Effects of acute ethanol or amphetamine administration on the acoustic startle response and prepulse inhibition in adolescent and adult rats

Rationale Adolescents differ from adults in their sensitivity to a variety of psychoactive drugs. For example, adolescent rats are less sensitive to locomotor stimulant and stereotypic effects of amphetamine as well as to motor-impairing and hypnotic effects of ethanol while more sensitive to ethanol-induced disruption of brain plasticity.Objective The current study further explored age differences in psychopharmacological sensitivity by examining the effects of d-amphetamine (1.0 and 4.0 mg/kg) or ethanol (0.5, 1.0 and 1.5 g/kg) given interperitoneally on the acoustic startle response (ASR) and prepulse inhibition (PPI) in male adolescent and adult Sprague–Dawley rats.Materials and methods The animals were given five startle trials (120 dB for 40 ms) before semi-randomized presentation of 12 startle trials interspersed with ten trials at each prepulse intensity (40 ms pulse of 5, 10, or 20 dB above background; 100 ms before the startle stimulus).Results Adolescent controls showed significantly less PPI than adults, replicating previous ontogenetic findings. The higher dose of amphetamine disrupted PPI in adult but not in adolescent animals, extending previous reports of an adolescent insensitivity to amphetamine to include this measure of sensorimotor gating. Ethanol exposure failed to alter PPI at either age, although both the 1.0 and 1.5 g/kg doses of ethanol significantly suppressed the magnitude of the ASR at both ages, potentially reflecting sedative or anxiolytic effects.Conclusion These data provide further evidence of the relative insensitivity of adolescent animals to amphetamine, although no age effects were found in terms of ethanol sensitivity using these measures of startle and sensorimotor gating.     

Long-term effects of developmental PCP administration on sensorimotor gating in male and female rats

Rationale Acutely administered N-methyl-D-asparate (NMDA) antagonists are used to model schizophrenia, as measured by impairments in sensorimotor gating reflected in decreases in prepulse inhibition of the startle response (PPI). Aspects of acute NMDA receptor antagonism limit the applications of these models.Objective The aim of this paper is to determine the long-term effects of developmental phencyclidine (PCP) treatment on sensorimotor gating in both male and female rats.Materials and methods Male and female Sprague Dawley rats were injected with PCP (10 mg/kg s.c.) on postnatal days (PN) 7, 9, and 11 and were tested for PPI on PN 32—34. The groups were then divided and some of the animals received a single dose of PCP (10 mg/kg s.c.) on PN 45. The animals were tested again for PPI at approximately 1, 4, and 6 weeks after the treatment.Results There were no significant effects of neonatal-only treatment. One week after the PN 45 treatment, animals that were treated as neonates and as adolescents (PCP/PCP) were significantly impaired in PPI in both sexes. Male and female PCP/PCP rats also had significant increases in acoustic startle response 4 weeks posttreatment, which subsequently declined. PPI impairments in both sexes recovered over time and the adolescent-only treated females showed significant increases (improvement) in PPI approximately 6 weeks posttreatment.Conclusion These data suggest that treatment with an NMDA receptor antagonist during adolescence or early adulthood can produce a relatively long-term impairment of PPI (approximately 1 week) and that this effect is more pronounced in male animals.     

Effects of pretest manipulation on elevated plus-maze behavior in adolescent and adult male and female Sprague-Dawley rats

The elevated plus-maze (EPM) is vulnerable to variations in pretest circumstances when testing adult rodents. Because of an increasing interest in adolescence, the present experiments examined the impact of pretest manipulations on anxiety levels in the EPM among adolescent and adult Sprague-Dawley rats of both sexes. In Exp. 1, animals removed from their home cage and immediately placed on the EPM were compared to rats tested following 30 min of social isolation, or following 30-min exposure to a novel context. These pretest manipulations only modestly decreased anxiety levels at both ages. In Exp. 2, more varied pretest conditions were examined: testing directly from the home cage; testing following 30 min of social isolation in a novel environment; or a large saline injection and rehousing 18 h prior to a 30-min period of social isolation in a novelty situation before testing. In adults, anxiety levels decreased linearly as pretest perturbation increased, whereas adolescents showed comparable levels of anxiety with both the moderate and large perturbations. As a result, observed age differences in anxiety differed as a function of pretest circumstances. Therefore, caution is urged when using the EPM for across-age comparisons of anxiolytic and anxiogenic effects of pharmacological or other manipulations.     

