also increased.

A preliminary study of the translocation of aldicarb across the duck eggshell.

The duck eggshell has the reputation of being more permeable than that of the domestic hen. If this is true, the developing embryo could be at greater risk from xenobiotic agents, since toxicants picked up on the feathers could be transferred to the embryo during incubation. This study looked for such an effect on the developing embryo after the application of aldicarb to the eggshell. At 72 hr, the eggs were painted with 3, 7, 11, or 15 microM aldicarb in 500 microliters water. The eggs were then incubated to Day 24. The gross morphological measurements were then recorded. A similar study was made using domestic hen eggs; these were treated after 36 hr incubation and incubated to Day 17. Direct injection into the yolk sac of both species was used for further comparison. There was a statistically significant reduction (P less than 0.01) in the middle web toe length with 11 and 15 microM aldicarb and the tarsometatarsus length with 7, 11, and 15 microM. Compared with the duck control group, the group given 15 microM aldicarb had reductions of approximately 8% in the tarsometatarsus and approximately 9% in the middle web toe. No statistically significant changes were produced in the chick embryos.

The characterization of oxotremorine-induced hypothermic response in the rat.

Oxotremorine is a muscarinic receptor agonist that induces a variety of physiological and behavioural effects including hypothermia in mice. These effects are antagonized dose-dependently by classical anticholinergic compounds such as atropine. Although the oxotremorine-induced hypothermic response has been demonstrated in mice, few studies of the effects of this muscarinic agonist have been made in the rat. The following studies were made in male Sprague Dawley rats: 1. an investigation of the dose-response relationship between oxotremorine and hypothermia; 2. an examination of the effect of housing on the oxotremorine-induced hypothermic response, and 3, an investigation of the acute administration of various doses of atropine sulphate on the hypothermia caused by oxotremorine. The results indicate that the dose-response relationship between oxotremorine and the antagonism of hypothermia is similar in rat as it is in mice. The results also showed that this effect did not occur in group-housed animals.

The toxicity profile of a single dose of paroxetine: an alternative approach to acute toxicity testing in the rat.

In this study we have examined the effect of a single administration of the selective serotonin reuptake inhibitor, paroxetine (120-300 mg kg(-1), orally) in a recently developed rodent model of acute toxicity testing. Reduced body-weight, food consumption, water consumption and body temperature were observed in all paroxetine-treated groups, which were reversible within 7 days. Five days after administration, a dose-dependent increase in red blood cells, haemoglobin and haematocrit was observed with the 3 higher dose levels of paroxetine, which was significant in the 240 and 300 mg kg(-1) treatment groups (P < 0.05). Hyperactivity was apparent in the first 24 hr following treatment, as was evidence of the serotonin syndrome. When the animals were sacrificed (11 days after drug administration), an increase in liver weight was observed in the highest dose. These results are in agreement with those previously observed with paroxetine at the preclinical and clinical levels. They demonstrate that this rodent model, because of its multi-parameter nature, is a useful method for examining the consequences of a single high dose of an antidepressant drug.

Acute toxicity profile of maprotiline in the rat.

The aim of the present study was to examine the toxic effects of single oral administrations of the antidepressant maprotiline at 150 mg/kg or 300 mg/kg using female Sprague-Dawley rats. Body-weight gain was significantly reduced in the group receiving 300 mg/kg on days 1-5 of the study (P<0.01). A significant reduction in food and water intake was observed on days 1 and 2 of the study (P<0.01) in the 300 mg/kg group and on day 1 in the 150 mg/kg group (P<0.05). There was a significant decrease in nocturnal home cage activity over the first five days of the study in the 300 mg/kg group (P<0.01). A significant hypothermic response was observed in both 150 and 300 mg/kg groups at 1, 2 and 4 hr after dosing (P<0.01), that had returned to control values within 8 hr following administration. This study demonstrates that a multi-parameter approach is appropriate for the investigation of high doses of antidepressants in rodents.