Charles S. Rebert

Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyrine (MPTP) in the squirrel monkey

1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) was administered via the intraperitoneal route to squirrel monkeys. Akinesia, rigidity and hypophonia were seen after repeated doses of 2 mg/kg. Postural tremor was present in one animal. Neuropathologic examination revealed cell loss restricted to the zona compacta of the substantia nigra. MPTP appears effective in producing an animal model for Parkinsons disease in the squirrel monkey, and may be one of the more selective neurotoxins described to date.

Solvent-induced ototoxicity in rats: An atypical selective mid-frequency hearing deficit ☆

Most previous reports of ototoxicity following exposure to several volatile organic solvents have restricted testing to the low- and mid-frequencies (2-20 kHz) of the hearing range in the rat (0.25-80 kHz). We report here that inhalation exposure to styrene, mixed xylene, toluene, and 1,1,2-trichloroethylene resulted in hearing dysfunction only in the mid-frequency range and spared function at lower and higher frequencies. Adult male Long Evans rats were exposed via inhalation (whole body) in flow-through chambers. The following exposures were used: styrene, 1600 ppm; 1,1,2-trichloroethylene, 3500 ppm; toluene, 2500 ppm; mixed xylenes, 1800 ppm (N = 7-8 per group, 8 h/day for 5 days), and n-butanol, 4000 ppm (N = 10/group, 6 h/day for 5 days). Testing of auditory function was conducted 5 to 8 weeks after exposure using reflex modification audiometry (RMA). RMA thresholds were determined for frequencies from 0.5 to 40 kHz. Results indicated increased RMA thresholds for the mid-frequency tones (e.g., 8 and 16 kHz), but not higher or lower tones, for all solvents except n-butanol. Toluene and xylene also increased thresholds at 24 kHz. These data indicate that for those solvents reported thus far to cause hearing loss, the deficit is restricted to mid-frequencies in rats.

Cortical and subcortical slow potentials in the monkey's brain during a preparatory interval ☆

Abstract 1. 1. Slow potential (SP) changes were recorded from a variety of brain regions of 6 adult stump-tailed macaque monkeys while the animals bar pressed to obtain juice reinforcement in a reaction time task with a warning cue. 2. 2. Contingent negative variation-like SP waves were recorded from motor and premotor cortices, in male and female animals respectively, and the premotor responses were larger than those in the motor cortex. 3. 3. Slow potential changes of both positive and negative polarity were recorded from several subcortical nuclei, including the caudate nucleus (positive), and several non-specific projection nuclei (negative). 4. 4. SP changes developed within 2–4 days in response to both warning (WS) and discriminative (DS) stimuli, reflecting a learned association between tone stimuli and the imperative the WS and DS appeared later and was reflected by a decreased response to DS and/or increased response to WS.

Differential hemispheric activation during complex visuomotor performance

Bilateral EEGs were recorded from central, temporal and parietal scalp locations from seven male and seven female human subjects (Ss) while they were engaged in verbal and non-verbal tasks. Alpha power was higher in the right hemisphere when Ss listened to verbal material being read to them; the reverse was true when Ss performed in an imaginative block rotation task. Compared with intergame rest periods, alpha power was suppressed in the right hemisphere when Ss either watched or played Pong (TV tennis). Watching Pong was as effective in producing in producing alpha asymmetry as playing the game in the parietal region, but motor involvement enhanced asymmetry at central and temporal leads. Performance was non-linearly related to asymmetry, first increasing and then decreasing as asymmetry increased.

Sensory-evoked potentials in rats chronically exposed to trichloroethylene: Predominant auditory dysfunction

Sensory-evoked potentials (EPs) were studied in male Long-Evans and Fischer-344 rats in order to characterize the electrophysiological consequences of chronic inhalation exposure to trichloroethylene (TCE). Groups of ten Long-Evans rats were exposed to air or 1600 ppm or 3200 ppm TCE for twelve weeks and evaluated periodically with a multisensory test battery. Brainstem auditory-evoked response (BAER) amplitudes were depressed by TCE, whereas somatosensory and visual potentials remained normal. The effects on BAERs, which varied with tone intensity and frequency, suggested that TCE causes a predominantly high-frequency hearing loss. Comparable effects were obtained in both strains of rats and were like those previously observed following exposure to toluene.

Sex differences in cognitive/motor overload in reaction time tasks ☆

Abstract The three studies described in this paper were follow-ups to a previous study in which reaction time (RT) was found to be longer when the hand used was contralateral to the hemisphere presumably most involved in a cognitive task. Twenty right-handed subjects (10 males, 10 females) performed in verbal target detection/discriminative RT tasks. The results indicated that for females, engaging a hemisphere in both cognitive processing and control of motor output produces interference with task execution. The difference between males and females appeared to be a function of task difficulty.

