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Discriminative stimulus properties of L-phenylisopropyl adenosine: blockade by caffeine and generalization to 2-chloroadenosine.

Recent neurochemical data on the effects of activation and blockade of adenosine A1 receptors has suggested a direct role of adenosine in neurotransmission. The present research used a drug discrimination procedure to test the hypotheses that A1 adenosine receptor activation could serve as a discriminative stimulus and that caffeine, a drug believed to be an A1 receptor antagonist, could block the adenosine discrimination. Food-deprived rats were trained to press one of two levers on an FR 10 schedule of food-pellet delivery. Responses on one lever were reinforced following i.p. injection of N6 - (L-phenylisopropyl) adenosine (L-PIA); responses on the other lever were reinforced following i.p. injection of saline. L-PIA training dose was increased from 0.064 to 0.08 mg/kg L-PIA in the course of the study. Subjects required an average of 91 sessions to acquire this discrimination. Stimulus control by L-PIA was dose-dependent, with the ED-50 being approximately 0.03 mg/kg. 2-Chloroadenosine (2CA) generalized to L-PIA with a tenth the potency. Caffeine blocked L-PIA-induced lever selection. These results indicate that 1) rats can be trained to discriminate L-PIA from saline in a two-lever food-reinforced task and 2) the discriminative stimuli produced by L-PIA are based on its agonistic action at the adenosine A1 receptor.

2-Chloroadenosine↗

Discrimination learning induced by training with identical stimuli.

Sensory stimuli become easier to detect or distinguish with practice. It is generally assumed that the task-relevant stimulus dimension becomes increasingly more salient as a result of attentively performing the task at a level that is neither too easy nor too difficult. However, here we show improved auditory frequency discrimination following training with physically identical tones that were impossible to discriminate. We also show that learning transfers across tone frequencies and across modalities: training on a silent visuospatial computer game improved thresholds on the auditory discrimination task. We suggest that three processes are necessary for optimal perceptual learning: sensitization through exposure to the stimulus, modality- and dimension-specific attention, and general arousal.

Acoustic Stimulation↗

Malignant hyperthermia and the general dentist: current recommendations.

Malignant hyperthermia is a potentially fatal disease that may be triggered by the administration of specific drugs or by stress. Although most often associated with general anesthesia, stress can be a significant stimulus and is therefore of concern to the general dentist. The decision as to how and where to treat these patients is complicated by conflicting recommendations from various sources. The aim of this article is to propose a protocol for the dentist to use in the treatment of patients with a history of malignant hyperthermia. The dentist must assess the patient for both their susceptibility to a crisis and the degree of stress of the planned procedure. For non-stressful treatment, it is reasonable to assume that the general dental practitioner can treat these patients in his office. For stressful treatment, advanced preparation is advised.

Anesthesia, Dental↗

A diet enriched in vitamin A acetate or in vivo administration of interleukin-2 can counteract a tolerogenic stimulus.

A conventional diet enriched in retinyl acetate (vitamin A acetate; VAA) or in vivo administration of exogenous interleukin-2 (IL-2) can effectively annul the otherwise tolerogenic stimulus represented by (CBA X C57BL/10ScSn) F1 cells injected intraperitoneally into newborn CBA mice. On the basis of these data and results of others, we postulate that an antigenic stimulus associated with a relative lack of IL-2 (or generally the lack of a 'secondary stimulus') can be tolerogenic rather than immunogenic. However, the tolerogenicity of the antigenic stimulus can be substantially reduced or even converted to sensitization (R. P. Cleveland & H. N. Claman, J. Immun. 124, 474-480, 1980), when the antigenic signal is appropriately associated with a concomitant or additional stimulus possibly mediated through IL-2.

Animals↗

An in vitro analysis of sound localization mechanisms in the gerbil lateral superior olive.

