Pentylenetetrazol-induced retrograde amnesia and brain seizures in mice

These experiments examined in three strains of mice (Ha/ICR, Swiss Webster and C57BL/6J) the influence of pentylenetetrazol injections on: 1) brain seizure activity recorded from cortical electrodes, and 2) retrograde amnesia in an inhibitory avoidance task. In Ha/ICR mice, pentylenetetrazol administered after training impaired retention in doses that elicited brain seizures as well as in doses just below those which elicit brain seizures. The degree of retention impairment decreased with increasing training-treatment intervals. In Swiss Webster and C57BL/6J mice, doses of pentylenetetrazol which produced brain seizures did not affect retention. The results indicate that elicitation of brain seizures is not a sufficient condition for producing retrograde amnesia with pentylenetetrazol.Supported by Research Grant MH 12526 and Predoctoral Training Grant MH 11095-05 from the National Institute of Mental Health, United States Public Health Service.     

Strain differences in the effects of chlorpromazine and chlordiazepoxide upon active and passive avoidance in mice

Summary Four inbred strains of mice were compared on an active and a passive avoidance task in a two-compartment cage. Active mice were trained to cross frequently between compartments to avoid shock; passive mice were shocked for crossing. Yoked controls in both procedures received shocks at the same time as experimentals. Strains learning the active task well did poorly in the passive task; strains poor in active learning were superior on the passive task. The results support the view that strain differences in avoidance learning are more related to variations in strength of a kinetic drive than to strength of fear. Chlordiazepoxide affected crossings similarly in actively and passively trained Ss; chlorpromazine reduced crossings in actively trained and increased crossings in passively trained Ss. This result is consistent with dual motivational systems differentially susceptible to alteration by administration of drugs. Chlordiazepoxide acts primarily upon kinetic drive; chlorpromazine upon fear.This investigation was supported in part by United States Public Health Service Research Grants MH-01775 and MH-11327 from the National Institute of Mental Health.The author acknowledges the technical assistance of Frank Clark and Jane Harris.The principles of laboratory animal care as promulgated by the American Psychological Association were observed in this study.     

Genetic analysis of the behavioral response to d-amphetamine in mice

The ambulatory and rearing responses to d-amphetamine were studied in a battery of recombinant inbred strains and in three closely related strains: C57BL/6J, C57BL/10J, and C57BL/6By. Differences in the increase of ambulation (stimulation) caused by d-amphetamine were seen between C57BL/6By and the other two C57BL strains. Analysis of F₁ and backcross matings suggests a one-gene model. A mutation at the genetic locus that affects the response to d-amphetamine seems to have taken place in the C57BL/6By strain. Strain differences in the decrease of rearing behavior (inhibition) produced by the drug were observed in recombinant inbred strains. Although the genetic analysis is not conclusive, it appears to be compatible with regulation by a single major gene.The two single-gene models reported here (one affecting the stimulatory response and the other the inhibitory response to d-amphetamine) may be useful in the study of neural mechanisms involved in stimulation and inhibition of behavior by d-amphetamine.     

Variation in effects of chlorpromazine in three strains of mice

Summary Mice of strains C3HeB/J, C57BL/6J and RF/J were trained in nondiscriminated avoidance (Sidman type). Experimental subject could terminate or defer shock by crossing between cage components. Controls received shock but could not control it. Chlorpromazine in doses up to 4 g/g body weight had no effect on the activity of controls. Avoidance activity, defined as the excess activity of experimentals, was reduced by the drug, particularly in C57BL. C3H avoided best at all drug levels. The poorest strain at low dosage was RF, at higher dosage, C57BL. The results suggest need for care in the choice of phenotypes in experimental pharmacogenetics.This investigation was supported in part by Public Health Service Grant MH-01775 from the National Institutes of Health.The author gratefully acknowledges the technical assistance of Jane Harris.     

