Biomedical subjects

J L Slangen

Publications and source records attributed to J L Slangen.

At least 55 records · Page 3Linked to original sources

PubMed1990

The long-term effects of diazepam and pentylenetetrazol on the potentiated startle response.

Stress desensitization is observed as a decrease in the disruptive effects of a stressor on behavior when the organism is repeatedly exposed to the stressor. For instrumental behavior, stress desensitization was also reported for rats preexposed to anxiogenic drugs; stress sensitization was reported for rats preexposed to an anxiolytic compound. The present study investigated whether similar effects are found in a noninstrumental task situation. First, rats received 12 daily injections of pentylenetetrazol (PTZ, 20 mg/kg, IP), diazepam (DZP, 5 mg/kg, IP) or saline. After each injection the effect of the drugs on the acoustic startle reflex was measured. No drugs were given during the remainder of the experiment. Eight days later rats were given 5 days of Pavlovian fear conditioning to establish a light as a shock signal. During the next 3 days, potentiation of the startle response by the light was measured. None of the drug treatments had an effect on startle potentiation, indicating that stress sensitivity is not affected by previous administration of PTZ and DZP in a noninstrumental task. An explanation for the different effects found for instrumental and noninstrumental tasks is suggested.

Acoustic Stimulation↗

PubMed1990

Discriminative stimulus properties of flesinoxan.

Different groups of rats were trained to discriminate either 0.3 mg/kg of flesinoxan (N = 13) or 0.1 mg/kg of 8-OH-DPAT (N = 7) from saline in a two-lever operant drug discrimination task using a fixed ratio 10 schedule of reinforcement. Once trained, animals in both groups displayed a dose-related decrease in discriminative performance upon administration of lower doses of the drug used in training. In generalization tests, flesinoxan generalized to 8-OH-DPAT in 8-OH-DPAT-trained animals and 8-OH-DPAT substituted for flesinoxan in flesinoxan-trained animals. Buspirone substituted partially for both the flesinoxan and the 8-OH-DPAT cue. The results of the present study indicate similarity between the discriminative stimulus effects of flesinoxan and the stimulus produced by the 5-HT1A agonist 8-OH-DPAT. These results, coupled with the finding that flesinoxan has a significant affinity and selectivity for 5-HT1A binding sites, suggest that the stimulus effects of flesinoxan are mediated by a 5-HT1A mechanism.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1990

Brain benzodiazepine receptor-mediated effects on plasma catecholamine and corticosterone concentrations in rats.

The effects of the benzodiazepine (BDZ) receptor agonist chlordiazepoxide (CDP) and antagonist flumazenil (Ro 15-1788), given alone and in combination, on basal and novel environment stress (NES)-elevated plasma noradrenaline (NA), adrenaline (A) and corticosterone (CS) contents were investigated. When administered on their own, a medium dose of CDP (2.5 mg/kg) and a moderate dose of flumazenil (5 mg/kg) did not affect basal hormone levels. However, flumazenil potentiated the NES-induced CS elevation and suppressed the NA rise in response to NES. The 2.5 mg/kg dose of CDP attenuated the NES-elicited rise of CS and A, without changing the NES-enhanced NA concentrations. High doses of CDP (10 and 12.5 mg/kg), which elevated basal CS levels, prevented a further CS increase by NES and completely abolished the NA and A response to NES. The CDP effects on CS and NA were antagonized by pretreatment with flumazenil, in contrast to the CDP effect on A which was not blocked. The data indicate that brain (central-type) BDZ receptor systems are involved in regulating the neurosympathetic and adrenocortical, but not adrenomedullary, responses to mild stress.

Animals↗

PubMed1990

Behavioral models of memory and amnesia.

In modelling memory and amnesia, the different forms of cognition must be distinguished. For memory, distinctions between acquisition, storage, and retrieval must be made and the different kinds of memory (e.g., immediate, working, reference) identified. Other notions, such as attention, orientation, and vigilance also belong under the heading "cognition". Thus the term "cognition enhancer" is imprecise because it does not indicate which kind of cognition is to be enhanced. Animal models should be developed for each type of cognition, be based on information from the clinic, and attempt to be specific. Examples of models more specific than the passive avoidance test were discussed and included the radial maze, in which different kinds of memory could be analyzed and correlated with, for example, changes in central cholinergic activity. From the point of view of drug development an important distinction was made between "empirical" and "simulation" models. In other areas of psychopharmacology "empirical" models have been widely used because they show predictable responses to known reference compounds. In the field of cognition there are no generally recognized reference compounds and therefore no "empirical" models. There is therefore a need for "simulation" models which imitate the various aspects of cognition and its pathology. The major criterion for validating this kind of model is that it should show changes similar to those observed in humans either resulting from a particular pathology or from a particular drug treatment.