One way in which animals localize sounds along the horizon is by detecting the level differences at the 2 ears. Neurons in the lateral superior olive (LSO) encode this cue by integrating the synaptic drive from ipsilateral excitatory and contralateral inhibitory connections. This synaptic integration was analyzed in 400-500-microns brain slices through the gerbil superior olive. Intracellular recordings from LSO neurons were obtained during the application of independent or conjoint electrical stimuli to the excitatory afferent and inhibitory afferent pathways. Stimulation of ascending fibers from the ipsilateral cochlear nucleus reliably evoked EPSPs and action potentials. Stimulation of the medial nucleus of the trapezoid body (MNTB) consistently evoked IPSPs. The evoked postsynaptic potentials differed in that IPSPs were 2 times the duration of EPSPs. An electrophysiological estimate of convergence indicated approximately 10 excitatory and 8 inhibitory afferents per LSO neuron. MNTB stimulation suppressed synaptically evoked action potentials. When stimulus amplitude was increased to the excitatory pathway, it was generally found that a greater MNTB stimulus was necessary to suppress the action potential. A similar commensurate rise in ipsilateral and contralateral acoustic stimulation was also found to be necessary to give the same criterion response. These results confirm that the LSO can integrate evoked action potentials and IPSPs to encode interaural level. Increasing stimulus voltage was found to decrease both action potential and IPSP latency, suggesting that intensity information may be encoded with temporal cues in the nervous system. It was also found that an evoked burst of action potentials could be inhibited in such a way as to yield intermediate discharge rates, dependent on contralateral stimulus level. Taken together, these results suggest that certain properties related to level-difference coding may be available for intracellular analysis using the brain-slice preparation. Several temporal characteristics of the synaptic potentials, including latency and duration, may play a critical role in this simple computation.

Acoustic Stimulation↗

[Function of the superior colliculi of the corpora quadrigemina during creation of a local focus of increased excitability in the mesencephalic reticular formation and sensomotor cortex].

In chronic experiments on waking rabbits, the foci of heightened excitability in the sensorimotor cortex and mesencephalic reticular formation affected in a similar way the background neuronal activity in the superior colliculi and that evoked by light stimuli. The effect was manifested in elimination of inhibitory pauses in the neuronal response to light stimulus and in a general increase of discharge frequency. Similarity of the cortical and reticular influences is due to their possible mediation by the same collicular interneurones participating in inhibitory pauses formation in the process of backward inhibition. Increased neuronal activity in the superior colliculi under the action of local foci in the sensorimotor cortex and mesencephalic reticular formation correlated with appearance of forelimb motor reaction to isolated light stimulus testifying to a formation of a functional connection between the visual and motor analyzers. Possible role of the superior colliculi in this process and their participation in the formation of a visually controlled reaction is discussed.

Animals↗

Attenuation of the bidirectional effects of chlordiazepoxide and FG 7142 on conditioned response suppression and associated cardiovascular reactivity by loss of cortical cholinergic inputs.

RATIONALE: Basal forebrain cortical cholinergic projections have been hypothesized to mediate the enhanced cardiovascular defensive response initiated by the putative anxiogenic benzodiazepine receptor (BZR) partial inverse agonist FG 7142 (FG). The present study was designed to test the broader hypothesis that the integrity of this cholinergic projection is required for the mediation of the bidirectional modulatory effects of BZR agonists and inverse agonists on anxiety and associated cardiovascular reactivity. OBJECTIVES: The interactions between the effects of 192 IgG-saporin-induced lesions of basal forebrain corticopetal cholinergic neurons and of the BZR agonist chlordiazepoxide (CDP) and FG on the performance of rats tested in a conditioned suppression paradigm and on associated cardiovascular reactivity were assessed. METHODS: Lesioned and control animals were equipped with a telemetric device to record heart rate, trained in an operant lever task, and then tested for suppression of responding during presentation of a conditioned stimulus (CS) and a general contextual cue that was previously associated with shock. FG, CDP (8 mg/kg) and vehicle were administered IP in separate extinction sessions. RESULTS: In control animals, operant responding was suppressed during presentation of the CS and contextual cue. Administration of FG enhanced this suppression, while CDP attenuated it. Lesions attenuated overall response suppression as well as the modulatory effects of BZR ligands on responding during presentation of the contextual stimulus. Likewise, lesions attenuated the cardioacceleratory response to the contextual stimulus and the ability of the BZR ligands to modulate this response. CONCLUSIONS: The behavioral and autonomic responses to anxiety-related stimuli, as well as the modulatory effects of BZR ligands, are mediated in part via cortical cholinergic inputs.

