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PubMed2002

Crystal structure and mechanism of a calcium-gated potassium channel.

Ion channels exhibit two essential biophysical properties; that is, selective ion conduction, and the ability to gate-open in response to an appropriate stimulus. Two general categories of ion channel gating are defined by the initiating stimulus: ligand binding (neurotransmitter- or second-messenger-gated channels) or membrane voltage (voltage-gated channels). Here we present the structural basis of ligand gating in a K(+) channel that opens in response to intracellular Ca(2+). We have cloned, expressed, analysed electrical properties, and determined the crystal structure of a K(+) channel (MthK) from Methanobacterium thermoautotrophicum in the Ca(2+)-bound, opened state. Eight RCK domains (regulators of K(+) conductance) form a gating ring at the intracellular membrane surface. The gating ring uses the free energy of Ca(2+) binding in a simple manner to perform mechanical work to open the pore.

Amino Acid Sequence↗
PubMed1992

Aminorex produces stimulus effects similar to amphetamine and unlike those of fenfluramine.

A 4-methyl derivative of aminorex has recently appeared on the clandestine market as a designer drug. In the present study, the stimulus effects of aminorex itself were evaluated in rats trained to discriminate either 0.75 mg/kg S(+)-amphetamine or 1.5 mg/kg fenfluramine from saline. The amphetamine stimulus (ED50 = 0.14 mg/kg) generalized to aminorex (ED50 = 0.23 mg/kg), which was found to be slightly less potent than (+)-amphetamine. Fenfluramine stimulus generalization did not occur to aminorex. Thus, the stimulus effects of aminorex are qualitatively similar to those of amphetamine and unlike those of fenfluramine.

Aminorex↗
PubMed2000

The perceptual magnet effect in Australian English vowels.

Recent research (Kuhl, 1991) has suggested that the internal structure of vowel categories is graded in terms of stimulus goodness. It has been proposed that a best instance stimulus reflects a central point or prototype, which effectively renders within-category members perceptually more similar. Discrimination experiments suggest a nonlinear relationship between acoustic and perceptual space near category centers (Iverson & Kuhl, 1995b). This phenomenon has been described as the perceptual magnet effect. The present study investigated the presence of the perceptual magnet effect in five Australian vowel categories. Australian English speakers identified, rated, and discriminated between a pool of 32 vowel stimuli that varied in F1 and F2 values. The results from Experiments 1 and 2 showed that subjects were able to judge the quality and identify of each stimulus and that a general grading of stimulus quality was reported. This was not symmetrical, and the subjects' responses varied considerably. In Experiment 3, closer control of the methodology in the discrimination task and of contextual factors influencing the test materials was exercised. Despite this, evidence of the warping of perceptual space in discrimination data was not found. In general, these results do not provide support for the existence of the perceptual magnet effect, and explanations for this finding are discussed.

Adult↗
PubMed1994

Stimulation-dependent effect of antiepileptic drugs in amygdala kindled rats on both seizure score and duration of afterdischarges.

The ED50 for abolition of generalized seizures and reduction of afterdischarges to 20% of the control duration was determined in kindled rats for phenobarbital, carbamazepine, phenytoin, valproic acid, clonazepam, and diazepam, both at a stimulation intensity of 200 microA and at 10 microA above the threshold for generalized seizures (threshold stimulation). Phenobarbital, carbamazepine, and valproic acid acted in a stimulus-dependent manner, i.e. the ED50 was higher at 200 microA than at threshold stimulation. Phenytoin had the same ED50 irrespective of the stimulus intensity. Generalized seizures and afterdischarges were suppressed by the same doses of the drugs mentioned. The benzodiazepines, clonazepam and diazepam, had a differential effect: they suppressed generalized seizures at low doses, whereas afterdischarges were only suppressed incompletely at relatively high doses. The ED50 of both benzodiazepines was independent of stimulus intensity. In order to avoid erroneous conclusions a standardization of kindling parameters, especially stimulation intensity, is proposed when drug effects are to be compared.

Amygdala↗
PubMed1993

Buprenorphine as a stimulus in drug discrimination learning: an assessment of mu and kappa receptor activity.