Amnesia↗

PubMed1990

Effects of chlordiazepoxide and buspirone on plasma catecholamine and corticosterone levels in rats under basal and stress conditions.

The effects of the classical benzodiazepine (BDZ) anxiolytic drug chlordiazepoxide (CDP) and the non-BDZ anxiolytic agent buspirone (BUSP) on basal and stress-induced plasma noradrenaline (NA), adrenaline (A) and corticosterone (CS) release were investigated. Male Wistar rats provided with a permanent heart catheter and a permanent stomach catheter were used. Placement of rats into an unfamiliar cage (novel environment stress; NES), that elevated CS, NA and A, was used as a stressor. Acute administration of CDP (1-27 mg/kg) produced dose-related increases in basal plasma CS secretion but was without effect on basal NA content. The largest dose of CDP caused a slight short-term A elevation. The CDP effect on basal CS secretion tolerated with repeated drug treatment and was completely blocked after acute pretreatment with the BDZ receptor antagonist flumazenil. Acute treatment with BUSP (2-20 mg/kg) caused a marked and dose dependent increase in the plasma levels of A, NA and CS. A medium dose of CDP (9 mg/kg) attenuated the NES-induced CS and A elevations. A high dose of CDP (27 mg/kg), that elevated basal CS release, prevented a further CS increase by NES and inhibited the NA and A response to NES. BUSP (2 or 20 mg/kg) was not effective in attenuating the NES-elicited rise of CS, NA and A. However, the 20 mg/kg dose of BUSP actually enhanced the NES-induced A response. In conclusion, BUSP did not show the BDZ-like property to inhibit stress-induced elevations in CS, NA and A. Furthermore, the findings suggest that CDP and BUSP differentially affect the mechanisms controlling CS, NA and A release during basal and stress conditions.

Analysis of Variance↗

PubMed1989

Discriminative stimulus properties of midazolam: comparison with other benzodiazepines.

Rats (N = 12) were trained to discriminate midazolam (1 mg/kg, IP) from vehicle in a food reinforced operant conditioning procedure. Midazolam, flunitrazepam, diazepam, chlordiazepoxide and pentobarbital showed dose-dependent substitution for midazolam. Buspirone and Ro 15-1788 did not substitute for midazolam. The midazolam cue was dose-dependently antagonized by Ro 15-1788. In rats (N = 12) trained to discriminate chlordiazepoxide (3 mg/kg, IP) from vehicle midazolam, flunitrazepam, diazepam and chlordiazepoxide substituted completely and dose dependently for chlordiazepoxide. The relative potency of chlordiazepoxide and diazepam was three times less in the midazolam-trained animals than in the chlordiazepoxide-trained animals. Response rate and latency data further support the main finding that the midazolam cue is similar, but not identical to the cue of classical benzodiazepines.

Animals↗

PubMed1989

Effects of midazolam, DMCM and lindane on potentiated startle in the rat.

Forty-eight male Wistar rats were exposed to contingent light-shock combinations and 48 rats received light and shock stimuli in a random order. One day after fear conditioning the animals were tested for startle potentiation after injection of midazolam (0, 0.5, 1.0, 2.0 mg/kg, IP) or DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; 0, 0.1, 0.2, 0.4 mg/kg IP) or lindane (0, 7.5, 15.0, 30.0 mg/kg PO). Midazolam attenuated potentiated startle dose dependently and the inverse benzodiazepine agonist DMCM had the opposite effect. The effects of lindane on startle amplitudes were identical to those of DMCM, indicating that lindane has anxiogenic effects on behavior. It is suggested that the anxiogenic effects of lindane are mediated by an effect at the GABA-ionophore complex.

Acoustic Stimulation↗

PubMed1989

Effects of fasting on plasma catecholamine, corticosterone and glucose concentrations under basal and stress conditions in individual rats.

