Biomedical subjects
Publications and source records attributed to E W Snyder.
Naloxone, at subconvulsive dose levels, from 1 to 15 mg/kg were administered to conscious rats. Significant increases in photically evoked afterdischarge occurrence were seen at naloxone dose levels above 5 mg/kg with no clinical evidence of seizure activity being observed. Typically photically evoked afterdischarge augmentation is only observed following the administration of convulsive drugs.
PREP P100 latency was significantly prolonged in patients maintained on renal hemodialysis. P100 latency also failed to show changes related to time past dialysis. PREPs may be of use in evaluating the progression of uremic induced dysfunction.
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Naloxone injected into the lateral septum caused intense electrocortical seizures which did not occur following callosal or periaqueductal gray (PAG) injections. Conversely, injections into periaqueductal gray caused a characteristic and pronounced backward circling with only moderate electrocortical changes. Intracerebral injection of naloxone had effects, including epileptogenesis, which appeared to be site-specific. These effects are in some ways similar to the effects of enkephalin and morphine.
Pattern reversal evoked potentials (PREPs) were recorded from people whose ages ranged from 4 to 90 years. Dramatic reductions in PREP amplitudes occurred between childhood and adolescence. These changes were most evident in females. Following adolescence there were no significant changes in amplitudes, even to old age. Latencies, on the other hand, have been shown to change most dramatically between adulthood and old age. PREP amplitudes and latencies, therefore, appear to provide different and unique information regarding development and aging. One cannot ignore PREP amplitudes without sacrificing information regarding early development.
Visually evoked potentials (VEPs) elicited by patterned and unpatterned flashes were recorded from 211 healthy males aged 4-90 years. A measure of similarity between the two kinds of VEPs was obtained by correlating the digital values comprising the two waveforms. Across the life-span, correlations followed a U-shaped curve; patterned and unpatterned flash VEPs were most alike for the youngest and oldest subjects. This age effect, localized to scalp areas overlying visual cortex, is compatible with a concept of reduced inhibitory functioning within the visual systems of the young and the old. At central scalp, patterned and unpatterned flash VEP waveforms were more effectively differentiated by the right hemisphere. This observation agrees that the right hemisphere specializes in analyses of spatial material.
Three intensities of patterned flash were used to elicit visually evoked potentials (VEPs) from central scalp of 220 healthy males aged 4-90 years. Intensities were based on visual thresholds. VEP components from children and oldsters were generally larger than those of subjects of intermediate ages and, in response to increased flash intensity, demonstrated greater amplitude enhancement. This pattern of age changes is thought to reflect decreased cortical inhibition in the young and the old with inhibitory capacity being maximal during late adolescent and early adult years. Hemispheric asymmetries were observed. VEP amplitudes from the right hemisphere were larger than those from the left and demonstrated a greater amplitude augmentation to brighter flashes.
Phencyclidine (PCP) at high doses causes both excitation and depression in the rat. The visual evoked potential (VEP) was measured in rats following PCP administration in doses ranging from 1 mg/kg to 56 mg/kg. Consistent lengthening of VEP latencies suggests that PCP has an unusual inhibitory effect on visual function in the presence of the excitatory signs of bilaterally synchronous cortical spiking. The epileptogenic properties of PCP are quite evident in rats.
The electroencephalographic effects of a range of doses of naloxone were evaluated in an effort to address the apparent epileptogenic properties of the drug. Electrographic activity was recorded from epidural electrodes in eight monkeys. The records were visually inspected and subjected to power spectral analyses. Concurrent visual evoked potentials were recorded and analyzed by standard procedures. Large doses (greater than 32.0 mg/kg i.m.) of naloxone were quickly and reliably succeeded by high voltage electrographic seizure activity at cortex. Lower doses (greater than or equal to 8.0 mg/kg) were followed by increased voltage in high frequency electroencephalogram (EEG) and spiking activity. Visual evoked potential latencies were reliably extended. As determined by power spectral analyses and third order slope analyses, the drug effects on EEG were related to time and dose. The early effects of high doses mimicked the maximal effects of low doses. It is concluded that seizures which follow high doses (48.0--64.0 mg/kg) of naloxone are derived from changes which are evident after doses which approach those used clinically to antagonize opiates. Such changes are, however, not readily apparent under visual inspection of the EEG.