Differential behavioral effects of nicotine exposure in adolescent and adult rats

Rationale Although the detrimental effects of nicotine in early brain development and the addictive properties in adulthood are well known, little is known about the neurobiological effects of nicotine in adolescence. An important question is whether adolescents and adults differ in the development of nicotine sensitization and drug-cue conditioning.Objective To examine the behavioral effects of multiple, repeated injections of nicotine on both sensitization and drug-cue conditioning in the adolescent rat, and to compare this profile with the adult rat.Methods Sixteen male adolescent (28 day) and 16 young adult (70 day) rats were given injections of either saline or nicotine and tested for motor activity for 90 min for ten consecutive days. Following 4 days of no testing, animals were given a sham injection and placed in the testing apparatus for 90 min. A dose–response curve for nicotine was also generated using two additional groups of ten adolescent and ten adult male rats.Results Adolescent rats, unlike adults, did not exhibit signs of nicotine-cue conditioning, and displayed less robust sensitization to the locomotor effects of nicotine than adults. Dose–response testing revealed differences in adolescent responsivity to nicotine in measures of rearing, but not ambulation. Initial exposure to nicotine resulted in increased sensitivity to the motor-activating effects of nicotine but less sensitivity to the depressant effects of nicotine in rearing in adolescents.Conclusions Adolescent animals display different long-term neuroadaptive responses to nicotine than adult animals, possibly related to immature or still-developing plasticity mechanisms in the prefrontal cortex.Electronic Supplementary Material Supplementary material is available for this article at .     

The differential effects of prenatal stress in rats on the acoustic startle reflex under baseline conditions and in response to anxiogenic drugs

RATIONALE: The prenatal stress syndrome (PS) is characterized by exaggerated behavioral and physiological responses to stressful stimuli and anxiogenic agents. OBJECTIVES: To characterize the behavioral effects of PS on the acoustic startle reflex (ASR) and to determine the possible role of PS-induced alterations in noradrenergic control of ASR by determining the effects of the alpha2-adrenoceptor antagonists, yohimbine, idazoxan, and RS79948-197. METHODS: PS was induced by exposing pregnant dams to a mild stressor of handling and saline injection (0.1 ml, s.c.) from gestational days 14 to 21. Control dams were left undisturbed throughout pregnancy. Using adult male offspring, all ASR studies consisted of either a 30- or 60-min testing period containing 60 or 120 acoustic startle stimuli trials (95 dB, 50 ms noise burst) at a fixed intertrial interval of 30 s after a 5-min acclimation period. For drug studies, a 3-day repeated measures design was implemented. RESULTS: With the exception of the response to the first startle stimulus on the first day of testing, there were no significant differences in baseline ASR between control and PS offspring. Low doses of yohimbine, idazoxan, and RS79948-197 were anxiogenic in the ASR test in both control and PS offspring. PS offspring were less responsive to higher doses of yohimbine (5 mg/kg) and idazoxan (8 mg/kg) but did not differ from control in their responses to any dose of RS79948-197. CONCLUSIONS: Anxiogenic effects of yohimbine, idazoxan, and RS79978-197, likely mediated via alpha2-adrenoceptor blockade, are similar in control and PS rats. Differences between control and PS rats occurred in the response to higher doses of yohimbine and idazoxan. Non-specific effects of these drugs, such as actions at 5HT1A receptors, may cause their behavioral profile to be altered by PS, and to differ from the highly selective RS79948-197.     