Using the conditioned taste aversion baseline of drug discrimination learning, different groups of animals were trained to discriminate either buprenorphine or morphine from distilled water. Specifically, animals were injected with buprenorphine or morphine prior to a saccharin-LiCl pairing and the drug vehicle prior to saccharin alone. By the fifth conditioning trial, animals differentially consumed saccharin on the basis of administration of the drug or its vehicle. In subsequent generalization tests, buprenorphine stimulus control generalized completely to the mu agonist morphine in four of the five subjects tested, while morphine stimulus control completely generalized to buprenorphine in two of five subjects and partially generalized in the remaining three. Buprenorphine failed to generalize to the relatively selective kappa antagonist MR2266 and the broad-based antagonist diprenorphine. Morphine also failed to generalize to MR2266, but did generalize to diprenorphine. That morphine and buprenorphine displayed some degree of cross-generalization suggests that these compounds share some stimulus property, presumably their agonist activity at the mu receptor, and that the mu activity of these compounds was used in the establishment of the discrimination, a conclusion supported by the fact that compounds with mu antagonist activity (e.g., naloxone, MR2266) blocked both buprenorphine and morphine stimulus control. That buprenorphine failed to generalize to compounds with kappa antagonist activity suggests that animals trained to discriminate buprenorphine from its vehicle do not use the kappa antagonist activity of the drug in the establishment of the discrimination. The basis for the differential ability of various receptor subtypes to mediate the discriminative properties of compounds with mixed receptor activity was discussed.

Animals↗
PubMed1990

Eye movements in Daphnia magna. Regions of the eye are specialized for different behaviors.

Three types of behavior of the compound eye of Daphnia magna are characterized: 'flick', a transient rotation elicited by a brief flash of light; 'fixation', a maintained eye orientation in response to a stationary light stimulus of long-duration; 'tracking', the smooth pursuit of a moving stimulus. The magnitudes of the flick and fixation responses vary with stimulus position and are generally proportional to stimulus intensity, although at high intensities there is an attenuation of both behaviors. When the stimulus is placed at a position approximately 80 degrees dorsal to the eye axis, there is no response; this area is called the null region. For stationary stimuli in other positions, the direction of the response is such as to bring the stimulus closer to the null region. During tracking, the relative positions of the eye and stimulus change; the eye velocity is approximately half that of the moving stimulus. The regions of the eye in which these behaviors may be induced are different, being largest for flick and smallest for tracking. It is proposed that flick and fixation responses are a means for rotating the eye so that the stimulus is within the area surrounding the null region which is used for tracking.

Animals↗
PubMed1962

Discrimination and generalization on a dimension of stimulus difference.

Four pigeons were trained to peck at one key when two identical stimuli were displayed, and at another key when the stimuli were displayed with a wavelength difference of 40 mmicro. With stimulus combinations ranging in difference from 0 to 70 mmicro in a generalization test, key preference was a function of the degree of difference between the stimuli.

Animals↗
PubMed1986

Effects of interaural time delays of noise stimuli on low-frequency cells in the cat's inferior colliculus. I. Responses to wideband noise.

We examined the responses of low-frequency neurons in the central nucleus of the inferior colliculus (ICC) of the cat to interaurally delayed, wideband noise stimuli. The stimuli were pseudorandom noise signals that were generated digitally with a nominal bandwidth of 60-4,000 Hz. We also compared the responses to noise with those obtained from interaural phase differences of pure tones. We studied 144 neurons with characteristic frequencies below 2.5 kHz. Eighty-five percent (85%) of these were sensitive to changes in both interaural time differences (ITDs) of noise and interaural phase differences of pure tones, only 2% were sensitive to one stimulus but not the other, and the remainder were insensitive to both stimuli. For most cells the discharge rate was modulated in an approximately cyclic fashion by changes in ITDs of the wideband noise stimuli. The maximal spike counts often occurred near zero ITD, and there was considerable variability in the nature of the cycling, though it usually disappeared for ITDs greater than +/- 4,000 microseconds. The position of the central peak was usually (65%) within the physiologically relevant range of +/- 400 microseconds, and most (80%) occurred at positive ITDs, which corresponded to delays to the ipsilateral stimulus. In general, the shapes of the responses were not affected by changes in stimulus level above threshold. As long as identical noises were delivered to both ears, the responses were not sensitive to the particular noise stimulus used. When uncorrelated noises were delivered to the two ears, there was no sensitivity to ITDs. Composite curves were computed by linear summation of the responses to ITDs of pure tones at frequencies spaced at equal intervals throughout each cell's response area. The shapes of composite curves were similar to the responses of the same cell to ITDs of wideband noise stimuli. The positions of the central peaks of these two functions were highly correlated (r = 0.91, slope = 0.97). The values of characteristic delay and characteristic phase computed from the tonal responses were found to be good indicators of the shapes of the noise delay curves. Characteristic phases (CPs) near zero were associated with noise delay curves symmetric about the central peak, CPs near 0.5 cycles with those symmetric about the trough, while CPs between 0 and 0.5 or between 0.5 and 1.0 had noise delay curves that were asymmetric with a prominent trough to the left or right, respectively, of the central peak.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1999