Animals↗

Using high frame rate CMOS sensors for three-dimensional eye tracking.

A novel three-dimensional eye tracker is described and its performance evaluated. In contrast to previous devices based on conventional video standards, the present eye tracker is based on programmable CMOS image sensors, interfaced directly to digital processing circuitry to permit real-time image acquisition and processing. This architecture provides a number of important advantages, including image sampling rates of up to 400/sec measurement, direct pixel addressing for preprocessing and acquisition,and hard-disk storage of relevant image data. The reconfigurable digital processing circuitry also facilitates inline optmization of the front-end, time-critical processes. The primary acquisition algorithm for tracking the pupil and other eye features is designed around the generalized Hough transform. The tracker permits comprehensive measurement of eye movement (three degrees of freedom) and head movement (six degrees of freedom), and thus provides the basis for many types of vestibulo-oculomotor and visual research. The device has been qualified by the German Space Agency (DLR) and NASA for deployment on the International Space Station. It is foreseen that the device will be used together with appropriate stimulus generators as a general purpose facility for visual and vestibular experiments. Initial verification studies with an artificial eye demonstrate a measurement resolution of better than 0.1 degrees in all three components (i.e.,system noise for each of the components measured as 0.006 degrees H, 0.005 degrees V, and 0.016 degrees T. Over a range of +/-20 degrees eye rotation, linearity was found to be <0.5% (H), <0.5% (V), and <2.0% (T). A comparison with the scleral search coil technique yielded near equivalent values for the system noise and the thickness of Listing's plane.

Equipment Design↗

Paroxetine, a selective 5-hydroxytryptamine uptake inhibitor with antidepressant properties, lacks amphetamine-like stimulus properties in an operant drug discrimination bioassay in rodents.

To evaluate whether the novel antidepressant paroxetine has any possible amphetamine-like actions, rats were trained to discriminate (+)-amphetamine sulphate in a standard two lever operant drug discrimination (DD) procedure using a fixed ratio 10 schedule of food reinforcement with a quantal, lever selection, index of the amphetamine stimulus. The 'training' dose of amphetamine was 1 mg kg-1, i.p. Rats trained with this dose of amphetamine (n = 15) learned the drug discrimination rapidly over 30 training sessions and discriminative performance in these animals was subsequently maintained at a high level of accuracy (90% correct) over a prolonged time. In tests in these trained animals, amphetamine itself and the antidepressant agents nomifensine and tranylcypromine all produced clear, unequivocal dose-related generalization to amphetamine with ED50s of 0.2, 0.5 and 1.6 mg kg-1 respectively (as determined by probit analyses). In tests with paroxetine hydrochloride it was established that, over the dose range 0.3 to 10 mg kg-1, no evidence was seen of generalization to the amphetamine stimulus. These data confirm earlier studies which suggested that some antidepressants may possess abuse potential because of their ability to induce amphetamine-like internal states. In contrast, paroxetine is devoid of such properties.

Animals↗

Discriminative stimulus effects of 5.6 mg/kg pregnanolone in DBA/2J and C57BL/6J inbred mice.

Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as gamma-aminobutyric acid(A) (GABA(A)). Two neurosteroids, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), possess anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination assays. A previous study examining the discriminative stimulus effects of 10 mg/kg pregnanolone in DBA/2J and C57BL/6J mice showed pregnanolone's discriminative stimulus to be mediated primarily through GABA(A) positive modulation. This study examined the discriminative stimulus effects of a lower training dose (5.6 mg/kg) of pregnanolone in DBA/2J and C57BL/5J mice. Twelve male DBA/2J mice and 12 male C57BL/6J mice were trained to discriminate 5.6 mg/kg pregnanolone. GABA(A)-receptor positive modulators, neuroactive steroids, NMDA receptor antagonists, and 5-HT(3) receptor agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for pregnanolone. In the DBA/2J mice, NMDA receptor antagonists showed generalization to the discriminative stimulus cues of pregnanolone, an effect not seen in the C57BL/6J mice. 5-HT(3) receptor agonists and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either strain. AlloTHDOC and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest GABA(A)-receptor positive modulation as the predominant receptor mechanism mediating the discriminative stimulus effects of pregnanolone. NMDA receptor antagonism was suggested in the DBA/2J mice and may represent a heterogenous cue produced by the lower training dose of pregnanolone.

Animals↗

Characterization of ion channels in stimulus-secretion coupling in pancreatic islets.

The regulation of insulin secretion from beta-cells of the pancreatic islets of Langerhans is a highly integrated process involving several plasma membrane ion channels. The key to our understanding of the normal process is the hypothesis that glucose-induced closure of K+ channels leads to a depolarization of the cell membrane potential and the opening of voltage-gated Ca2+ channels. Support for this is provided by direct electrophysiological recordings of ion channel activity, and by recent data that have revealed how gene defects in ion channel subunits leads to the loss of regulated insulin secretion. Here, we review the general features of stimulus-response coupling in beta-cells, and how novel initiatives are providing key insights into beta-cell pathogenesis.

Adenosine Triphosphate↗

Involvement of mesolimbic kappa-opioid systems in the discriminative stimulus effects of morphine.

The neuroanatomical basis of opiate addiction has been studied using a variety of behavioural techniques. The aim of the present study was to investigate the role of mesolimbic opioid systems, in particular kappa-opioid systems, in the expression of the discriminative stimulus effects of abused drugs. Rats were trained to discriminate morphine (3.0 mg/kg s.c.) from saline under a fixed ratio schedule of food reinforcement. Once rats had acquired the discrimination, a randomized sequence of different doses of the highly selective kappa-opioid receptor agonist U69593 (0.02-0.16 mg/kg s.c.) was given 20 min prior to a systemic morphine injection. U69593 dose-dependently blocked the morphine discrimination. It is important to note that U69593 at these doses failed to generalize to the systemic morphine cue. The site of action by U69593 (0.02-0.16 microgram) was examined by microinjecting discrete amounts into target brain regions. Intra-nucleus accumbens injections of U69593 dose-dependently blocked the systemic morphine cue, whereas, U69593 failed to generalize to the discriminative stimulus. The same doses did not affect morphine discrimination after intra-ventral tegmental area or striatum injections. Besides the rewarding effects of drugs of abuse, the discriminative stimulus properties of these agents are seen as a major factor in drug seeking behaviours. The present study shows that the discriminative effects of morphine, a measure of the subjective effects of this drug can be blocked by the activation of kappa-opioid receptors located in the nucleus accumbens. In view of these findings which show that the activity of endogenous potassium-opioid systems (dynorphin) may serve as physiological antagonists to counteract the effects of morphine, potassium-agonists therefore may be useful in the treatment of opioid addictions.

Analgesics↗

Favored patterns in spike trains. II. Application.

In this paper we apply the two methods described in the companion paper (4) to experimentally recorded spike trains from two preparations, the crayfish claw and the cat striate cortex. Neurons in the crayfish claw control system produced favored patterns in 23 of 30 spike trains under a variety of experimental conditions. Favored patterns generally consisted of 3-7 spikes and were found to be in excess by both quantized and template methods. Spike trains from area 17 of the lightly anesthetized cat showed favored patterns in 16 of 27 cases (in quantized form). Some patterns were also found to be favored in template form; these were not as abundant in the cat data as in the crayfish data. Most firing of the cat neurons occurred at times near stimulation, and the observed patterns may represent stimulus information. Favored patterns generally contained up to 7 spikes. No obvious correlations between identified neurons or experimental conditions and the generation of favored patterns were apparent from these data in either preparation. This work adds to the existing evidence that pattern codes are available for use by the nervous system. The potential biological significance of pattern codes is discussed.