Subchronic treatment with the tricyclic antidepressant DMI increases isolation-induced fighting in rats

Male rats treated with desmethylimipramine (DMI) (20 mg/kg for 7 days) were more likely than controls to attack an intruder rat placed in their home cage; they were also more likely to submit when attacked by the intruder. These behavioural changes were not seen at lower doses of DMI. Similar results were obtained in experiments in which a drugged animal and a control were placed together in a ‘neutral’ cage; in this paradigm it was also found that lower doses of DMI were effective, provided that either the period of drug treatment was increased, or a delay of 3–4 days after withdrawal of DMI preceded behavioural testing. A dose dependent resistance to handling developed during drug treatment; drugged animals also showed weight loss and decreased open-field activity. In previous studies, acute treatment with tricyclic antidepressants has not been found to increase fighting; the present results underline the importance of chronic drug studies.     

Prolonged treatment with vitamins C and E separately and together decreases anxiety-related open-field behavior and acoustic startle in hooded rats

Adult male and female hooded rats (about 110 days old) consumed vitamins C and E separately and combined together in their drinking water and were assessed for anxiety approximately 50 and then 80 days later in an open field and an acoustic startle apparatus. They were tested when 160+ days old, and then again at 190+ days. For both testing ages combined, the vitamins and their combination increased open-field ambulation and occupancy of the four center squares of the apparatus, while also accordingly decreasing occupancy of the four corners. Treatment with vitamins C and E separately and combined together also decreased acoustic startle amplitude. While there were several significant overall sex and testing age differences, there was no evidence that the vitamin treatment effects were dependent on the operation of either variable. There was also no evidence of synergism between vitamins C and E in their effects. It was suggested that decreases in anxiety produced by the vitamins may have arisen from their antioxidant properties, attenuation of cortisol activity or some as yet undetermined effects on anxiety-related brain structures and neurotransmitters.     

Social instability in female rats: effects on anxiety and buspirone efficacy

Rationale Buspirone produces inconsistent effects in laboratory rodents. Individual housing increases the efficacy of buspirone in male rats, suggesting that the effects of this (and other) compounds become conspicuous in animals showing anxiety-like states. The effect of individual housing was, however, weak, and evident only when the locomotor suppressive effects of buspirone dissipated (i.e. 4 h after treatment).Objectives The effects of social instability, a recently developed model of social stress in female rats, was investigated on both anxiety and the anxiolytic efficacy of buspirone.Methods Female rats were exposed to alternate days of isolation and moderate crowding for 2 weeks. Group composition was changed for each crowding phase. Basal anxiety and the anxiolytic efficacy of buspirone were assessed by the social interaction test of anxiety 24 h after the last crowding phase.Results Crowding appeared stressful, as it increased plasma glucocorticoid levels in less than 1 h. Anxiety-like behaviours were increased by social instability compared with stable group housing. In group housed controls, buspirone markedly suppressed locomotion, without clear effects on anxiety-related behaviours. Social instability attenuated the locomotor suppressive effects of buspirone, but made the anxiolytic effects of the compound more conspicuous. The effects of individual housing (assessed earlier) and social instability (assessed here) on buspirone efficacy appear qualitatively different.Conclusions Buspirone abolishes stress-induced anxiety, but has no anxiolytic effects in controls. This is consistent with clinical findings, as the drug decreases anxiety in anxious patients but not in healthy humans. Laboratory models involving stress-induced anxiety-like states can improve our understanding of drug effects and efficacy.     

Prenatal melamine exposure induces impairments of spatial cognition and hippocampal synaptic plasticity in male adolescent rats

Our previous studies showed that chronic melamine exposure could affect hippocampal synaptic plasticity and impair learning and memory on adult rats. In this study, we investigated whether prenatal melamine exposure (PME) induced cognitive deficits and impairment of synaptic plasticity in postnatal offspring. An animal model was produced by melamine exposure throughout gestational period with 400 mg/kg/day, while male offspring rats were employed. Rats’ performance in Morris water maze (MWM) was tested to evaluate learning and memory. To examine the variations of paired-pulse facilitation (PPF) and synaptic plasticity, field excitatory postsynaptic potentials (fEPSPs) were recorded in hippocampal CA1 by stimulating Schaffer collaterals path. The result showed that PME probably impaired spatial learning and memory. The fEPSPs amplitudes of LTP were much lower and the PPF ratio was significantly higher in PME group than controls. These data suggested that PME impaired hippocampal synaptic function, which was partly involved in spatial cognition impairments.     