Differences between alcohol-preferring and alcohol-nonpreferring rats in ethanol generalization.

Alcohol-preferring (P rats) and alcohol-nonpreferring rats (NP rats) were trained to discriminate intraperitoneal injections of 0.5 g/kg ethanol, or subcutaneous injections of 0.6 mg/kg nicotine from saline. P rats learned the ethanol discrimination more rapidly and made a higher percentage (88%) of their responses on the ethanol lever after ethanol and a lower percentage (7%) after saline than NP rats (78 and 15%, respectively). In substitution tests, increasing doses of ethanol produced increases in the percentage of responses on the ethanol lever with similar ED50s (0.43 and 0.44 g/kg) in P and NP rats. P rats trained to discriminate ethanol from saline made more responses on the ethanol lever after nicotine (80%) and d-amphetamine (63%) than NP rats (33 and 40%). The ethanol stimulus did not generalize to morphine in either P or NP rats. NP rats trained to discriminate ethanol from saline responded more on the ethanol lever after bupropion (77%) than P rats (49%). In rats trained to discriminate nicotine from saline, the nicotine discriminative stimulus did not generalize to ethanol in either P or NP rats, suggesting that the genetic difference in the stimulus generalization of ethanol was not symmetrical.

Alcohol Drinking↗
PubMed1996

Evaluation of the discriminative stimulus and reinforcing effects of gammahydroxybutyrate (GHB).

Gammahydroxybutyrate (GHB) satisfies many of the criteria for consideration as a neuro-transmitter including having specific receptor sites, endogenous synthesis, and heterogeneous CNS distribution. GHB has been reported to be illicitly used, to induce physical dependence, and to relieve effects from alcohol and heroin withdrawal. GHB has also been shown to have antidopaminergic activity to displace 3H[MK-801] binding in brain membranes, and to have some in vivo effects similar to the typical antipsychotics. To characterize the behavioral pharmacology of GHB further, we evaluated it for its reinforcing effects upon IV administration in rhesus monkeys with PCP self-administration histories, its ability to produce heroin- and PCP-like discriminative stimulus effects, and for its ability to antagonize cocaine discrimination in rats. The results indicated that GHB (300-7500 micrograms/kg per infusion) was not self-administered above vehicle control rates, although self-infusions occurred at levels sufficient to produce signs indicative of sedation. Also, neither heroin nor PCP discriminative stimulus effects generalized to injections of GHB up to 300 mg/kg IP, and GHB did not effectively antagonize the cocaine discriminative stimulus when tested up to 300 mg/kg IP. These data indicate that GHB is unlike PCP as a reinforcer and that neither PCP nor heroin generalize to injections of GHB, nor can injections of GHB attenuate the discriminative stimulus effects of cocaine.

Animals↗
PubMed1989

Noradrenaline and 5-hydroxytryptamine release in the hippocampus during seizures induced by hippocampal kindling stimulation: an in vivo microdialysis study.

