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 potentation 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.     

Effects of d-amphetamine and chlordiazepoxide on positive conditioned suppression

Six rats lever-pressed under a variable-interval 80-sec food reinforcement schedule. After responding had stabilized, an 8-sec tone terminating with food delivery was superimposed on the variable-interval schedule on the average once every five minutes without regard to the animal's behavior. This positive conditioned suppression procedure consistently reduced responding during the pre-food stimulus (tone). Neither d-amphetamine (0.5, 1.0, 2.0 mg/kg) nor chlordiazepoxide (7.5, 15, 30 mg/kg) significantly affected the relative suppression produced by the tone. Instead, both drugs produced generally non-selective effects, similarly affecting response rate in the presence and absence of the tone.     

Intraspecies aggression in rats: Effects of d-amphetamine and chlordiazepoxide

d-Amphetamine sulfate and chlordiazepoxide hydrochloride, administered to either the dominant or subordinate rat, altered several components of fighting behavior in a dose-dependent biphasic manner. Stereotypic sequences of attack, threat, defense, and submission were generated between pairs of previously isolated Sprague-Dawley rats by extinction of a food-reinforced response. Low doses of amphetamine (0.05, 0.1 mg/kg) and chlordiazepoxide (2.5, 5.0 mg/kg) given i.m. to the dominant rat 30 min prior to 15 min tests increased attack bites and leaps and the display of aggressive postures and threats, whereas higher doses of both drugs (0.5, 1.0 mg/kg amphetamine; 20 mg/kg chlordiazepoxide) suppressed attacks and threats. Amphetamine and chlordiazepoxide, administered to the subordinate rat, caused a more prolonged display of submissive-supine and defensive-upright postures; chlordiazepoxide (10.0, 20.0 mg/kg) prolonged immobile crouching whereas amphetamine (0.5, 1.0 mg/kg) greatly reduced this response. Drugged subordinate rats also provoked more attacks and threats by the non-drugged opponents. The multi-response analysis of fighting reveals that various elements of aggressive and defensive-submissive behavior patterns are differentially sensitive to drug action. The results indicate that amphetamine and chlordiazepoxide can facilitate or inhibit attack or defense depending on the dose level and which of the opponents was injected, but do not reverse dominance-subordination relationships.     

The light-enhanced startle paradigm as a putative animal model for anxiety: effects of chlordiazepoxide,flesinoxan and fluvoxamine

RATIONALE: Recently, a new putative animal model of anxiety, "light-enhanced startle" was introduced. By placing a rat in a brightly lit environment, which is a naturally aversive stimulus to rats, the amplitude of the startle response to a startle-eliciting noise burst is increased. OBJECTIVES: The present study aimed to determine the predictive validity of the light-enhanced startle as a putative model for anxiety. METHODS: The effects of the GABA(A)-benzodiazepine receptor agonist chlordiazepoxide (CDP), the 5-HT1A receptor agonist flesinoxan and the specific 5-HT reuptake inhibitor fluvoxamine on light-enhanced startle were studied. RESULTS: Both CDP and flesinoxan decreased startle potentiation, whereas fluvoxamine was devoid of any effects on potentiation. Effects on baseline startle amplitude were only seen after CDP administration. CONCLUSIONS: The present experiment provides evidence for the predictive validity of the light-enhanced startle as an animal model for anxiety. Due to the use of an unconditioned anxiogenic stimulus, the light-enhanced startle offers several benefits over animal models that depend on conditioning. Drug effects can be ascribed more directly to effects on anxiety, as opposed to memory retrieval and, as shown in this study, non-specific drug effects can easily be detected without the interference of contextual fear.     