Effects of diazepam on conflict behaviour and on plasma corticosterone levels in male and female rats

The anxiolytic properties of diazepam and its effects on plasma corticosterone levels were compared in male and female, water deprived rats exposed to the punished (0.8 mA) drinking procedure. The effects of diazepam on unpunished licking, tested under familiar or unfamiliar conditions, and on the lick latency were also studied and a comparison between the two sexes was made. Both punished and unpunished drinking were less in females than in males. In both sexes, a clear anticonflict effect, i.e. a much greater effect on punished than on unpunished drinking, was obtained with 2 and 4 mg/kg, but not with I mg/kg, of diazepam i.p. Plasma corticosterone levels were higher in water deprived females than in males. Following the punished and unpunished drinking procedure, plasma corticosterone levels were found to have decreased more in female than in male rats, especially after administration of 1 mg/kg of diazepam. Diazepam had similar anticonflict effects in rats of both sexes but had a greater suppressive effect on the plasma corticosterone levels in female rats. There was no correlation between the anxiolytic effects of diazepam and its effect on the plasma corticosterone levels. When testing was done under unfamiliar conditions, the latency to licking was greater in female than in male rats and diazepam (1, 2 and 4 mg/kg) increased this latency in both sexes. The results suggest sex differences in the neuroendocrine, but not in the anxiolytic, effects of diazepam.     

Low doses of amphetamine lead to immediate and lasting locomotor sensitization in adolescent, not adult, male rats

Although there is much evidence for age differences in behavioural responses to psychostimulants in rats, the differential, lasting impact of drug exposures has rarely been investigated using direct comparisons of adolescent and adult rats. Male rats were pre-treated with 0.5 mg/kg amphetamine or saline on either postnatal days (P) 31 and P33 or P76 and P78, and locomotor activity was measured for 1 h. Adolescent, and not adult, rats showed a significant increase in distance traveled from the first to second pre-treatment. There was no evidence of sensitization of locomotor activity in either adolescents or adults on Challenge 1 to the same dose of amphetamine when tested 12 days later on P45 (late adolescence) or on P90. Rats that were pre-treated as adolescents exhibited locomotor sensitization to 1.5 mg/kg amphetamine as adults (P60) on Challenge 2, 27 days after pre-treatment, particularly in the group that had also received amphetamine on Challenge 1 at P45. Rats that were pre-treated as adults did not show sensitization on Challenge 2. The results suggest that the rapid adaptations to drug exposures in adolescence have greater consequences than identical treatment in adulthood, and highlight the unique vulnerability of adolescents to brief, low dose drug exposure.     

Chronic treatment with imipramine reverses immobility behaviour, hippocampal corticosteroid receptors and cortical 5-HT(1A) receptor mRNA in prenatally stressed rats

Prenatal stress in the rat induces enhanced reactivity of the hypothalamus-pituitary-adrenal (HPA) axis, disturbances in a variety of circadian rhythms and increased anxiety-like behaviour. Such abnormalities parallel those found in human depressed patients. Prenatally stressed (PS) rats could represent, therefore, an interesting animal model for the evaluation of the efficacy of pharmacotherapeutic intervention in psychiatric disorders that has often been addressed using control animals. In the present study, PS and non-stressed rats were chronically treated with the tricyclic antidepressant imipramine (10 mg/kg i.p. for 21 days) and assessed in the forced swim test. Glucocorticoid receptor binding sites in the hippocampus were measured and 5-HT(1A) receptor mRNA levels in the frontal cortex were also assessed. PS rats were characterised by increased immobility in the forced swim test, reduced hippocampal corticosteroid receptor binding and increased levels of cortical 5-HT(1A) mRNA. All these parameters were significantly reversed by chronic imipramine treatment. Conversely, no significant effects were observed for non-stressed rats. All these effects are consistent with the expected pharmacotherapy of depression-like abnormalities in PS rats. These results further indicate that PS rats are a relevant animal model of depression.     

