Active Avoidance Performance Research Articles

Developmental toxicity of the dopamine agonist pergolide mesylate in CD-1 mice. II: Perinatal and postnatal exposure

Pergolide mesylate is a dopamine agonist and, therefore, reduces prolactin secretion. In Experiment I, pregnant mice were given oral doses of 0, 0.1, 0.3, 1.0 or 3.0 mg/kg/day pergolide on GD 15 through PD 10 or 20 to identify a tolerated dose which would not markedly reduce offspring survival during late gestational and lactational exposure. Offspring survival was not affected at any dose, but dose-related decreases in progeny body weights occurred at weaning. On PD 10, suckling-induced increases in maternal serum prolactin concentrations did not occur in dams treated with 3.0 mg/kg/day. In Experiment II, pregnant mice were given oral doses of 0, 0.002, 0.1 or 3.0 mg/kg/day pergolide on GD 15 through PD 20. Dams were allowed to deliver and maintain their offspring throughout a 21-day lactation period. Growth and behavioral performance of one F 1 male and one F 1 female per litter were monitored, followed by a reproduction trial and terminal organ weight measurements. There were no treatment-related effects on maternal body weights, food consumption, or terminal organ weights and pathology. Three dams showed overt signs of mammary inflammation and lactational insufficiency and mean progeny survival was decreased slightly in the 3.0 mg/kg/day group. There were no adverse effects on growth, development or reproductive performance in the F 1 treatment-derived generation. Neonatal negative geotaxis, 1-h activity levels at 30 and 60 days of age, auditory startle habituation at 55 days of age, and two-way active avoidance performance at 65 days of age were not affected significantly by treatment. Thus doses of pergolide that did not inhibit lactation completely in the F 0 dams were found to have no enduring effects on offspring development.

Dihydroergotoxine treatment improves active avoidance performance and increases dopaminestimulated adenylate cyclase activity, in young and aged rats

Dihydroergotoxine (DHET) improved the acquisition of a conditioned avoidance response in both young and old rats, although old animals, reached a lower percentage of conditioned responses than did young rats. DHET dose-dependently reduced locomotor activity in aged animals, while, in young rats, increasing doses caused a triphasic effect, inhibitory at low doses, stimulatory at intermediate doses and again inhibitory at high doses. In young rats, the stimulation of spontaneous movements by DHET was abolished by L-sulpiride; L-sulpiride had no effect in old animals. DHET treatment also potentiated both norepinephrine- and, to a greater extent, dopamine-stimulated frontal cortex adenylate cyclase activity, an effect more pronounced in young than in old rats. These data show that DHET effects both locomotor activity and active avoidance performance in young and aged rats, and modulates dopamine-sensitive adenylate cyclase activity.

A Comparison of Bromopride and Domperidone Effects on Rat Conditioned Avoidance and Motor Activity

Acute intraperitoneal administration of bromopride (BRO) and domperidone (DOMP), two dopamine D2 blockers used as antiemetics in gastroenterology, were tested in male rats for effects on motor activity and on active and inhibitory conditioned behaviour. BRO dose-dependently depressed ambulation and rearing, impairing the performance of active conditioned avoidance (CAR) even when injected prior to the retention session. It also impaired inhibitory avoidance responses (IAR). All these effects were dose-dependent. DOMP was ineffective at modifying any of the above described parameters. These results suggest that BRO exerts neuroleptic effects which are neither mediated by actions on peripheral dopamine receptors nor by increased prolactin levels. These data also suggest that DOMP is a more appropriate drug for gastroenterology.

Effects of social isolation and crowding upon active-avoidance performance in the rat

Male and female Sprague-Dawley rats reared in social isolation and in crowded conditions were tested on their active-avoidance performance. Only males appeared to be affected by the treatments; no housing-condition effect was found on the performance of females. The most severe housing-condition effect was that of social isolation; the isolated males showed impaired acquisition of the avoidance response. We have previously reported diminished adrenocortical flexibility in male isolates, which might account for the present results. A possible failure of the inhibition mechanisms of isolates is also taken into account.