Plasma noradrenaline (NA), adrenaline (A), corticosterone (CS) and glucose concentrations were determined in blood sampled via a cardiac catheter from freely moving male rats under ad lib fed and 24 hr food deprived conditions using a repeated measures within-subject design. Resting plasma NA and glucose levels were lower in the fasted condition as compared to the fed situation. One day of refeeding reinstated the decreased NA and glucose values to prefasting level. Exposing 24 hr food deprived animals to the psychological stress of a novel environment resulted in larger NA and glucose increases, an unchanged A release and a lower CS rise in comparison with the responses during the free feeding state. The results show the usefulness of a within-subject design to detect subtle changes in plasma NA contents. Additionally, the data support the concept of selective control of the sympathetic nervous system and adrenal medullae. It is argued that hypothalamic noradrenergic mechanisms may be linked to the fasting-induced effects on the sympatho-adrenal system.

Animals↗

PubMed1989

Plasma catecholamine and corticosterone responses to predictable and unpredictable noise stress in rats.

Plasma noradrenaline (NA), adrenaline (A) and corticosterone (CS) increases were determined in individual rats subjected to either 20 regularly or irregularly scheduled white-noise stimulations (4 min, 100 dBA). Blood was frequently sampled during the first and twentieth noise exposure, and during a reexposure after 24 hr. During the sampling periods, behavioral activities of the rats were recorded. The initial noise-induced CS release was partially reduced following the regular noise presentations. The increase after irregular presentations remained high. The difference in adrenocortical responsiveness between regular and irregular exposure persisted for 24 hr. The NA response to noise was partially attenuated following irregular administration of noise. However, regular exposure produced increased NA levels prior to noise presentation and a subsequent decrease during stimulation. After 24 hr, noise evoked an exaggerated initial NA release in the regular group. The noise-elicited rise in A was completely abolished after 20 noise presentations irrespective of whether these were applied regularly or irregularly. Reexposure after 24 hr evoked again a significant A response in both groups. No differences were observed in the habituation pattern of behavioral reactions among the regular and irregular groups. The results show that the sympathetic neural, adrenomedullary and adrenocortical systems differ in degree and speed of adaptation to intermittent stressful stimuli and in sensitivity to the predictability of stressors.

Animals↗

PubMed1989

"Initial-" and "change-orienting reactions": an analysis based on visual single-trial event-related potentials.

The present study was concerned with brain potentials elicited by, respectively, the first of a series of stimuli ("initial-orienting reaction", I-OR), and infrequent deviants ("change-orienting reaction", C-OR). Single-trial event-related potentials (ERPs) to visual stimuli were estimated from recordings at Oz, Pz, Cz and Fz. The design included both a habituation series as well as a series of occasional deviant trials against a background of standards. This was done with both task-relevant and neutral stimuli, and in two interstimulus interval (ISI) conditions: 2.45 s and 8.45 s. In the latter ISI condition, skin conductance responses (SCRs) were recorded as well. Decrease (Habituation) in the habituation series was found for a non-specific N1, a posteriorly distributed P3, and the SCR, but not for P2-N2. Deviant stimuli produced an enhancement of the central P2-N2, the P3, the N1 (on the first few deviant trials only, in both ISI conditions), and the SCR (with task-relevant stimuli only). Elongation of ISI delayed both short-term and long-term decrease of P3, but had no effect on enhancement of P2-N2 due to stimulus deviance. It was concluded that, with respect to ERP parameters, the I-OR is marked by the N1, whereas the C-OR coincides with the P2-N2.

Adult↗

PubMed1988

Adaptation of plasma catecholamine and corticosterone responses to short-term repeated noise stress in rats.

Plasma noradrenaline (NA), adrenaline (A) and corticosterone (CS) concentrations were determined in blood frequently sampled via a cardiac catheter from freely moving rats exposed to three successive trials of white-noise stimulation (10 min, 100 dBA) with an intertrial interval of 30 min. During the sampling period, behavioral activities of the rats were recorded. It was demonstrated that the first exposure to noise induced a specific temporal pattern of neuroendocrine changes: Plasma A and NA contents increased rapidly and peaked early after stimulus onset but their peak-latencies were different (1 and 5 min, respectively). Noise offset was followed by quick return to basal levels. The changes in plasma CS concentrations were considerably slower in onset and slower in decline. The second and third exposure to this type of stressor resulted in attenuated hormonal responses and a reduced decrement of the NA/A-ratio, concurrent with a gradually less intense behavioral reaction. This differential pattern of plasma NA, A and CS responses following repetitive exposure to identical stressors, referred to as adaptation, is discussed with regard to the biochemical changes at various levels of the neuroendocrine systems involved.