Behavioral decrements and brain catecholamine changes in rats exposed to hypobaric hypoxia

The behavior of rats trained on an avoidance schedule was used to assess performance decrements at altitude. After adequate baseline behavior of 95±5% avoidance on three consecutive days was attained, the rats were subjected to hypobaric hypoxia (23,000 feet) for two or four hours prior to an experimental session. Performance in this environment was disrupted in that the animals responded primarily to the shock rather than an auditory or visual cue. Brain norepinephrine levels were reduced about 20% in untrained and performing rats at altitude. Inhibition of monoamine oxidase with tranylcypromine, 0.5 mg/kg, prevented the reduction in norepinephrine in untrained rats at altitude and increased the levels above normal in performing rats at altitude but did not improve the performance. The data suggest that alterations in the behavior of performing rats at altitude are not related to absolute levels of norepinephrine.In conducting the research described in this report, the investigators adhered to the Guide for Laboratory Animal Facilities and Care, as promulgated by the Committee on the Guide for Laboratory Animal Facilities and Care of the Institute of Laboratory Animal Resources, National Academy of Sciences —National Research Council.     

Pharmacogenetic correlates of pentylenetetrazol and electroconvulsive seizure thresholds in mice

Summary DBA/2J mice, susceptible to audiogenic seizures, were found to be more susceptible to pentylenetetrazol- and electrically-induced seizures than either C57BL/6J or F₁ hybrid mice, which are resistant to audiogenic seizures. Reserpine increased susceptibility to both pentylenetetrazol and electroconvulsive seizures in C57BL/6J, DBA/2J and F₁ hybrid mice. 5-hydroxytrptophan, iproniazid and amino-oxyacetic acid decreased seizure susceptibility in all groups of mice. These results were interpreted to mean that DBA/2J mice are more susceptible to seizures than C57BL/6J or F₁ hybrid mice regardless of the agents used to induce the seizures, and that levels of 5-HT, NE and GABA are important in determining seizure thresholds.This research was supported by Research Grant MH-13026 from the National Institute of Mental Health.     

Effects of morphine and chlordiazepoxide on avoidance behaviour in two inbred strains of mice

Morphine and chlordiazepoxide were tested in the inbred strains of mice DBA/2J (DBA) and C57BL/6J (C57), subjected to three daily 50-tria1 avoidance sessions in the shuttle-box. The DBA strain reached higher avoidance levels in comparison to the C57 strain after the administration of saline. Morphine facilitated avoidance responding in the C57 strain but not in DBA mice. An improvement in avoidance behaviour was observed following the administration of chlordiazepoxide in both strains of mice. Some favourable effects were obtained in DBA mice by combining morphine with chlordiazepoxide, whereas no interaction between these drugs was found in the C57 strain.     

Resistance of one-trial discriminated avoidance to chlorpromazine

Summary Rats were either trained or tested after receiving injections of either 0, 1, 5, or 10 mg/kg of chlorpromazine in an effort to separate drug effects on learning or memory processes from effects on performance. One-trial place avoidance discrimination was used so that response choice could provide a relatively unequivocal indicator of retention. In substantial agreement with previous results, no drug effects on discriminated avoidance were found in spite of profound motor impairment at the highest drug level. Failure of the drug to affect response latencies was discussed in terms of possible contrasting effects on avoidance and motor behavior.The experiment is from a thesis submitted by the first author to the School of Graduate Studies of Queen's University in partial fulfillment of the requirements for the MA degree. This research was supported by the National Research Council of Canada, Grant APA-244, and the Ontario Mental Health Foundation, Grant 161. These data were presented at the Canadian Psychological Association meeting, Toronto, 1969.     

Modification of audiogenic and pentylenetetrazol seizures with gamma-aminobutyric acid,norepinephrine and serotonin

Summary Intracranial injections of gamma-aminobutyric acid, norepinephrine and 5-hydroxytryptamine were found to protect DBA/2J, C57BL/6J and F₁ hybrid mice against pentylenetetrazol-induced seizures. Similar treatments were also found to protect DBA/2J mice against audiogenic seizures. These results are in agreement with those reported in pharmacological experiments which indicate that increasing levels of the biogenic amines and of gamma-aminobutyric acid decreases seizure risk.This research was supported by research Grant Number MH 13026 from the National Institute of Mental Health, and research Grant Number GM 14549 from the National Institute of General Medical Sciences.     

Differential effects of scopolamine and D-amphetamine on avoidance: Strain interactions.