Sodium valproate: Effects on social behaviour and physical development in the mouse

Sodium valproate given in drinking fluid at 600 mg/l (160–180 mg/kg daily) to breeding mice did not affect fertility, birth weights or physical development of pups. Postnatal and postweaning administration of this dose also had no effects upon development or weight gain. The offspring ingested 103–158 mg/kg valproate daily after weaning. Behaviour was examined in a neutral enclosure by ethological methods. Offspring exposed to valproate in utero and throughout postnatal life showed no behavioural changes at 5 weeks, although at 15 weeks Immobility was reduced in females and Social Investigation increased. At 25 weeks when encountering mice of the opposite sex, treated males showed increase in Social Investigation and treated females increases in Other Non-social Activity. Postnatal and postweaning treatment with valproate caused behavioural changes both in juveniles and adults. After postnatal exposure, reduced Immobility with increased Social Investigation and Explore and Scan occurred at 5 and 15 weeks, at 25 weeks valproate increased Social Investigation in males encountering females and at 30 weeks enhanced Aggression in pair-housed males. Stimulation of Social Investigation was the only significant behavioural effect after postweaning exposure. Overall valproate appears to enhance behaviour stimulated by the test situation; urinary pheromones do not appear to play a part in this behavioural action.     

Concurrent choice for social interaction and amphetamine using conditioned place preference in rats: Effects of age and housing condition

Background

Social interaction can serve as a natural reward that attenuates drug reward in rats; however, it is unknown if age or housing conditions alter the choice between social interaction and drug.

Methods

Individually- and pair-housed adolescent and adult male rats were tested using conditioned place preference (CPP) in separate experiments in which: (1) social interaction was conditioned against no social interaction; (2) amphetamine (AMPH; 1 mg/kg, s.c.) was conditioned against saline; or (3) social interaction was conditioned against AMPH.

Results

Social interaction CPP was obtained only in individually-housed adolescents, whereas AMPH CPP was obtained in both individually-housed adolescents and adults; however, the effect of AMPH was not statistically significant in pair-housed adults. When allowed to choose concurrently between compartments paired with either social interaction or AMPH, individually-housed adolescents preferred the compartment paired with social interaction, whereas pair-housed adolescents preferred the compartment paired with AMPH. Regardless of housing condition, adults showed a similar preference for the compartments paired with either social interaction or AMPH.

Conclusions

Although some caution is needed in interpreting cross-experiment comparisons, the overall results suggest that individually-housed adolescents were most sensitive to the rewarding effect of social interaction, and this hypersensitivity to social reward effectively competed with AMPH reward.     

Characterizing the behavioral effects of nerve agent-induced seizure activity in rats: increased startle reactivity and perseverative behavior

The development and deployment of next-generation therapeutics to protect military and civilian personnel against chemical warfare nerve agent threats require the establishment and validation of animal models. The purpose of the present investigation was to characterize the behavioral consequences of soman (GD)-induced seizure activity using a series of behavioral assessments. Male Sprague-Dawley rats (n = 24), implanted with a transmitter for telemetric recording of encephalographic signals, were administered either saline or 1.0 LD₅₀ GD (110 μg/kg, sc) followed by treatment with a combination of atropine sulfate (2 mg/kg, im) and the oxime HI-6 (93.6 mg/kg, im) at 1 min post-exposure. Seizure activity was allowed to continue for 30 min before administration of the anticonvulsant diazepam (10 mg/kg, sc). The animals that received GD and experienced seizure activity had elevated startle responses to both 100- and 120-dB startle stimuli compared to control animals. The GD-exposed animals that had seizure activity also exhibited diminished prepulse inhibition in response to 120-dB startle stimuli, indicating altered sensorimotor gating. The animals were subsequently evaluated for the acquisition of lever pressing using an autoshaping procedure. Animals that experienced seizure activity engaged in more goal-directed (i.e., head entries into the food trough) behavior than did control animals. There were, however, no differences between groups in the number of lever presses made during 15 sessions of autoshaping. Finally, the animals were evaluated for the development of fixed-ratio (FR) schedule performance. Animals that experienced GD-induced seizure activity engaged in perseverative food trough-directed behaviors. There were few differences between groups on other measures of FR schedule-controlled behavior. It is concluded that the GD-induced seizure activity increased startle reactivity and engendered perseverative responding and that these measures are useful for assessing the long-term effects of GD exposure in rats.     