Buspirone, gepirone and ipsapirone disrupt both active and passive avoidance responding in rats

The anxiolytic drug buspirone and its structural analogues gepirone and ipsapirone produce behavioural effects which differ from those seen with benzodiazepines and barbiturates. Buspirone has been reported to disrupt active avoidance responding without interfering with the ability to escape the aversive stimuli, an effect usually associated with antipsychotic drugs. In the present study, buspirone, gepirone and ipsapirone produced dose-related decreases in one-way, active avoidance responding of rats. However, these drugs did not consistently give rise to a within-session decline in avoidance responding as was seen with the dopamine antagonist metoclopramide. In a second experiment, buspirone, gepirone and ipsapirone disrupted the performance of a passive avoidance response. Rats previously conditioned to remain on a raised platform to avoid shock stepped off the platform after injection of these drugs. A similar effect on the passive avoidance response was not produced by chlordiazepoxide; diazepam, CL 218, 872, haloperidol, imipramine or d-amphetamine. These disruptions of the performance of both active and passive avoidance indicate a unique pharmacological profile for buspirone and similar drugs.

Interactions between angiotensin II and baclofen in shuttle-box and passive avoidance performance

In experiments on male rats, we established that angiotensin-II (AT II) at a dose of 0.1 μg injected intracerebroventricularly immediately after training improved memory when retention tests (active and passive avoidance) were given 24 hours later. Baclofen at doses of 2,5 and 10 mg/kg injected intraperitoneally immediately after training also improved retention in both active and passive avoidance tasks. Baclofen at a dose of 20 mg/kg was without effect on active avoidance performance. Combination of AT II and baclofen (2,5 and 10 mg/kg) facilitated memory in active avoidance as compared to controls, but impaired retention as compared to the AT II-treated group. The impairment of the AT II-improved retention was stronger when the dose of baclofen in the combination was 20 ng/kg. Combination of AT II and baclofen (10 mg/kg) did not impair retention in passive avoidance. These data favor the view that GABA receptors may interfere with the AT II effects on memory consolidation or retention and that interactions of GABA (GABA A and GABA B) receptors with AT II receptors are of importance for memory processes.

Effects of maternal exposure to polychlorobiphenyls (PCBs) on F1 generation behavior in the rat

The effect of Fenclor 42 (PCB) exposure of female rats (Fischer 344 strain) was studied through assessment of the behavioral development of their F1 progeny. Female rats were exposed to PCB according to the following treatment schedule: (A) (5 days) 2 weeks prior to mating, (B) during gestation (Days 6–15 of pregnancy), (C) during lactation (Days 1–21 after delivery). Behavioral endpoints of motor reflexes, motor coordination, activity (preweaning behaviors), and learning (postweaning behavior) were evaluated for PCB ip dosages of 5–10 mg/kg/day for 5 days (preconception exposure), and PCB oral dosages of 2–4 mg/kg/day for 10 days ( in utero exposure) and of 1–2 mg/kg/day for 20 days (during lactation exposure). Dosage-dependent differnces in the evaluated behaviors were found in the offspring of the PCB-exposed females when compared to the offspring of corn-oil (vehicle)-exposed females. Significant differences in the development of cliff avoidance reflexive behavior, swimming ability, and open field activity were particularly evident. Furthermore the PCB exposure of female rats during gestation and lactation resulted in impaired acquisition of the active avoidance behavior while preconceptional PCB exposure significantly affected active avoidance performance as reflected in increased number of avoidance responses to reach criterion for extinction. These results show that Fenclor 42 does possess a significant risk to the offspring of exposed females, and further illustrate the sensitivity of progeny behavioral assessment in detecting suspected functional teratogenesis.