Validating a human model for anxiety using startle potentiated by cue and context: the effects of alprazolam,pregabalin, and diphenhydramine

Background  Fear-potentiated startle has been suggested as a translational model for evaluating efficacy of anxiolytic compounds in humans. Several known anxiolytic compounds have been tested as well as several putative anxiolytics. Because results of these studies have been equivocal, the aim of the present study was to examine another pharmacological permutation of the human potentiated startle model by comparing two anxiolytic agents to a non-anxiolytic sedative and placebo. Methods  Twenty healthy volunteers participated in a double-blind, placebo-controlled, cross-over study with four sessions in which they received single doses of the anxiolytics alprazolam (1 mg) and pregabalin (200 mg), as well as diphenhydramine (50 mg) as a non-anxiolytic sedative control and placebo. The design included a cued shock condition that presumably evokes fear and an unpredictable shock context condition presumably evoking anxiety. Results  None of the treatments reliably reduced either fear- or anxiety-potentiated startle. Alprazolam and diphenhydramine reduced overall baseline startle. Alprazolam was found to only affect contextual anxiety in a statistical significant way after two subjects who failed to show a contextual anxiety effect in the placebo condition were excluded from the analysis. Pregabalin did not significantly affect any of the physiological measures. Discussion  The negative findings from this study are discussed in terms of methodological differences between designs and in variability of startle both between and within study participants. Conclusion  Even though fear-potentiated startle may be used to translate preclinical evidence to human populations, methodological issues still hamper the application of this model to early screening of putative anxiolytic drugs.     

Effects of d-amphetamine,scopolamine, chlordiazepoxide and diphenylhydantoin on self-stimulation behavior and brain acetylcholine

The effects of d-amphetamine (0.25–8), scopolamine (0.25–8), chlordiazepoxide (2.5–40), and diphenylhydantoin (25–75), given i.p. or s.c. on a mg/kg basis, were studied on self-stimulation behavior in the male albino rat. The dose-effect relationships, the role of baseline rates of responding and their effects on brain acetylcholine (ACh) were determined in rats trained to self-stimulate for electrical reward in the lateral posterior hypothalamus. The effects of d-amphetamine were both dose and baseline-rate dependent. Low-moderate doses (0.5–2.0 mg/kg inclusive) facilitated self-stimulation and larger doses (2.0 to 8.0 mg/kg) depressed responding. Baseline rates before d-amphetamine administration were extremely important in the effect observed. Low rates of responding were facilitated and high rates were depressed by this agent. The effects of scopolamine in a wide range of dosage were less consistent. A small dose (0.5 mg/kg) facilitated only transiently self-stimulation and larger doses (1–8 mg/kg) tended to depress this behavior. Baseline rate effects were less important but high-rate responders were usually depressed by scopolamine.The effects of chlordiazepoxide were dose-dependent. A dose of (5 mg/kg) caused facilitation but larger doses (10–40 mg/kg) produced depression of selfstimulation irrespective of baseline rates. However, high-rate stimulators showed the most dramatic increases with 5 mg/kg of chlordiazepoxide. In contrast, diphenylhydantoin (25–75 mg/kg) usually depressed self-stimulation. Low rate self-stimulators showed the most marked depressant effects.Brain ACh was progressively reduced by handling of naive animals, injection of saline, and 1/2 h of self-stimulation and escape behavior. Animals not allowed to self-stimulate but given d-amphetamine (2.0 mg/kg), scopolamine (2.0 mg/kg) showed a significant decrease in brain ACh. Self-stimulation, in addition to medication with the various drugs, showed a trend for further reduction in brain ACh but the differences were not statistically significant.Supported in part by Grant MH-11846 (to EID) and MH-11627 (to JO), U.S. Public Health Service.     