In a discriminated Y-maze avoidance task it was observed that mice of the A/J strain were superior to mice of the DBA/2J strain, which in turn made more avoidance responses than C57BL/6J mice. Moreover, the A strain was also observed to acquire a discrimination problem more readily than either of the other strains. Administration of scopolamine enhanced active avoidance performance in A, but not DBA/2 or C57BL/6 mice. D-Amphetamine improved performance in both A and DBA/2 mice but had negligible effects on the performance of the C57BL/6 strain. Neither drug affected discrimination performance irrespective of strain. In an inhibitory avoidance task the C57BL/6 strain was found to perform more poorly than the A strain which was inferior to DBA/2 mice. Scopolamine disrupted performance in all three strains, while d-amphetamine was found to disrupt the performance of the A and DBA/2 strains only. The results were interpreted in terms of the role of associative and nonassociative effects of shock in modulating avoidance behavior.     

Effects of chlorpromazine,secobarbital and sleep deprivation on attention in monkeys

Summary In order to develop a method for studying sustained attention in the monkey, animals were trained to perform a rapid, serially-presented visual discrimination task. Two versions of the task were developed, one dependent upon shock avoidance, the other on water reward. The effects of varying doses of chlorpromazine (0.075 to 0.6 mg/kg) and of secobarbital (5 to 25 mg/kg) were studied; the shock avoidance task was also used to measure the effects of continuous work-sleep deprivation for periods up to 48 hours.The results suggest that the task is a useful and reliable measure of attentive behavior and that there are similarities between the monkey attention task and the procedures designed to study attention in man; chlorpromazine produces more impairment in performance than secobarbital; impairment is manifest chiefly in increased errors of omission; chlorpromazine and sleep deprivation seem to share certain common effects which distinguish them from secobarbital. No marked differences in drug effects were found between the water and shock versions of the task. The relation between these findings and those obtained in human subjects was discussed.Supported by grants from the Foundations Fund for Research in Psychiatry (61–241) the National Science Foundation (G-21382) and the National Institute of Mental Health (MH-10324). Thanks are due to Mrs. Diane D. Arenella and Mrs. Ellen B. Stechler for their efficient and devoted technical assistance.Career Development Awardee, Level II of the National Institute of Mental Health K3-MH-14,915.     

Limitations on the use of the C57BL/6 mouse in the tail suspension test

RATIONALE: The C57BL/6 is one of the most widely used mouse strains in behavioral, pharmacological, and genetic research but little is known about their response on tests for antidepressant drugs. OBJECTIVES: The behavior of C57BL/6 mice, and mice from other strains, was examined in the tail suspension test (TST), a common behavioral test used for the screening of antidepressant compounds. METHODS: C57BL/6J mice from the Jackson Laboratory, C57BL/6N mice from Harlan, A/J, 129-SV-ter and DBA/2 mice were tested under baseline conditions in the TST. RESULTS: The majority of the C57BL/6 mice from the Jackson Laboratory tested in this paradigm (70%) climbed up their tails during the 6-min test session. C57BL/6 mice obtained from Harlan (35%) also demonstrated this climbing behavior, suggesting that it is not specific to mice from a particular supplier. Other strains (A/J 18%), 129-SV-ter (0%) and DBA/2 (0%) mice) showed less propensity for tail climbing. CONCLUSIONS: The occurrence of this behavior is an important consideration when testing antidepressant drugs or the effects of stress using the TST with inbred mouse strains, especially those from the C57BL/6 strain.     

Genotype-dependent sensitivity and tolerance to morphine and heroin: Dissociation between opiate-induced running and analgesia in the mouse

Morphine and heroin-induced running activity (running fit), analgesia and tolerance were studied in the inbred strains of mice BALB/cJ, C57BL/6J and DBA/2J. Acute tolerance developed in all strains tested within 48 h. The effects of the opiates on the running fit and analgesia were strain-dependent and a negative strain correlation was evident between the two measures. The development and the recovery from acute tolerance were also genetically determined. It is concluded that the motor and analgesic effects of morphine in the mouse are two distinct phenomena and that the same neuronal and biochemical model cannot explain them. The results are discussed in relation to the brain regional and biochemical differences reported for these strains.This work was supported by an Italian and French National Research Council Research grant and from European Training Program Brain and Behaviour Research grant. The technical assistance of Mr. Giuseppe Olimpieri is gratefully acknowledged. Thanks are due to Dr. F. Satriani, The Ministry of Health, Rome, for providing us with Morphine and Heroin.     