Exploration and latent learning: Differential effects of dexamphetamine on components of exploratory behaviour in rats

Summary Exploratory behaviour of undrugged rats in a modified Y-maze was recorded during repeated daily trials. Two types of exploration entries into the arms of the maze and a non-locomotor measure, investigation of troughs at the ends of the arms were scored. Latent learning about the location of food-mash in particular troughs was found to be a function of the number of training trials; also there was evidence that learning was greatest in rats which had the highest scores on entries and trough investigation, which validated these as measures of exploration.Dexamphetamine 0.25, 0.50, 1.0 mg/kg had differential effects on activity. Entries were increased while trough investigation was reduced. It is suggested that dexamphetamine reduces true exploration while increasing locomotor activity in a non-specific manner.I thank Mr. J. R. H. Bryant for technical assistance and Mr. B. Hutchings for acting as the co-observer in Experiment II. I am extremely grateful to Dr. I. P. Stolerman and Dr. H. Steinberg for help and discussion and to Smith Kline & French for gifts of rats. This work was supported by research grant No. MH-03313 from the National Institute of Mental Health, U. S. Public Health Service.Beit Memorial Research Fellow     

Effects of food deprivation and mCPP treatment on the microstructure of ingestive behaviour of male and female rats

A preliminary experiment showed that a 2.5 mg/kg dose of the 5-HT agonist 1-(3-chlorophenyl)piperazine di hydrochloride (mCPP) produced a greater reduction of food intake in female rats when weight-matched rats of both sexes were compared following 24 h food deprivation. A second experiment showed that this dose of mCPP led to higher drug concentrations in female than in male brain tissue. In two meal pattern studies non-drugged females took a shorter first meal, but ate more rapidly during that meal, than males; these differences were also seen in records of ad libitum feeding. mCPP produced an anorectic effect that lasted for < 1 h with rebound feeding becoming apparent within 1-2 h. The drug increased latency to feed, reduced the size of the first meal and feeding rate during that meal and had effects that were most marked in older rats and in female rats. In addition, effects of mCPP on water intake were as profound as those on food intake. These effects are discussed in relation to sex differences in feeding and the behavioural specificity of mCPP.     

Harmaline effects on the sensory-motor reactivity: Modifications of the acoustic startle pattern

The effects of harmaline, an indoleamine and a MAOI, were tested on the acoustic stratle pattern. EMG measures of the startle reflex, the pinna reflex as well as the characteristic of the vertex evoked responses to brief intense tone burst (60 msec, 110 dB,8000 Hz) were simultaneously studied in 4 alert guinea-pigs. The basic experimental design was a 4 latin square, with the treatments being given at 2 day intervals. The four harmaline-HCI treatments were isotonic saline, 0.25 5.0 and 10.0 mg/kg. Compared with saline baselines, all the doses resulted, throughout the 60 min session, in overall high significant depressions of the startle reflex, the pinna reflex and the initial wave of the acoustic evoked potential at the vertex. In contrast, harmaline had little or no influence on amplitude and latency of the late wave of the vertex response. The effects of harmaline on the general behavior of the guinea-pig are also reported. These results may support an involvement of serotonergic systems in the modulation of the sensory-motor reactivity at the brainstem level. Nevertheless, the probab;y more complex cortical processes involved in startle responsivity do not appear univocally affected by the indoleamine drugs such as harmaline.     

Interaction between prior experience and the effects of chlorpromazine on exploration in the rat

4 mg/kg chlorpromazine increased the latency to start exploring a new environment, and decreased the time spent exploring it and novel objects in it A prior, undrugged experience of the apparatus reduced this drug effect, whereas a prior, drugged experience had little effect on later exploration under saline conditions. Rats placed undrugged in the apparatus on two trials showed significant habituation of exploration, but rats given both trials when drugged did not.