Cholinergic mechanisms in startle and prepulse inhibition: effects of the false cholinergic precursor N-aminodeanol.

We examined the effects of cholinergic deficiency on prepulse inhibition (PPI) of the acoustic startle. Rats treated with a choline-free diet that contained the false cholinergic precursor N-aminodeanol showed great deficit in PPI. This deficit does not appear to be secondary to an increase of stereotyped behaviors. Startle threshold was also greatly reduced, as these rats startled to the 70-dB prepulse and the baseline startle amplitude was increased by 60% over the control rats. Arecoline (4 mg/kg) partially reversed the deficit in PPI. This improvement persisted beyond the period of drug treatment. On the other hand, scopolamine (1 mg/kg) reduced PPI in the control rats. These results suggest that cholinergic systems play a major role in both the elicitation and prepulse inhibition of startle.

Transfer between chemical and electrical kindling in the septal-hippocampal system.

We re-investigated the interaction between chemical and electrical kindling in two anatomical locations: the amygdaloid region and the septal-hippocampal complex. Amygdaloid animals were implanted with a chemitrode into the left basolateral amygdala, which could then be stimulated electrically (400 microA, 1 s, 60 Hz, AC) or chemically by injection of carbachol (1 microliter, 2.7 nmol, sterile, isotonic). Septal-hippocampal animals were implanted with an electrode high in the medial septum, a cannula in the dorsal hippocampus. In both groups, half the animals were kindled electrically, and after one week of rest chemical kindling was begun. The other half were kindled chemically first, then electrically. The result differed with the anatomical location. With amygdaloid implants, no significant transfer was observed. In the septal-hippocampal group, by contrast, significant interactions were observed in both directions. These results suggest that chemical and electrical kindling involves similar mechanisms, and that the extent to which transfer occurs reflects the degree to which they share a common chemical anatomy.

Habituation of the local cyclic GMP response during amygdaloid carbachol kindling in the rat.

Seizures kindled with amygdaloid carbachol injections are transynaptic, dependent on activation of a specific population of muscarinic receptors, and some components of their expression could be mediated by intracellular second messengers. We measured cyclic GMP and cyclic AMP concentrations in micropunch biopsies of multiple brain regions after microwave fixation during the development and the expression of carbachol-kindled seizures in the rat. In the naive carbachol-injected amygdala, cyclic GMP concentrations rose from 1.03 +/- 0.15 pmol/mg protein to 2.21 +/- 0.46 after 2 min, and significant rises occurred in caudate, hypothalamus and contralateral amygdala. This response did not occur in implanted controls, after injection of mock cerebrospinal fluid, or when carbachol actions were blocked with atropine. The rise in cyclic GMP progressively disappeared upon repeated stimulation (injected amygdala on tenth stimulation: 0.72 +/- 0.23 pmol/mg protein). However, a late rise in both cyclic GMP and cyclic AMP concentrations occurred in many brain regions during convulsive seizures. These data suggest that during the development of kindling, changes in neuronal and synaptic excitability are associated with changes in intracellular second messengers.

Perfusion with lithium modifies neurophysiological responses in the CA1 region of the hippocampal slice preparation.

The effects of acute lithium exposure on extracellular electrophysiological responses in the CA1 region of the in vitro hippocampus were investigated. Field potentials were assessed while perfusing slices with normal media or media in which LiCl was substituted for NaCl in 30, 20, 10 and 2 mM amounts. Lithium concentration in the slice following 20 min perfusion with 20 mM lithium was determined to be about 14 mM. At the higher concentrations, lithium exposure depressed the presynaptic fiber volley and antidromic population spike. On the other hand, the population EPSP and orthodromic population spike were enhanced. No significant changes were found at 2 mM. The findings are compatible with one action of lithium being on the excitability of axons and synaptic terminals. Comparisons were drawn between previous studies involving chronic lithium exposure and the present results. In this acute preparation lithium effects, as reflected in the population EPSP, were in opposition to those found with chronic lithium exposure. Changes demonstrated in this preparation in fiber volley and antidromic population spike paralleled those found with chronic lithium exposure.