Electrographic seizure activity was recorded shortly following naxolone injections in artificially ventilated, methadone-treated stump-tailed macaques. Plasma-methadone concentrations prior to seizure activity were many times higher than those that have produced respiratory depression and death in nonventilated monkeys. The duration of seizure activity was clearly related to the dose of naloxone. Naloxone was without epileptogenic properties in animals that had not been pretreated with methadone. The results suggest that methadone and naloxone have additive epileptogenic properties when high blood levels of methadone are achieved in the artificially ventilated primate. Naloxone was devoid of antagonistic properties with respect to opiate-induced electroencephalographic spiking activity.
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Visual evoked responses (VERs) and EEG were recorded following the i.p. administration of five doses of methadone (0.5--4 mg/kg) to 12 adult cats, which were implanted with cortical and subcortical electrodes. Additional cats, subjected to the same drug regimen, were used to evaluate plasma methadone concentrations. Doses of methadone that produced plasma concentrations between 80 and 190 ng/ml differentially affected VERs recorded from cortical and subcortical sites. Of the subcortical structures evaluated, the limbic system, specifically the hippocampus, was the most sensitive to the effects of the drug. These effects appeared to be primarily depressant. Responses recorded from the reticular formation and centromedian were affected only by the highest dose of methadone, while VERs recorded from cortical sites were reliably altered following the two highest doses and appeared to reflect both excitation and depression. Behavioral changes, however, were clearly evidenced in some cats at lower doses of methadone. Therefore, the data suggest (1) that those structures evaluated electrophysiologically did not reflect the full force of the drug's action as evidenced by its effect on behavior, (2) that cortical and subcortical recording sites have differential sensitivities, and (3) that one clearly defined, principal size of action of methadone is absent in the cat.
Visual evoked responses (VER's) of stump-tailed macaques were studied from birth to 80 weeks in an attempt to establish the utility of this species as a model of human neurophysiological development. Although human subjects and monkeys share a unique complexity of the VER at birth, the postnatal development of their VER's does not appear to follow a parallel sequence. The relatively dynamic nature of the VER during the 1st few weeks in a monkey's life may limit the usefulness of this species as a model of human development. The rapid changes in the VER of the developing monkey and the observation that these changes continue beyond 2 years of age should be considered in studies of the VER in which repeated measures are obtained over a prolonged period of time.
Visual evoked potentials (VEPs) were recorded from 2 cortical sites in stump-tailed macaques. VEPs recorded from striate cortex were basically consistent between animals (especially at low light intensity), remained remarkably stable over time, and compared favorably to VEPs reported by other investigators. We concluded that the VEP recorded from the striate cortex of day-active monkeys consists of 5 major peaks within the first 250 msec. The potentials recorded from post-central gyrus were simpler and more individualized and did not show intensity-related latency changes or increases in inter-subject variability. However, amplitudes of potentials recorded from both electrode placements increased with light intensity apparently reflecting the amplitude of individual potentials rather than the variability of these potentials from which the average VEPs were derived.
Methadone HCl was administered daily to four stump-tailed macaques. The animals' sleep was periodically examined throughtout a year of methadone maintenance and, in two animals, during eight months of withdrawal. REM sleep was substantially decreased by methadone treatment and gradually returned to predrug values over a 6- to 8-month period of maintenance. Measures of non-REM sleep and awakenings showed similar disruption with no return to predrug values. These changes were not correlated with alterations in plasma-methadone concentrations. REM sleep rebound occurred temporarily upon drug withdrawal in two animals, but no consistent sleep disruption was apparent during the subsequent eight months. Contrary to some suggestions, therefore, tolerance to the sleep-disruptive effects of the drug may be specific and incomplete, and extended REM rebound upon withdrawal is not a universal response.
Sawtooth waves, 2--3 c/sec activity of at least 40 micro V, occurred primarily during clusters of REMs in stump-tailed macaques. On the average the activity began well after the onset of REMs but occasionally occurred soon before or immediately after a cluster of REMs. The activity was clearly defined but occupied less than 0.6% of an 8-h sleep record. A sawtooth burst was, on the average, 7.5 sec in duration.
A sudden and potentially lethal toxic reaction to a previously well-tolerated maintenance dose of methadone occurred in 4 of 6 monkeys. The reaction was characterized by gross behavioral and respiratory depression and a marked attenuation of both early and late components of the visual evoked response with an increase in most latencies. The nature of the evoked response alteration suggests a widespread central nervous system depressant effect of the drug during toxicity. Concomitant with the toxic reactions were dramatic increases in plasma methadone concentrations. Therefore the observed changes in sensitivity to methadone would appear to be the consequence of a sudden shift in pharmacokinetics resulting in toxic plasma concentrations.