Effects of chlordiazepoxide,ripazepam and d-amphetamine on conditioned acceleration of timing behaviour in rats

The lever-pressing behaviour of three rats was maintained by a schedule in which food reinforcement was obtained by any response which was emitted at least 15 s after the previous response (DRL 15 s). When performance on this schedule had stabilised, the animals were presented intermittently with 1-min periods of a white noise stimulus, the termination of which was accompanied by the delivery of a mild electric footshock. This procedure led to reliable increases in response rates during the stimulus although responding at other times continued to be appropriate to the DRL 15-s schedule. Administration of the benzodiazepine chlordiazepoxide (1, 3, 10, 17 and 30 mg/kg) and of ripazepam (1, 3, 10, 30 and 56 mg/kg), a non-benzodiazepine reported to have anxiolytic properties, increased response rates on the DRL baseline while decreasing the acceleration of responding produced by the preshock stimulus. Baseline response rates were also increased by d-amphetamine (0.25, 0.5, 1.0 and 2.0 mg/kg) and at the higher doses this drug completely abolished the accelerated responding during the preshock stimulus. Although the effects of chlordiazepoxide and ripazepam are consistent with the suggestion that these drugs may attenuate the behavioural effects of aversive stimuli, in this experiment the behavioural effects of d-amphetamine were similar in many respects.     

Buspirone, chlordiazepoxide and diazepam effects in a zebrafish model of anxiety

Zebrafish are becoming more widely used to study neurobehavioral pharmacology. We have developed a method to assess novel environment diving behavior of zebrafish as a model of stress response and anxiolytic drug effects. In a novel tank, zebrafish dwell in the bottom of the tank initially and then increase their swimming exploration to higher levels over time. We previously found that nicotine, which has anxiolytic effects in rodents and humans, significantly lessens the novel tank diving response in zebrafish. The specificity of the diving effect was validated with a novel vs. non-novel test tank. The novel tank diving response of zebrafish was tested when given three anxiolytic drugs from two different chemical and pharmacological classes: buspirone, chlordiazepoxide and diazepam. When the test tank was novel the diving response was clearly seen whereas it was significantly reduced when the test tank was not novel. Buspirone, a serotonergic (5HT_1A receptor agonist) anxiolytic drug with some D₂ dopaminergic effect, had a pronounced anxiolytic-like effect in the zebrafish diving model at doses that did not have sedative effects. In contrast, chlordiazepoxide, a benzodiazepine anxiolytic drug, which is an effective agonist at GABA-A receptors, did not produce signs of anxiolysis in zebrafish over a broad dose range up to those that caused sedation. Diazepam another benzodiazepine anxiolytic drug did produce an anxiolytic effect at doses that did not cause sedation. The zebrafish novel tank diving task can be useful in discriminating anxiolytic drugs of several classes (serotonergic, benzodiazepines and nicotinic).     

Effects of chlordiazepoxide and secobarbital on film-induced anxiety

Summary Normal college students were given a single dose of chlordiazepoxide, secobarbital or placebo 85 min before being shown an anxiety-inducing film. Measures of sedation and of subjective anxiety were taken before and after the film. Results indicate that chlordiazepoxide and secobarbital had a measurable sedative action compared with placebo. Neither medication showed a significant anti-anxiety effect.This project was supported by NIMH grants MH-7753, MH-08954, a GRS grant to University Hospital, and by Roche Laboratories through Dr. Stanley Gould who also kindly supplied the chlordiazepoxide (Librium). The authors are pleased to acknowledge the assistance of Kim Atkinson, Susan Saaz, Betsy Janes, Andrew Strasfogel, George Fishman, and Mary Sheldon. Medical screening was done by Robert Rood, M.D. Films were borrowed from Audio-Visual Support Center, Mr. R. A. Cudworth, Director, First Army Base, Boston, and from the Boston Public Library.     

Dissociable effects of d-amphetamine,chlordiazepoxide and α-flupenthixol on choice and rate measures of reinforcement in the rat

The role of reinforcers in influencing choice was studied by use of a schedule that included a random intermixing of reinforced and explicitly non-reinforced components. The just-reinforced response had a high likelihood of being repeated (win-stay), although there was no differential reinforcement for doing so, whereas responses just followed by explicit non-reinforcement had a very low probability of repetition (lose-stay). Non-parametric indices based on the theory of signal detection were used to derive a choice measure of reinforcement which was independent of alterations in average response rate. Treatments with d-amphetamine (0.2-4.5 mg/kg), chlordiazepoxide (0.25-16 mg/kg) and alpha-flupenthixol (0.03-0.6 mg/kg) showed that changes in the choice measure could be dissociated from changes in the response rate. These findings were supported by extinction and satiation tests.     