Sleep-wake disturbances in an animal model of chronic cholinergic insufficiency.

Rats reared on a diet in which choline is replaced with N-aminodeanol (NADE), undergo > 50% replacement of brain acetylcholine with acetylated NADE, a false cholinergic transmitter. We examined amounts of sleep and wakefulness in 7 littermate pairs of rats fed either NADE-substituted, or a choline control diet for > 100 days after weaning. During the lights-on portion of the 12/12 h light/dark cycle, NADE rats spent more time awake, and less time in both non-REM and REM sleep compared to littermate controls. Average durations of waking episodes were significantly increased in NADE rats. During the 12 h dark period, there were no between-group differences in sleep-waking amounts. Behavioral hyper-responsiveness which interferes with sleep onset, combined with reduced activity in brainstem cholinergic mechanisms involved in REM sleep generation may underlie daytime sleep-waking disturbances in NADE rats.

Kindled seizure induction alters and is altered by zinc absorption.

Amygdala kindling stimulation produced significant changes in plasma zinc levels in cats otherwise unaffected by zinc loading or deprivation. While a normal diet had no effect, moderate zinc loading was accompanied by a marked increase in plasma zinc during kindling. Conversely, plasma zinc sharply declined in animals fed a zinc-deficient diet. Corresponding differences were obtained in the development of generalized seizures with kindling such that loading delayed and deprivation accelerated this process.

A hypoxic injury potential in the hippocampal slice.

In rat hippocampal slices, neurons in the stratum pyramidale of the CA1 were stimulated orthodromically and antidromically while the resultant extracellular population spikes were monitored. Hypoxic conditions were then induced. After disappearance of the orthodromic population spike, a second orthodromic population spike appeared. We have titled this the hypoxic injury potential since it reflects the onset of permanent injury to neurons in area CA1 of the hippocampus.

Chromatic adaptation to natural and incandescent illuminants.

A color CRT image display system was used to present adapting backgrounds that were spatially and temporally varied. Three observers adjusted the chromaticity of test stimuli to produce an achromatic appearance under a variety of adapting conditions. The achromatic-appearing chromaticities were used as measures of the observers' states of chromatic adaptation. The spatial configuration of the adapting background was varied to measure the spatial extent of the mechanisms responsible for chromatic adaptation. The temporal configuration of the adapting background was varied to measure the time-course of these mechanisms. The results show that chromatic adaptation is spatially localized with a time-course on the order of 10 sec. Since the mechanisms were shown to be spatially localized, the observed temporal integration across eye movements is required to allow these mechanisms to adjust to the spatially integrated scene chromaticity.

Ganglion cell pathways for rod vision.

Measurements of the acuity of rod vision made by two different techniques show it to vary only slightly with eccentricity. At eccentricities beyond 15 deg acuity is well predicted from the sampling properties of the mosaic of the P-class of ganglion cells. With decreasing eccentricity acuity falls progressively below the sampling limit of P-cells, but even at the lowest eccentricity examined (5 deg) does not reach the limit imposed by the sampling properties of the mosaic of M-cells. At an eccentricity of 5 deg rod vision could be supported by as few as 20% of P-cells.

Synaptic mechanisms in the kindled epileptic focus: a speculative synthesis.