Adaptation, Physiological↗

PubMed1988

Ethanol suppression of schedule-controlled responding: interactions with Ro 15-4513, Ro 15-1788 and CGS 8216.

Rats (N = 14) were trained to respond under a five seconds differential reinforcement of low rate (DRL 5'') schedule and under a fixed ratio 10 (FR10) schedule of reinforcement. Ro 15-1788 did not influence the number of responses in the DRL 5'' schedule, but increased responding in the FR10 schedule. Ethanol (ETOH, 1250 mg/kg) and CGS 8216 (5 mg/kg) suppressed responding in both schedules and these effects were not antagonized by Ro 15-1788. The response suppressing effects of ETOH in both schedules were not influenced by CGS 8216. These results indicate that the response suppressing effects of ETOH and CGS 8216 are not mediated by the BDZ receptor. Ro 15-4513 suppressed responding strongly in the FR10 schedule. The response suppressing effects of Ro 15-4513 were additive with the response suppressing effects of ETOH. In rats (N = 11) trained to respond under a variable interval 40 seconds-fixed ratio 10 (VI 40''-FR10) schedule Ro 15-4513 dose-dependently suppressed responding. These results indicate that Ro 15-4513 has sedative effects and is not able to antagonize all the behavioral actions of ETOH.

Alcohol Deterrents↗

PubMed1988

Effects of task relevance on habituation of visual single-trial ERPs and the skin conductance orienting response.

Single-trial event-related potentials were recorded at Oz, Pz, Cz, and Fz, concurrently with skin conductance reactions and fixation behavior in a habituation paradigm. A total of 48 subjects received 16 identical visual stimuli; 24 of them were instructed to pay attention, whereas the other half were given a neutral instruction. Two early negative components (N1 and N2), as well as a late positive component (P3) were identified. N1 and skin conductance reaction (SCR) showed fast decrement over trials, whereas N2 and P3 habituated slowly. Habituation of N1 and SCR was delayed by task instructions; N2 was hardly seen at all in the neutral condition. The task effects on N1 and N2 were observed only at Oz. It is concluded that the processing of relevant stimuli differs structurally from the processing of neutral stimuli; this difference may be observed even at a latency of 100 ms. The N1 appears to be related to the SCR, whereas this does not hold for P3; the N2 is related to selection negativities reported by other authors.

Adult↗

PubMed1988

Changes in plasma corticosterone and catecholamine contents induced by low doses of deltamethrin in rats.

The effects of low doses of (S)-alpha-cyano-3-phenoxybenzyl (1R)-cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate (Roussel UCLAF, Paris, France), (deltamethrin) upon sympathetic-adrenomedullary and pituitary-adrenocortical activity were investigated in rats by measuring plasma noradrenaline (NA), adrenaline (A) and corticosterone (CS) concentrations. Blood was sampled from freely-moving animals provided with heart catheters at short intervals up to 60 min after intravenous administration of deltamethrin (0.05, 0.15 and 0.45 mg/kg) or vehicle. Behavioral activity was recorded shortly after the sampling times. Time course and magnitude of the biochemical changes were compared with the effects of exposure to uncontrollable white noise in a similar sampling and recording procedure. Dose-dependent increases were observed for NA and A as well as for CS contents. The dose-response relations however, were different among the neuro-edocrine respondents. Discrete step-wise increases were observed for plasma CS only, indicating greater sensitivity for neurotoxical actions. Already at a dose of 0.15 mg/kg of deltamethrin, CS contents rose to values that were considerably higher than those found during noise exposure. In contrast, plasma CA concentrations increased to noise stress values only after the 0.45 mg/kg dose. The behavioral activity pattern appeared to resemble both CA patterns. The results suggest that rather low doses of deltamethrin elicit vigorous autonomic and neuro-endocrine responses that indicate high levels of stress, presumably caused by the neurotoxic effect of the insecticide.

Animals↗

PubMed1988

Effects of pyrethroids on the acoustic startle reflex in the rat.