Effects of nicotine,nicotine monomethiodide,lobeline, chlordiazepoxide., meprobamate and caffeine on a discrimination task in laboratory rats

Hungry rats were trained on a discrimination task in order to obtain food rewards. During each experimental session, discrete stimuli of 1 min duration were delivered through a small speaker in the experimental chamber at random intervals on the average of once every 2 min. Lever responses in the presence of a light and tone were correct and produced food rewards. Lever responses in the presence of the light stimulus were incorrect and were punished by total inactivation of the experimental chamber. Rats were selected for this experiment based on their inability to acquire the discrimination task even after six months of training. Administration of nicotine, lobeline, chlordiazepoxide and meprobamate produced an improvement in discrimination performance through a reduction of responses to incorrect stimuli. Caffeine and nicotine monomethiodide, the quaternary salt of nicotine, were without effect on the discrimination.     

Effects of nicotine on the acoustic startle reflex amplitude in rats

The acoustic startle reflex was used to measure changes in sensorimotor reactivity in response to nicotine administration and cessation. Male rats received saline, 6 mg/kg/day or 12 mg/kg/day nicotine delivered subcutaneously by osmotic minipumps. The pumps delivered their contents during a 10-day period of implantation, after which time they were explanted. Animals were tested for startle reflex amplitudes using two levels of white noise bursts prior to pump implantation, on days 1 and 7 of nicotine or saline administration, and on several days following drug cessation. Nicotine produced a dose-dependent increase in startle amplitude during the period of administration that decreased during cessation. Results are interpreted in terms of nicotine's actions to enhance attentional processes.This research was supported in part by USUHS protocol CO 7223. The views and opinions contained herein are the private ones of the authors and do not represent the opinions of the Uniformed Services University of the Health Sciences, the Department of Defense, or the Armed Forces Radiobiology Research Institute.     

Latent inhibition of fear potentiated startle in rats

Non-reinforced pre-exposure to a prospective conditioned stimulus impairs subsequent conditioning. This phenomenon is termed latent inhibition. In this report, we demonstrate latent inhibition in a classical conditioning procedure, the fear-potentiated startle reflex. Normally, the startle response is enhanced in the presence of a conditioned stimulus that has previously been paired with an aversive stimulus. We show that fear-potentiation of the startle response is significantly less pronounced in rats that have been repeatedly pre-exposed to a conditioned light stimulus. Similar to other procedures reported in the literature, the administration of the psychostimulant drug amphetamine (1.0 mg/kg) before pre-exposure and conditioning disrupts latent inhibition. A good deal is known about the neuronal mechanisms underlying the acquisition and expression of fear-potentiated startle, and therefore this new procedure could be a useful tool for investigating the neuronal basis of latent inhibition.     

Predictive validity of the potentiated startle response as a behavioral model for anxiolytic drugs

The fear-potentiated startle (PSR) paradigm is a putative behavioral model for the determination of anxiolytic properties of drugs. The present study further investigated the predictive validity of the model. Predictive validity is high, when only drugs clinically used as anxiolytics attenuate PSR dose dependently. Results showed that startle potentiation decreased dose dependently after the administration of the anxiolytics CDP (2.5–10 mg/kg, IP) and alprazolam (1–3 mg/kg, IP). After administration of the clinically non-anxiolytic drugs amitriptyline (2.5–10 mg/kg, IP), carbamazepine (5–20 mg/kg, IP), fentanyl (0.0025–0.04 mg/kg, SC), naloxone (2.5–10 mg/kg, IP), nicotine (0.4–1.6 mg/kg, IP), alcohol (500–2000 mg/kg, IP), andd-amphetamine (0.6–2.4 mg/kg, IP), a dose-dependent decrease in startle potentiation was not found. The PSR correctly discriminated most of the drugs tested in clinically anxiolytic and clinically non-anxiolytic drugs. However, haloperidol behaved as a false positive, and results of nicotine and alcohol were at variance with results reported by others.     