Differential effects on active avoidance performance and locomotor activity of two major enkephalin metabolites, Tyr-gly-gly and des-tyr-[leu]enkephalin

We examined the effects of two enkephalin metabolites, des-tyr-[leu]enkephalin and tyr-gly-gly, on one-way active avoidance conditioning in mice. These metabolites are products of the two major enkephalin hydrolyzing enzymes in plasma, aminopeptidase and angiotensin converting enzyme. Like [leu]enkephalin from which it may be formed, tyr-gly-gly impaired avoidance acquisition, and its dose-response function for this effect was U-shaped. Also like [leu]enkephalin, tyr-gly-gly did not alter locomotor activity. On the other hand, des-tyr-[leu]enkephalin, at the doses tested, was without effect on avoidance conditioning but produced decreased locomotion. These data suggest that the tyrosine end of the enkephalin molecule may be important for its effects on conditioning. Because of their low opioid potencies, it is unlikely that the behavioral actions of tyr-gly-gly and des-tyr-[leu]enkephalin are mediated through opioid receptors.

Active avoidance performance in genetically defined mice

It has been concluded by several investigators that active avoidance performance in mice is primarily influenced or even determined by a single gene. The genetically defined strains C57BL/6 and BALB/c have provided evidence that an aberrant development of pyramidal cells and mossy fiber configuration in the hippocampus of BALB/c mice also is determined by a single gene. As a test of the generality of the single gene influence on avoidance learning, and to examine the relationship of the hippocampal defect to avoidance learning, adult male mice of the inbred progenitor strains C57BL/6ByJ and BALB/cByJ and their seven recombinant inbred strains were tested in a variant of the shuttle-box paradigm used in previous studies. BALB/c were found to acquire the avoidance response at a faster rate than C57BL/6, consistent with most earlier reports, but performances of the recombinant inbred strains failed to dichotomize about the progenitor strains. The rank order of performance scores for the recombinant inbred strains was different from that reported in previous studies. Thus the present data failed to support the interpretation of a single major gene influencing active avoidance learning. It is concluded that avoidance learning and performance cannot be considered as unitary variables and that the interaction of genetic with environmental factors, including the conditions of the specific testing situation, are important considerations in any interpretation of genetic effects. No relationship between the hippocampal lamination defect and avoidance performance was demonstrated.

Analysis of the avoidance learning deficit induced by the serotonin releasing compound p-chloroamphetamine

The effects of the serotonin-releasing compound p-chloroamphetamine (PCA, 2.5 mg/kg) on avoidance acquisition, retention and memory retrieval were examined in male Sprague-Dawley rats using a one-way active avoidance and a one-trial passive avoidance task. The drug was injected IP prior to training, following acquisition and prior to the retention test 24 hr after training using a state-dependent design. In the normal context situation pretraining administration of PCA markedly impaired active avoidance acquisition, but PCA-treated rats did not differ from controls in their retention performance when tested 24 hr after training. In the dark/light box test pretraining administration of PCA caused a dose-dependent impairment of both active and passive avoidance retention which could not be explained in terms of changes in locomotor activity or behavioural disinhibition at the time of testing or state-dependent retention. Post-training administration of PCA failed to affect avoidance retention in both tasks. The drug was found to impair memory retrieval in a dose- and time-dependent fashion in the one-way active but not in the passive avoidance test. Pretraining administration of PCA produced a progressive loss of passive and active avoidance performance at increasingly longer retention intervals. The present results suggest that serotonin has dual effects on processes underlying learning and memory involving effects on both associative and non-associative learning processes in the rat. The time-dependent loss of memory retention following 5-HT release indicates that serotonin has a role in the way information is processed in the brain.

Behavioral activity and active avoidance learning and retention in rats neonatally exposed to painful stimuli

Twice daily for the first 15 days after birth, rats from the same litters were either placed for 5 sec on a hot plate (55°C) (treated group), or on a plate maintained at body temperature (38°C) (manipulated group). Controls were left undisturbed. When 90 days old, they were studied for pain threshold, open-field behavior, and two-day active avoidance learning and retention. Weight gain, pain threshold, open-field behavior, and active avoidance retention were not significantly different in the three groups. On the other hand, the rate of two-way active avoidance learning was significantly greater in treated rats. These results suggest that repeated neonatal exposure to painful stimuli, in rats raised under otherwise normal conditions, improves later active avoidance performance. The most likely mechanisms are discussed.

