Robert S. Dyer

Dopamine depletion slows retinal transmission

Abstract In male hooded rats, depletion of norepinephrine and dopamine by α-methyl- para -tyrosine (AMT) significantly increased the latencies of early peaks in flash-evoked potentials recorded from the visual cortex, lateral geniculate nucleus, and optic tract. These effects were not produced by depletion of norepinephrine by FLA-63, blockade of muscarinic acetylcholine receptors by scopolamine, or blockade of opiate receptors by naloxone. AMT effects occurred only when flashes were used; optic tract stimulation failed to reveal the drug-induced changes. In a dose-response study, haloperidol produced effects similar to those of AMT. l -Dopa + RO4-4602 reversed some of the effects of AMT. It is concluded that depletion of retinal dopamine impairs the timing of retinal responses to light.

The use of sensory evoked potentials in toxicology

The rationale for studying sensory systems as an integral part of neurotoxicological examinations is presented. The role of evoked potentials in assessing brain dysfunction in general and sensory systems in particular is also presented. Four types of sensory evoked potentials (brainstem auditory evoked response, somatosensory evoked potentials, flash evoked potentials, and pattern reversal evoked potentials) are discussed in terms of their demonstrated contributions to neurotoxicology and clinical neurology. Research needed to allow these methods to achieve their full value for neurotoxicology is identified and briefly discussed.

Amygdaloid kindling increases enkephalin-like immunoreactivity but decreases dynorphin-A-like immunoreactivity in rat hippocampus

The effects of amygdaloid kindling on the regional levels and distribution of enkephalin-like and dynorphin-A (DN)-like immunoreactivity (LI) were examined. One day after completion of kindling, radioimmunoassay revealed a 71% decrease in DN1-8-LI and a 43% increase in [Met5]-enkephalin-LI in the hippocampus. Immunostaining revealed a depletion of DN1-17-LI in the hippocampal mossy fiber pathway and an increase in [Leu5]-enkephalin-LI in the temporoammonic pathway. Four weeks after completion of kindling, the levels and immunostaining intensity of dynorphin and enkephalin in the hippocampus had returned to control values.

Possible role of the brainstem in the mediation of prepulse inhibition in the rat.

Bilateral stimulation of electrodes aimed at the cuneiform nucleus produced significant inhibition of the startle response produced by presentation of an 8-kHz, 110-dB tone. Stimulation of electrodes aimed at the deep mesencephalic nucleus also reduced the magnitude of the startle response, but the effect was less than that following stimulation sites near the cuneiform nucleus. Histological reconstruction of the electrode tip locations revealed a significant negative correlation between the maximum magnitude reduction of the acoustic startle response following an electrical prepulse stimulus and the distance from the cuneiform nucleus. Histological examination also indicated that some electrodes aimed at the cuneiform nucleus were located in or near the inferior colliculus or parabrachial nucleus, all of which are thought to be part of an inhibitory circuit parallel to the acoustic startle reflex arc. These experiments support the view that the prepulse inhibition of the acoustic startle reflex originates in the brainstem.

Focal lesions of visual cortex—Effects on visual evoked potentials in rats

Focal lesions were placed in the visual cortex of Long-Evans hooded rats, immediately below skull screw recording electrodes. Lesions were produced by heat, and extended an average depth of about 0.9 mm below the cortical surface. Evoked potentials recorded from the electrode overlying the cortical lesion were compared with simultaneously recorded potentials from a contralateral homotopic site. The effects of the lesion were selective. Flash-evoked potential peaks P1, P2, and N2 were depressed by the lesion, and peaks N1 and P3 were augmented; peak N3 was unaffected. Pattern reversal evoked potential peak N3 was depressed by the lesion, and peaks N1 and P2 were made more distinct. The results emphasized that different peaks have different generators, and suggest in particular that flash-evoked potential peaks P1 and N2, and peak N3 of the pattern reversal-evoked potential require the superficial layers of the cortex.

Chlordimeform produces profound, selective, and transient changes in visual evoked potentials of hooded rats

Rat visual function was tested after acute exposure to chlordimeform (CDM), a formamidine insecticide/acaricide. Adult male Long-Evans rats were surgically implanted with epidural recording electrodes overlying visual cortex and tested 1 week later. Pattern reversal-evoked potentials (PREPs), flash-evoked potentials (FEPs), and FEP recovery ratios were measured after acute CDM administration. Averaged recordings obtained during 200 reversals of a black-and-white square wave grating comprised the PREPs, and those obtained during 128 paired strobe lamp flashes comprised the FEPs. In the first study, which examined dose-response relationships, i.p. injections of 0 (saline), 5, 15, or 40 mg/kg CDM-HCl were administered 30 min prior to testing. The PREP amplitudes showed large dose-related changes in the CDM-treated rats. PREP N1P1 and P1N3 peak-to-peak amplitudes increased more than 200% in the 40 mg/kg group. In contrast, FEP amplitudes and FEP recovery ratios were unchanged by CDM. Both PREP and FEP peak latencies were increased by CDM in dose-related fashions. In the second study, which examined the time course of CDM action, PREPs and paired-pulse FEPs were recorded 3, 6, and 24 h after dosage with either 0 or 40 mg/kg CDM. All evoked potential changes were large at 3 and 6 h, but had returned to control values by 24 h. In summary, acute exposure to CDM temporarily increased both the amplitude and latency of PREPs, but only the latency of FEPs.