The effects of chlorpromazine and secobarbital on matching from sample and discrimination tasks in monkeys

Summary Monkeys were trained in the performance of a matching from sample task and in two simultaneous visual discrimination tasks differing in level of difficulty. In the case of the matching task, four doses each of chlorpromazine and of secobarbital were administered to the animals according to a balanced design. The procedure was then replicated. The results of the matching task indicated that chlorpromazine produced many errors of omission and few errors of commission. The latter kind of error as well as other measures of confused responding were seen primarily with secobarbital. In the case of the visual discriminations, secobarbital produced greater impairment of the more difficult (pattern) task than of the simpler (color) task; chlorpromazine had equivalent effects on the two tasks. The similarity between the secobarbital action and the behavioral consequences of certain cortical lesions in the monkey was discussed.This work was supported by the following grants from the National Institute of Mental Health, Public Health Service: Research Grant MH-12568; Special Fellowship 1-F3-25,128 (Dr. Bakay Pragay); Research Scientist Award 5-KO-5MH-14,915 (Dr. Mirsky); Predoctoral Fellowship 1-F2-NB-32-103 (Dr. Abplanalp).     

Verticalization of behavior elicited by dopaminergic mobilization is qualitatively different between C57BL/6J and DBA/2J mice

Behavioral effects of dopaminergic stimulation were evaluated in C57BL/6J mice and compared to the effects occurring in DBA/2J mice, an inbred strain with reduced densities of striatal dopamine receptors. Effects of apomorphine (0.5–64 mg/kg) alone and in combination with cocaine (30 mg/kg) were assessed using a time-sampling technique that classified climbing and leaning in separate categories. Locomotion was also assessed in a separate experiment. Climbing occurred in DBA/2J mice only at doses of apomorphine that were 16 times higher than the smallest effective dose in C57BL/6J mice; nevertheless, relative to baseline values, effects were fairly comparable. By contrast, whereas DBA/2J mice showed dose-dependent leaning under apomorphine, C57BL/6J mice exhibited little leaning even at doses not producing climbing, and only after the highest apomorphine dose was leaning significantly increased. Apomorphine was equipotent in inducing gnawing across strains, although somewhat less efficacious in DBA/2J mice. When given alone, cocaine produced significant climbing, but not leaning or gnawing, in either strain. Whereas cocaine potentiated apomorphine-induced climbing and gnawing in both strains, apomorphine-induced leaning was not consistently changed by cocaine in either strain. These effects were not indirectly due to hyperkinesia, since neither apomorphine alone nor apomorphine and cocaine in combination was stimulant; apomorphine alone reduced locomotor activity and attenuated cocaine-induced hyperkinesia. The present data do not support a unitary, purely quantitative, account of insensitivity to dopaminergic stimulation based upon low densities of striatal dopamine receptors in DBA/2J mice. Rather, this constellation of results is suggestive of qualitative interstrain dissimilarities in dopaminergic responsiveness that could reflect organizational differences in receptor populations.The facilities in which the mice were maintained are fully accredited by the American Association for the Accreditation of Laboratory Animal Care (AAALAC), and the studies described here were conducted in accordance with the Guide for Care and Use of Laboratory Animals provided by the NIH and adopted by NIDA.     

Role of endogenous enkephalins in locomotion and nociception studied with peptidase inhibitors in two inbred strains of mice (C57BL/6J and DBA/2J)

Acetorphan, a parenterally active enkephalinase inhibitor, induced dose-dependently a naloxone-reversible analgesia on the hot-plate jump test in DBA/2J (DBA2) mice but was devoid of effects in C57BL/6J (C57) mice. By contrast, acetorphan increased locomotion in both strains; however, the DBA2 strain was much more sensitive than C57 mice to the locomotor stimulant effect. The increased locomotion was antagonized by naloxone in both strains. These data suggest that endogenous enkephalins modulate nociception and locomotion in the two inbred strains differently.     