Action Potentials↗

Auditory temporal integration and the power function model.

The auditory temporal integration function was studied with the objective of improving both its quantitative description and the specification of its principle independent variable, stimulus duration. In Sec. I, temporal integration data from 20 studies were subjected to uniform analyses using standardized definitions of duration and two models of temporal integration. Analyses revealed that these data were best described by a power function model used in conjunction with a definition of duration, termed assigned duration, that de-emphasized the rise/fall portions of the stimuli. There was a strong effect of stimulus frequency and, in general, the slope of the temporal integration function was less than 10 dB per decade of duration; i.e., a power function exponent less than 1.0. In Sec. II, an experimental study was performed to further evaluate the models and definitions. Detection thresholds were measured in 11 normal-hearing human subjects using a total of 24 single-burst and multiple-burst acoustic stimuli of 3.125 kHz. The issues addressed are: the quantitative description of the temporal integration function; the definition of stimulus duration; the similarity of the integration processes for single-burst and multiple-burst stimuli; and the contribution of rise/fall time to the integration process. A power function in conjunction with the assigned duration definition was again most effective in describing the data. Single- and multiple-burst stimuli both seemed to be integrated by the same central mechanism, with data for each type of stimulus being described by a power function exponent of approximately 0.6 at 3.125 kHz. It was concluded that the contribution of the rise/fall portions of the stimuli can be factored out from the rest of the temporal integration process. In Sec. III, the conclusions that emerged from the review of published work and the present experimental work suggested that auditory temporal integration is best described by a power function in conjunction with the assigned duration definition. The exponent for the power function is typically less than 1.0, and varies with frequency and hearing level. Second, a means of empirically assaying the contribution of the rise-fall portions of the stimuli is presented and evaluated. Finally, properties of a central auditory integrator are hypothesized.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Serotonin receptor subtype mediation of the interoceptive discriminative stimuli induced by 5-methoxy-N,N-dimethyltryptamine.

Male Wistar rats were trained to discriminate the interoceptive effects of 5-methoxy-N,N-dimethyltryptamine (5-OMe-DMT; 1.25 mg/kg, IP) from saline in a two-lever operant chamber. Following discrimination learning, the following drugs (with ED50 dose in mg/kg IP) dose-dependently generalized: lysergic acid diethylamide (LSD, 0.04), 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.11), 6-methoxy-4-(dipropyl-amino)-1,3,4,5-tetrahydrobenz(c,d)indole hydrochloride (BAY R 1531, 0.15), 5-OMe-DMT itself (0.63), ipsapirone (TVX Q 7821, 2.7), and buspirone (3.8). The potencies of these drugs in generalization tests were best correlated with their binding affinities for the 5-HT1A serotonin receptor subtype (as measured by displacement of 3H-ipsapirone in the hippocampus). Drugs not, or only partially generalizing included quipazine, bufotenin, m-trifluoromethylphenylpiperazine (TFMPP), 5-methoxy-3(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole succinate (RU 24969), citalopram, clomipramine, 1,4-dihydro-2,6-dimethyl-3-nitro-4(2-trifluoromethylphenyl)-pyridine-5- carboxylate (BAY K 8644), the buspirone metabolite 1-pyrimidinyl-piperazine (1-PP), methysergide, metergoline, and metitepine. Of the last three compounds with antagonistic activity at 5-HT receptors, as well as ketanserin, pizotifen, and ritanserin, only metitepine and pindolol could fully block the 5-OMe-DMT stimulus. Pizotifen blocked the generalization of quipazine fully, that of 5-OMe-DMT only partially, and that of ipsapirone not at all. These data indicate that the 5-HT1A receptor subtype is strongly involved in the transduction of the interoceptive discriminative stimuli induced by 5-OMe-DMT, with 5-HT2 agonism also playing a possible role.