The effects of NAK 1901 (Pentafluorbenzyl (1R, cis)-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-carboxylate) and cypermethrin ((S,R)-alpha-cyano-3-phenoxybenzyl-2,2-dimethyl (1R, 1S, cis, trans)-3-(2,2-dichlorovinyl) cyclopropane-carboxylate) (RU 24 501) on amplitude and prepulse inhibition of the acoustic startle reflex were studied in male Wistar rats. NAK 1901 (0, 1, 2.5, 4 mg/kg p.o.) enhanced the amplitude of the startle reflex in a dose-dependent way. Startle latency was not affected. Cypermethrin (0, 0.5, 1, 2 mg/kg p.o.) had no effect on the amplitude or the latency of the startle reflex. Both NAK 1901 and cypermethrin administration produced a dose-dependent increase in toxic signs and a dose-dependent increase in weight loss during the experimental session. None of the pyrethroids affected prepulse inhibition of the startle reflex. Because the neural substrate of the inhibitory processes involved in prepulse inhibition are probably of supraspinal origin, it is suggested that these substrates are not affected by pyrethroids.

Acoustic Stimulation↗

PubMed1988

Effects of type I and type II pyrethroids on the startle response in rats.

The effects of type I and type II pyrethroids on the acoustic startle response of male Wistar rats were studied in three experiments. Pyrethroids were administered p.o. in 0.2 ml corn oil. In Expt. 1, techn. cis-permethrin (0, 30, 60, 90 mg/kg) and techn. cis, trans-cypermethrin (0, 60, 90, 120 mg/kg) increased startle in a dose-dependent way, whereas overt behavior and habituation of the startle response were not affected. In Expt 2, NAK 1901 (0, 1, 2.5, 4 mg/kg) enhanced startle amplitudes dose dependently and deltamethrin (0, 2, 4, 6 mg/kg) had no effect on startle. After both deltamethrin and NAK 1901 toxic signs increased dose dependently but an effect on potentiation of the startle reflex was not found. In Expt. 3, deltamethrin (0, 2, 4, 6 mg/kg) was administered and the highest dose attenuated startle amplitudes significantly, whereas toxic signs increased dose dependently. Deltamethrin had no effect on habituation of the startle response. It is concluded that type I pyrethroids increase the amplitude of the startle reflex; this effect does not depend on the presence of overt signs of toxicity. Type II pyrethroids have dissimilar effects on startle. Results are discussed suggesting that the effects of type II pyrethroids on startle amplitude are mediated by an indirect metabolic effect and a direct effect at the site of the muscle.

Animals↗

PubMed1988

Acute effects of bromazepam on signal detection performance, digit symbol substitution test and smooth pursuit eye movements.

Effects of 6 and 12 mg bromazepam on reaction time, stimulus sensitivity and response bias in a 1-hour visual attention task, on smooth pursuit eye movements, and on performance in the digit symbol substitution test (DSST) were investigated in 12 healthy male volunteers. It was a placebo-controlled, double-blind, crossover study that used repeated measures. Three saliva samples and a blood sample were taken for correlating drug concentration and performance. Bromazepam lowered stimulus sensitivity dose-dependently. Response times for hits and response bias were affected by the 12-mg dose only. DSST performance decreased dose-dependently. Smooth pursuit was equally impaired by 6 and 12 mg. Concentrations in serum correlated with concentrations in saliva, but serum and saliva concentrations did not correlate with task performance.

Adolescent↗

PubMed1986

Effects of training dose on discrimination and cross-generalization of chlordiazepoxide, pentobarbital and ethanol in the rat.

Six groups of rats (N = 8), trained to discriminate chlordiazepoxide (5 or 20 mg/kg), pentobarbital (5 or 15 mg/kg) or ethanol (750 or 1500 mg/kg) from saline in a two-lever food-reinforced procedure, were tested for stimulus generalization with the three drugs. Training drug, but not training dose, affected the extent of generalization to a test drug; symmetrical generalization between chlordiazepoxide and pentobarbital and asymmetrical generalization between chlordiazepoxide and ethanol and between pentobarbital and ethanol was observed. Training dose level affected slope and ED50 of the generalization gradients of training drugs and substitution drugs, discriminative performance, response bias and threshold dose for response suppression. Indices of lever selection and percentage drug-appropriate lever responses yielded similar generalization maxima, slopes and ED50S. The potency of chlordiazepoxide relative to the potency of pentobarbital to induce drug stimulus generalization varied across the experimental groups. The results indicate differences between the discriminative effects of chlordiazepoxide, pentobarbital and ethanol. It is suggested that the discriminative effects of chlordiazepoxide, pentobarbital and ethanol are not based on their response rate modulating effects and that training dose is not a determinant for the extent of cross-generalization between these compounds.

Animals↗