The intracerebral microdialysis technique has been used to monitor extracellular levels of noradrenaline, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the rat hippocampus in vivo in response to focal and generalized seizures induced by hippocampal kindling stimulation. In fully kindled animals a stimulus-induced generalized seizure gave rise to a three-fold increase of noradrenaline levels in the stimulated hippocampus as compared to baseline levels (15-min samples). The maximal increase of noradrenaline levels occurred within the first minutes after onset of seizure activity, as assessed in 2-min sample fractions with the noradrenaline uptake blocker desipramine added to the perfusion medium. After the peak increase, the noradrenaline levels tapered off, reaching baseline after 8-10 min. In 6-hydroxydopamine-treated animals, baseline noradrenaline levels were markedly reduced and there was no significant increase in noradrenaline release in response to a generalized seizure. These data support the hypothesis that the high extracellular levels of noradrenaline measured in seizures are of neuronal origin. There were no significant changes in extracellular 5-hydroxytryptamine or 5-hydroxyindoleacetic acid levels after a generalized seizure. In non-kindled animals the steady state noradrenaline levels during uptake blockade were two-three times higher than in the kindled rats. However, the peak noradrenaline levels measured in both hippocampi after the first two electrical kindling stimulations giving rise to focal epileptiform activity (afterdischarge) were similar to those observed in the kindled animals in response to generalized seizures. The increase of noradrenaline release in the non-kindled animals was significantly correlated to the duration of afterdischarge. In conclusion, the present study demonstrates the usefulness of the intracerebral dialysis technique for monitoring noradrenaline, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid release during seizures. The results indicate that both focal and generalized hippocampal seizures evoked by electrical kindling stimulation lead to a marked increase of transmitter release from noradrenergic but not from serotonergic neurons in the hippocampus. The ability of the noradrenergic system to respond by increased transmitter release to epileptic seizures is thus retained also in the kindled state.

Animals↗
PubMed2005

Parent training: acquisition and generalization of discrete trials teaching skills with parents of children with autism.

This study examined the effects of an intensive parent training program on the acquisition and generalization of discrete trial teaching (DTT) procedures with two parents of children with autism. Over the course of the program, parents applied the DTT procedures to teach four different functional skills to their children, which allowed for an assessment of "free" and programmed generalization across stimulus exemplars. Parent training was conducted by the first author utilizing instructions, demonstrations, role-play, and practice with feedback. Parents' use of DTT skills and children's correct and incorrect responding were measured. A within-subject multiple-baseline across stimulus exemplars (functional skills taught) design was employed both to demonstrate control of the training program over parents' correct use of DTT, and to allow a preliminary investigation of the generalized effects of training to multiple stimulus exemplars. Results demonstrate initial control of the training program over parent responding, and the extent to which each parent extended her use of DTT procedures across untrained and topographically different child skills. The potential for designing more generalizable and thus more cost-effective parent training programs is discussed.

Adult↗
PubMed1977

Signalled free-operant avoidance of shock by pigeons pecking a key.

Two pigeons were trained to peck a key under a free-operant avoidance schedule. Then, changes in key color signalled the beginning (safe period) and the end (warning period) of the response-shock interval, with a response required to change the key color. Finally, a change in key color signalled the warning period and either a response or a shock reinstated the safe stimulus. During signalled avoidance, response rate was higher during the warning stimulus than during the safe stimulus. More responding tended to occur in the warning stimulus when it was terminated by either a response or a shock than by only a response. In either procedure, response latency during the warning stimulus was a function of the duration of the warning stimulus. In general, response and shock rate were higher during unsignalled than during signalled avoidance. When the warning stimulus was brief, the results were similar to those of unsignalled avoidance. These results confirm previous findings with pigeons, are in general agreement with data provided by other species in studies of signalled avoidance, and thereby indicate the transituationality of the key-pecking operant.

Journal Article↗
PubMed1969

Neural readout from memory during generalization.

Eight cats with implanted electrodes were trained to obtain food on presentation of one flicker frequency and to avoid shock on presentation of a second flicker frequency. A third flicker frequency, midway between the first and the second, was then presented. Differential generalization ensued, in which either the food response or the avoidance response was performed. Average evoked potentials from generalization trials with different outcomes were significantly different. The wave shape elicited by the stimulus for generalization closely resembled the usual response to the appropriate signal for the behavior which was displayed. This constitutes evidence for release of a neural process representing previous experience. The release of this process begins about 35 milliseconds after stimulation.

Animals↗