Susceptibility to amphetamine-induced place preference is predicted by locomotor response to novelty and amphetamine in the mouse

Rationale It has been demonstrated that major differences between mice of the C57BL/6J and DBA/2J inbred strains for amphetamine-induced place conditioning (preference and avoidance, respectively) are evident in standard housing conditions but abolished by temporary restricted feeding. This gene-experience model may be usefully exploited to dissect behavioral phenotypes related to place conditioning induced by addictive drugs.Objectives This study evaluated a number of behavioral phenotypes related to amphetamine-induced place preference for strain differences (C57BL/6J vs DBA/2J) susceptible to be abolished by temporary food restriction.Methods Mice of the two inbred strains were tested for: (1) conditioned taste aversion and place preference induced by amphetamine within the same dose-range; (2) preference for a novel compartment 24 h after a single exposure to only one of two compartments; (3) amphetamine-induced behavioral sensitization and conditioned hyperactivity; and (4) locomotor activity during exploration of a novel environment.Results The two strains showed consistent taste aversion at doses of amphetamine that promoted opposite strain-dependent place conditioning. Both strains spent more time exploring the novel rather than the known compartment of the place conditioning apparatus. Instead, only mice of the C57 strain showed amphetamine-induced behavioral sensitization and conditioned hyperactivity. However, temporary food restriction did not affect strain differences for these phenotypes. Finally, C57 mice were more active than DBA in a novel environment and restricted feeding abolished this strain-dependent difference.Conclusions These results relate individual differences for amphetamine-induced place conditioning with locomotor response to amphetamine and novelty.     

Effects of chlorpromazine and imipramine on discrimination learning,consolidation, and learned behavior in two inbred strains of mice

Chlorpromazine and imipramine were administered to DBA/2J and C57BL/6J mice swimming in a Y water maze toward a light source (L Procedure, corresponding to innate tendency) or towards the dark (D Procedure, sorresponding to the acquisition of a new pattern of behavior). In two sets of experiments the drugs were administered to naive mice before and after each training session, respectively.In both strains, in the pretrial experiments, the innate tendencies were improved by both drugs; the acquisition of a new pattern of behavior was improved following imipramine but impaired following chlorpromazine. In the posttrial experiments (D procedure) the consolidation processes of both strains were improved following imipramine and impaired following chlorpromazine.In a third set of experiments imipramine was administered to previously trained mice of both strains and chlorpromazine to previously trained C57 mice. In both procedures the administration of increasing doses of both drugs was followed by a progressive lengthtening of the swimming times in the previously trained C57 mice; performance disruptions were evident in both procedures in trained DBA mice following imipramine.     

Sensitivity to the effects of pharmacologically selective antidepressants in different strains of mice

RATIONALE: Recent advances in neurobehavioral genetics have increased the importance of research on the behavioral patterns of different mouse strains. A comprehensive comparison of inbred and outbred mouse strains was conducted to provide information on the range of performance and pharmacological effects in the forced swimming test, a behavioral test commonly used to measure the effects of antidepressant drugs. OBJECTIVES: Baseline performance and pharmacological responses to desipramine, a selective norepinephrine reuptake inhibitor, and fluoxetine, a selective serotonin reuptake inhibitor, were compared in seven inbred and four outbred mouse strains in the forced swimming test. METHODS: Swim sessions were conducted by placing mice in individual glass cylinders filled with water for 6 min. The duration of behavioral immobility during the last 4 min of the test was scored from videotapes. RESULTS: A 10-fold range of immobility values and coefficient of variation supported the existence of substantial behavioral differences between mouse strains in baseline performance in the FST. In general, inbred strains demonstrated lower variability than outbred strains. Desipramine dose-dependently reduced immobility in seven of the 11 strains tested, with DBA/2J and the C57BL/6J mice showing greater sensitivity than the other strains. In contrast, fluoxetine reduced immobility in only three out of the 11 strains tested, DBA/2J, BALB/cJ and NIH Swiss mice. CONCLUSIONS: Background strain is a critical variable in determining baseline performance and the sensitivity to different types of antidepressant drugs in the mouse FST. The use of such mouse strains may provide information on the genetic basis for strain differences in depressive behavior and differential sensitivity to diverse classes of antidepressants.