This chapter reviews the chemical kindling model of epilepsy and speculates on its significance. Both human and experimental epilepsies are extremely heterogeneous, and it is unlikely that a single molecular or cellular mechanism can account for such a diversity of behavioral manifestations. Recent studies of chemical kindling favor the view that in this model, epilepsy is a property of neuronal networks that can take place in a structurally intact brain and does not depend on the presence of gross or microscopic brain damage. Kindling can be obtained by daily injections of nanomolar amounts of multiple muscarinic agonists in selective brain regions such as the amygdala and, once acquired, it is very persistent and frequently accompanied by spontaneous seizures. No evidence exists for creation of a novel pathway, and studies of seizure threshold suggest the need for a critical mass of neurons even on initial stimulation. The amounts of muscarinic agents injected are small enough to have little recordable effect initially, and the number of stimulations needed varies directly with the dose and inversely with the interstimulus interval. Carbachol kindling is inhibited by picomolar amounts of muscarinic antagonists, and the relative potencies of drugs on the kindling behavior in vivo parallel their affinity for muscarinic receptors in vitro. The (+) isomer of acetyl-beta-methylcholine, with good affinity for the muscarinic receptor, can induce kindling, whereas the (-) stereo isomer with poor affinity for the receptor cannot. No morphological differences are observed between animals injected with the (+) or the (-) isomer. These experiments suggest that the development of chronic focal epilepsy can take place in a structurally intact brain, be independent of the production of brain damage, and totally dependent on synaptic excitation. In other words, in this model, epilepsy may be a disease of cell-cell communication in which structurally normal neurons develop epileptiform responses as their interactions are modified through synaptic activation. A study of the relationships between carbachol and electrical kindling of the same site gave different results depending on the site of stimulation. In the amygdala, no interaction was found, but when both stimuli were aimed at the cholinoceptive hippocampal cells, a strong facilitation in both directions was observed. Thus, it appears that chemical and electrical kindling share similar mechanisms and that cross-facilitation depends on the existence of a common anatomy. The same anticonvulsants that block electrical kindling also inhibit chemical kindling.(ABSTRACT TRUNCATED AT 400 WORDS)

EEG effects of hallucinogens and cannabinoids using sleep-waking behavior as baseline.

Three hallucinogens (d-lysergicacid diethylamide (LSD), mescaline, psilocybin) and two cannabinoid derivatives (tetrahydrocannabinol (THC), synhexyl) were tested for their long-term effects on the EEG of the cat. The drug-induced alterations in the EEG frequency spectrum were "drug-specific" in the sense that they would be statistically unlikely to occur during sleep-waking behavior. The two classes of compounds produced distinctly different EEG effects which were remarkably similar within each class. The duration of activity and relative potencies were consistent with those obtained by other measures, both in cats and in other species including man.

Psychophysical evaluation of gamut mapping techniques using simple rendered images and artificial gamut boundaries.

Using a paired comparison paradigm, various gamut mapping algorithms were evaluated using simple rendered images and artificial gamut boundaries. The test images consisted of simple rendered spheres floating in front of a gray background. Using CIELAB as our device-independent color space, cut-off values for lightness and chroma, based on the statistics of the images, were chosen to reduce the gamuts for the test images. The gamut mapping algorithms consisted of combinations of clipping and mapping the original gamut in linear piecewise segments. Complete color space compression in RGB and CIELAB was also tested. Each of the colored originals (R,G,B,C,M,Y, and Skin) were mapped separately in lightness and chroma. In addition, each algorithm was implemented with saturation (C(*)/L(*)) allowed to vary or retain the same values as in the original image. Pairs of test images with reduced color gamuts were presented to twenty subjects along with the original image. For each pair the subjects chose the test image that better reproduced the original. Rank orders and interval scales of algorithm performance with confidence limits were then derived. Clipping all out-of-gamut colors was the best method for mapping chroma. For lightness mapping at low lightness levels and high lightness levels particular gamut mapping algorithms consistently produced images chosen as most like the original. The choice of device-independent color space may also influence which gamut mapping algorithms are best.

Goniospectrophotometric analysis of pressed PTFE powder for use as a primary transfer standard.

Pressed polytetrafluoroethylene (PTFE) powder, pressed BaSO(4), and Russian opal glass were evaluated as possible reflectance factor standards for goniospectrophotometry. Pressed PTFE was chosen based on reflectance properties, ease of preparation, durability, availability, and cost. A method of preparation was developed which combined the most Lambertian behavior with high reproducibility. Several of these PTFE preparations were then measured goniospectrophotometrically to provide a set of data which would sufficiently define the bidirectional spectral reflectance factors for use as a transfer standard for nonstandard instrumental geometries.