Early effects of trimethyltin on the dentate gyrus basket cells: a morphological study

Electrophysiological evidence for reduction of recurrent inhibition in the dentate gyrus in animals exposed to trimethyltin (TMT) suggested alterations in the inhibitory neurons (basket cells) by TMT. The present study was designed to investigate the morphology of basket cells after TMT exposure. Long-Evans hooded rats were injected with TMT chloride in a dose of 6.0 mg/kg body weight (b.w.). Tissue samples from the dentate gyri were examined by both light and electron microscopy at 24 and 72 h after TMT exposure. Except for isolated basket cell damage at 72 h, no remarkable pathological changes were observed with light microscopy. Consistent with previous data, electron microscopy revealed that the basket cells of the dentate gyrus are large neurons situated just below the granule cell layer with characteristic large, infolded nuclei and intranuclear filamentous rods. Increased cytoplasmic density and degenerative changes of the Golgi complex were evident in the basket cells as early as 24 h after TMT exposure. By 72 h, neuronal vacuolation, accumulation of lysosomes, and occasional neuronal necrosis were observed. No significant pathological changes were found among the granule cells at this time. This report provides the first morphological evidence for early damage to the basket cells by TMT, which may account for the reduction of recurrent inhibition and hyperexcitability among the granule cells reported previously.

Sulfolane-induced hypothermia enhances survivability in mice

Mice injected intraperitoneally with sulfolane (tetrahydrothiophene-1,1-dioxide) underwent a significant decrease in metabolic rate and body temperature at ambient temperatures of 20 and 30 degrees C but not 35 degrees C. If given the opportunity, mice treated with sulfolane preferentially sought a cool ambient temperature. When given an LD50 dose of sulfolane (1270 mg/kg), the percentage mortality varied directly with ambient temperature. For example, at 35 degrees C mortality was 75% whereas at 25 degrees C mortality was only 8%. By undergoing an autonomically and behaviorally mediated decrease in body temperature (i.e., regulated hypothermia), sulfolane-treated mice appear to enhance their chance of survival.

Effect of triethyltin on autonomic and behavioral thermoregulation of mice

The organotin compound, triethyltin (TET), produces toxic effects in a variety of physiological systems. Thermoregulatory control appears to be especially susceptible to TET toxicity, since TET administration has been shown to cause a pronounced hypothermia in rats. To further elucidate effects of TET on thermoregulation, we measured metabolic rate, evaporative water loss (EWL), body temperature, and preferred ambient temperature (Ta) of mice treated intraperitoneally with TET (bromide salt). At a Ta of 23 to 24 degrees C, TET (6 and 8 mg/kg) inhibited metabolic rate by 23 and 66%, respectively. TET resulted in hypothermia at Tas of 20 and 30 degrees C but not 35 degrees C. TET had little effect on EWL. Mice given TET at doses of 4, 6, and 8 mg/kg selected a cooler Ta (ca. 25 degrees C) compared to controls (ca. 29 degrees C). Thus, the mice selected a Ta associated with a hypothermic body temperature. At a relatively cool Ta, mice treated with TET had a reduced rate of heat production and, consequently, were hypothermic. At a relatively warm Ta, TET had no effect on heat production and did not increase active heat dissipation (i.e., EWL), thus the mice remained normothermic. The behavioral data indicate that TET evokes a type of regulated hypothermia in mice.

Chlordimeform produces contrast-dependent changes in visual evoked potentials of hooded rats

Previous experiments found that acute exposure to the insecticide/acaricide, chlordimeform (CDM), produced large increases in the amplitude of pattern reversal evoked potentials (PREPs) without changing the amplitude of flash evoked potentials (FEPs) in the same rats (W. K. Boyes and R. S. Dyer, Exp. Neurol. 86: 434-447, 1984). Current work investigated the influence of physical characteristics of the evoking stimuli on the action of CDM. Adult male Long-Evans rats with epidural visual cortex electrodes were used. In experiment 1, PREPs were elicited with alternating gratings having equal contrast (99%) and a square wave spatial luminance profile at several spatial frequencies. Rats treated 1 h previously with 40 mg/kg CDM had increased PREP amplitudes at 0.1, 0.2, and 0.4 cycles per degree (cpd), but not at 0.8 cpd. No changes were found after 5 mg/kg CDM. In experiment 2, PREPs were elicited with gratings oriented at 0 degrees (horizontal), 45 degrees, 90 degrees, or 135 degrees. Treatment with 40 mg/kg CDM increased PREP amplitudes and latencies regardless of orientation. In experiment 3, FEPs elicited with strobe flashes spanning four log units of intensity showed a small but significant CDM dose X intensity interaction on P2N2 peak-to-peak amplitude. In experiment 4, PREPs were elicited with alternating gratings having a sinusoidal spatial luminance profile, spatial frequency of 0.2 or 0.8 cpd, and contrast ranging from noise levels to 65%. Rats treated with 40 mg/kg CDM showed increased peak-to-peak amplitudes only at 0.2 cpd and only at contrast values above 10%. The failure of CDM to alter PREPs at 0.8 cpd was attributed to low contrast sensitivity at that spatial frequency. The results demonstrated that the action of CDM on visual evoked potentials was dependent on the amount of contrast in the stimulus pattern, and suggested that CDM alters the encoding of visual contrast.