Effects of methylphenidate and d-amphetamine on timing in the rat

Rats were trained to press a lever for food pellets provided according to a fixed interval 60-sec schedule of reinforcement. Probe trials (peak trials) assessed responding over two-min periods with no pellet delivered. The low rates of responding found early and late in probe trials were increased by methylphenidate and 1.0 mg/kg d-amphetamine (rate-dependent effect). Further, the mean time of responding (peak time) was shortened for both drugs (timing effect).     

Effects of d-amphetamine on operant behaviour in the rat

d-Amphetamine given intraperitoneally to albino rats at various doses produced different results, depending on the subjects: it increased the response rate in certain rats while decreasing it in others. These differences depend on the dose as well as on the control response rate. These observations are discussed in the light of possible individual differences at the level of autonomic reactivity.

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Résumé La d-amphétamine injectée I. P. à différentes doses à des rats blancs produit des effects qualitativement différents selon les sujets: chez certains, elle augmente le débit de réponse, chez d'autres, elle le diminue. Ces différences dépendent de la dose et du débit de réponse de contrÔle. Ces conclusions sont discutées à la lumière d'une éventuelle différence individuelle au niveau de la réactivité émotionnelle.

     

Interaction of d-amphetamine with pentobarbital and chlordiazepoxide: Effects on punished and unpunished behavior of pigeons

Key pecking of two pigeons was maintained under a multiple schedule of food presentation. In the presence of one keylight stimulus responding produced food according to a fixed-interval 5-min schedule. Additionally, during this component, each 50th response produced electric shock. When a different keylight stimulus was present, key pecking resulted in food delivery under a variable-interval 3-min schedule. Responding was suppressed by schock presentation (punishment) but was still positively accelerated throughout each fixed-interval cycle; steady response rates occurred during the alternate component when only the variable-interval schedule was in effect. Overall rates of punished responding were largely unchanged with d-amphetamine (0.1–3.0 mg/kg); unpunished responding was generally either increased slightly or was decreased. Pentobarbital and chlordiazepoxide (1.0–17.0 mg/kg) administered alone increased both punished and unpunished responding at most doses. Combinations of d-amphetamine with either pentobarbital or chlordiazepoxide produced increases in punished responding that exceed those obtained with either of these drugs alone. The combined effects of d-amphetamine and either pentobarbital or chlordiazepoxide on unpunished responding depended on the individual dose combinations. Combinations of d-amphetamine with pentobarbital or chlordiazepoxide produced effects on both punished and unpunished responding that differed substantially from those obtained when any of these drugs were administered separately.     

Anxiolytic profile of GR 38032F in the potentiated startle paradigm

The potentiated startle paradigm has been demonstrated to be a model of anxiety sensitive to a range of established and putative anxiolytics. This study reports a preliminary investigation of the effects of the 5-HT(3) antagonist GR 38032F on potentiated startle. Doses of 0.01 and 0.1mg/kg each showed an anxiolytic profile in significantly reducing startle amplitude, with the lower dose having an effect comparable to chlordiazepoxide at 5.0mg/kg. 5-hydroxytryptophan at 25mg/kg significantly enhanced startle amplitude, and a mutual antagonism was found when 5-HTP was combined with GR 38032F. The results extend previous work with other models of anxiety suggesting anxiolytic potential for GR 38032F, and further demonstrate the possibility that the anxiolytic effect is mediated by serotonergic mechanisms.