Time course of chromatic adaptation for color-appearance judgments.

Observer production of achromatic appearance has previously been used to measure the time course of chromatic adaptation for changes from daylight to incandescent illuminants at constant luminance, indicating an exponential decay of chromatic adaptation with a time constant of the order of 10 s. The work extends previous results in several ways. The psychophysical technique was significantly improved to provide more reliable estimates of color appearance as a function of adaptation duration, and the time course of chromatic adaptation was measured for six chromaticity changes. Three observers tracked achromatic appearance on a computer-controlled CRT display during transitions of 2-min duration between the various chromaticities. The results indicate that observer differences are statistically significant. However, differences in time course for different chromaticity changes are not statistically significant (within observer). Single or piecewise exponential decay functions cannot be fitted to the data. However, sum-of-two-exponentials functions provided accurate descriptions of the data. The results suggest two stages of adaptation: one extremely rapid (a few seconds) and the other somewhat slower (approximately 1 min). Chromatic adaptation at constant luminance was 90% complete after approximately 60 s.

An application of long-term frequency analysis in measuring drug-specific alterations in the EEG of the cat.

A method is described for the quantitative measurement of "drug-specific" effects on the EEG of the cat. These effects are dose-related and are independent of the normal sources of EEG variation associated with the sleep-waking cycle. Drug-induced changes are expressed as characteristic alterations in frequency spectra and the time courses of these effects are followed for 5 h following administration of the test compounds. Atropine sulfate (0.5 and 2.0 mg/kg) and physostigmine salicylate (0.05 and 0.20 mg/kg) were administered to three unanesthetized and unrestrained cats and a broad-band frequency analysis was performed on the spontaneous brain electrical activity recorded from the prepyriform cortex, ventral hippocampus, lateral geniculate nucleus and the midbrain reticular formation. The resulting data were used as input to discriminant and canonical statistical analysis programs employed to abstract "drug-specific" patterns of frequency change. It was found that both atropine and physostigmine produce alterations in EEG frequency spectra which are clearly distinct from those patterns associated with the sleep-waking cycle and thus neither compound results in what has been characterized as an "EEG-behavioral dissociation".

The quantitative measurement of changes in EEG frequency spectra produced in the cat by sedative-hypnotics and neuroleptics.

The sedative-hypnotic secobarbital and the sedative-anti-anxiety agent, chlordiazepoxide and two neuroleptics, chlorpromazine and halopridol, were treated for effects on the EEG of the cat using broad-band frequency analysis of 6 brain sites. Dose-related, 'drug-=specific' effects were abstracted from the data by the use of multivariate statistical techniques. These demonstrated that the two neuroleptic agents produced very similar alterations in the EEG frequency spectrum which were distinctly different from those resulting from the administration of the sedative-hypnotic and the sedative-anti-anxiety agent. The time-course of the central activity of the 4 compounds was also depicted.

Protective effects of felbamate against hypoxia in the rat hippocampal slice.

BACKGROUND AND PURPOSE: Felbamate is a new dicarbamate anticonvulsant with low toxicity currently being investigated in human clinical epilepsy trials. In this study, we examined the protective effects of felbamate against hypoxia. METHODS: We exposed paired rat hippocampal slices to hypoxia with and without felbamate treatment while monitoring the CA1-evoked population spike. RESULTS: Felbamate provided dose-dependent neuroprotection against hypoxia at concentrations of 45 mg/l and greater (p less than 0.05). At a felbamate concentration of 300 mg/l, recovery of CA1 evoked population spike amplitude after hypoxic exposure was 99% compared with 0.5% for unmedicated paired slices. The appearance and disappearance of the hypoxic injury potential was delayed in slices treated with 300 and 400 mg/l (p less than 0.05). CONCLUSIONS: In this model of hypoxia, felbamate provided neuroprotection against hypoxia at concentrations similar to serum felbamate levels currently being used in human clinical epilepsy trials.