Combined effects of solvents on the rat's auditory system: styrene and trichloroethylene

Because exposures to toxic agents typically involve more than one substance, it is necessary to know if combined exposures pose different risks than those to single agents. Many solvents have been implicated in central nervous disorders and some of them are known to produce hearing loss, probably mediated by damage to cochlear hair cells. Hearing loss was studied by recording the brainstem auditory evoked response (BAER) in male Long Evans rats exposed 8 h/day for 5 days to mixtures of styrene (STY) and trichloroethylene (TCE). Dose groups included air or solvent pairs (STY/TCE) in the following concentrations (ppm): (0:3000), (250:2250), (500:1500), (750:750) and (1000:0). Decreased BAER amplitude, indicative of hearing loss, was correlated with blood levels of total solvent. The effects were as predicted by a linear dose-addition model, indicating neither synergistic nor antagonistic interactions at the concentrations studied.

The hearing loss associated with exposure to toluene is not caused by a metabolite.

Exposure to toluene causes a marked hearing loss in rats, and this effect has been observed in some human solvent abusers. The issue of whether toluene or one of its metabolites is responsible for this effect has not been examined. To attempt to resolve this issue, we manipulated the metabolism, and thus the circulating levels, of toluene as follows. Two groups of rats were exposed to phenobarbital (PB) in their drinking water (0.1%) for seven days to induce detoxifying liver enzymes; two other groups had access to PB-free water. Then half of the rats exposed to PB or water were exposed to filtered air or a concentration of toluene expected to cause hearing loss. Levels of toluene in blood were markedly reduced by the PB and the excretion of hippuric acid was increased. All rats were tested for auditory sensitivity by brainstem auditory-evoked response (BAER) audiometry using a 16-kHz tone pip. The rats exposed to toluene alone showed a marked reduction in the integrated BAER waveform, indicative of the expected hearing deficit. None of the other treated rats showed any deviation from controls (i.e., water and air). These results provide strong evidence that toluene itself is responsible for the auditory dysfunction. Toluene also caused the rats to increase their fluid consumption and urine output; these effects were not altered by PB. Identification of toluene as the proximal ototoxicant should facilitate the search for the mechanism of this effect.

Combined effects of paired solvents on the rat's auditory system

A number of volatile organic solvents have been shown to be ototoxic to rats, but there is little information regarding how solvents might act in this way when encountered in combination. To examine this issue, male Long Evans rats were exposed by inhalation to pairs of solvents known to be ototoxic when administered individually; those reported on here are trichloroethylene+toluene, mixed xylenes+trichloroethylene, xylenes+chlorobenzene, and chlorobenzene+toluene. Rats were exposed 8 h/day for 5 consecutive days, using complementary proportions of isoeffective concentrations of the solvents alone. Hearing was assessed by brainstem-evoked response audiometry. The effects were as predicted by a linear dose-addition model, indicating additive rather than synergistic or antagonistic interactions at the concentrations studied.

Multimodal effects of acute exposure to toluene evidenced by sensory-evoked potentials from fischer-344 rats

Male Fischer-344 rats were exposed by inhalation to 500, 2000, 5000, 8000 and 16000 ppm toluene for 30 min in two experiments. Exposures up to 8000 ppm in Experiment 1 caused concentration-related changes in the click-elicited brainstem auditory-evoked response (CBAER), flash-evoked potential (FEP) and somatosensory-evoked potential (SEP). Latencies of CBAER components were prolonged and amplitudes of late components were increased by toluene. Toluene did not detectably alter the latencies of FEP or SEP components. Early FEP component-amplitudes were increased and late component-amplitudes were decreased; toluene also induced a poststimulus oscillation in the FEP. Most component-amplitudes of the SEP were substantially increased, but N2P2 amplitude appeared to be more sensitive than other components to depressant effects of the solvent. The same effects on the CBAER were observed in Experiment 2, but a more substantial increase in the amplitudes of late components elicited by tone pips suggested that frequency-dependent cochlear irritation might underlie previously observed subchronic ototoxicity. These effects were increased by exposure to 16000 ppm toluene. Effects like those observed in Experiment 1 were noted on the FEP, but the oscillations were less with exposure to 16000 than 8000 ppm. Changes in the SEP were evident within 2 minutes of exposure onset, and amplitudes increased over the course of about 15 min, leveling off or decreasing thereafter. The amplitude of the N2P2 component was again less influenced than other components during exposure to 8000 ppm and was reduced to less than baseline amplitude by 16000 ppm. Effects of concentration and rates of development and recovery were systematically related to SEP component latency. Toluene appears to have both enhancing and inhibiting effects on neural pathways serving sensory systems, depending on the modality and the site of generation of the components within modalities. A particular balance between these properties might relate to the hedonic characteristics of this abused solvent.