Animals↗

Environmental determinants of enhanced sensitivity to the behavioral effects of naltrexone.

Dose-effect curves for naltrexone were determined in three squirrel monkeys studied sequentially under four different schedule conditions: a schedule of shock postponement; a fixed-interval schedule of shock presentation; a fixed-ratio schedule of food presentation; and a fixed-ratio schedule of stimulus-shock termination. In general, responding under the shock-postponement or the fixed-interval schedules was decreased minimally by doses of naltrexone up to 30 mg/kg, and these effects were not altered appreciably after daily injections of naltrexone under the fixed-interval schedule. Under the fixed-ratio schedule of food presentation naltrexone (0.3 to 10 mg/kg) produced dose-related decreases in responding, and after repeated daily injections of naltrexone the dose-effect curve was shifted more than 3-fold to the left. Under the fixed-ratio schedule of stimulus-shock termination, however, this supersensitivity to naltrexone was not apparent: responding was decreased appreciably only after 17.6 mg/kg of naltrexone. When the fixed-ratio schedule of food presentation was reinstated, the supersensitivity to naltrexone observed previously under this schedule was not evident initially, but reappeared quickly in two of the monkeys. The greater rate-decreasing effects of naltrexone under the fixed-ratio schedules compared to the other schedules may reflect a dependency related to the control rate of responding. Supersensitivity to naltrexone occurred only under the fixed-ratio schedule of food presentation and could be reversed temporarily by intervening exposure to the schedule of stimulus-shock termination. These results extend earlier findings that the behavioral effects of drugs can be dependent upon both past and present environmental influences.

Animals↗

Rate fluctuations and fractional power-law noise recorded from cells in the lower auditory pathway of the cat.

The noise properties of the sequence of action potentials recorded from adult-cat auditory nerve fibers and lateral superior olivary units have been investigated under various stimulus conditions. Large fluctuations exhibited by the spike rate, and spike clusters evident in the pulse-number distribution, both indicate an unusual underlying sequence of neural events. We present results demonstrating that (i) the firing rate calculated with different averaging times can exhibit self-similar behavior; (ii) the pulse-number distribution remains irregular even for large numbers of samples; (iii) the spike-number variance-to-mean ratio increases with the counting time T in fractional power-law fashion for sufficiently large T; and (iv) the exponent in the power law generally depends on the stimulus level. The results obtained in our laboratories support the notion that all auditory-nerve and LSO units exhibit fractal neural firing patterns, as indicated earlier by Teich (IEEE Trans. Biomed. Eng. 36, 150-160, 1989).

Action Potentials↗

A comparison of N,N-dimethyltryptamine, harmaline, and selected congeners in rats trained with LSD as a discriminative stimulus.

1. A series of N-substituted tryptamines was compared with a series of beta-carbolines in rats trained to discriminate LSD (0.1 mg/kg) from saline. 2. Intermediate levels of substitution were elicited by MDMT (76.4%), DMT (77.9%), and DET (48.7%). 6-F-DET produced 41.3% LSD-appropriate responding at a dose of 6.0 mg/kg but only 4 of 8 subjects completed the test session thus precluding statistical analysis. Bufotenine (25.8%) also failed to substitute. Although none of the tryptamines substituted completely for LSD, the pattern of substitution is consonant with what is known of their activity in humans. MDMT, DMT, and DET are well established in the literature as hallucinogens but the same cannot be said for 6-F-DET and bufotenine. 3. Of the beta-carbolines tested, none substituted for LSD completely and only harmane elicited intermediate substitution (49.5%). No significant generalization of the LSD stimulus to 6-methoxyharmalan, harmaline, or THBC was observed. Thus, in contrast to the tryptamines, scant ability to substitute for LSD was observed in the beta-carbolines tested. 4. Taken together, the present data indicate that the representative tryptamines employed in the present study exhibit greater similarity to the LSD stimulus than do representative beta-carbolines. The receptor interactions responsible for these differences remain to be determined.

Animals↗

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