Involvement of spinal serotonergic pathways in nociception but not in avoidance learning.

The effects of selective lesions of the descending serotonergic (5-HT) pathways on analgesia and avoidance deficit induced by the 5-HT releasing compound p-chloroamphetamine (PCA, 2.5 mg/kg) were investigated in male rats. Intrathecal injection of 5,6-DHT (20 micrograms/rat) reduced the uptake of labelled 5-HT into spinal synaptosomes by approximately 85% but did not significantly affect the uptake of noradrenaline. The lesions produced a significant hyperalgesia and strongly attenuated the analgesic effect of PCA in the hot-plate test. In the flinch-jump test 5,6-DHT lesioned rats receiving PCA did not differ from the saline control group. Spinal lesioning did not, however, affect one-way active avoidance performance and did not prevent the marked impairment of avoidance performance induced by PCA. Thus, the avoidance deficit caused by PCA is independent of the descending serotonergic pathways and of the analgesia induced by PCA. These results support the view of a differential involvement of the ascending and descending serotonergic projections in behavioural processes controlled by aversive stimuli.

Neonatal brain damage and recovery: Intraventricular injection of NGF at time of injury alters performance of active avoidance

Rats were given lesions of either the ventromedial hypothalamus (VMH) or septal nucleus at 7 days of age and then were tested repeatedly in an active avoidance task (A.A.) from 20 to 80 days. VMH rats were consistently impaired on the A.A. task beginning at 40 days of age. The animals with septal lesions performed the A.A. task consistently better than VMH or control animals throughout the entire test period, the septal syndrome becoming more pronounced as the rats reached maturity. In intact rats a single, intraventricular injection of NGF given at 7 days of age resulted in a greater reactivity, especially as the rats approached maturity. NGF, given at time or surgery, also improved performance of the A.A. task in VMH-damaged rats tested at 40–80 days. In rats given septal lesions, NGF treatment at time of injury attenuated the septal syndrome of improved A.A. performance. The data indicate that NGF treatment, given to neonatal rats, can produce long-lasting effects on CNS functions and can contribute to functional recovery from brain lesions.

Active and passive avoidance performances following bilateral olfactory bulbectomy.

Three experiments were performed to study the effects of bilateral olfactory bulbectomy upon active and passive avoidance conditioning. In the first experiment, olfactory bulbectomized rats were found not to be impaired on a one‐way active avoidance task but showed a fear retention deficit. In Experiment 2, sham‐operated rats demonstrated a degree of fear retention that was a positive linear function of the number of shock presentations; olfactory bulbectomized rats showed a total absence of fear retention. In the third experiment olfactory bulbectomized rats failed to demonstrate the inverse relationship between shock intensity and two‐way avoidance performance normally evidenced. The pattern of data obtained suggests that while bulbectomized rats do not show any general avoidance impairment they do seem to be unaffected by the suppressive effects of shock upon ongoing behavior.

Strain specific cholinergic changes in response to stress: Analysis of a time-dependent avoidance variation

Investigators have established that the performance of an incompletely learned avoidance task is a U shaped function of the time since the original partial acquisition. Thus rats perform more poorly when retested at intermediate time intervals (1–8 hr) after training than they do when tested at longer post-acquisition intervals (24–48 hr). Studies have suggested that such time-dependent deficits are not related to changes in learning ability, but rather result from shock-induced motor suppression which interferes with active avoidance responding. Pharmacological studies utilizing drugs which effect cholinergic function have indicated that an inhibitory cholinergic system may be involved in mediating post-shock motor suppression. To obtain direct biochemical evidence for possible cholinergic mediation of post-shock motor suppression, measurements of high affinity choline uptake and acetylcholine turnover were made at varying time intervals following partial active avoidance training in F-344 rats. An increase in cholinergic function was found in the dorsal, but not the ventral hippocampus 30 min, 1 hr and 4 hr following acquisition training. These biochemical alterations were temporally correlated with deficits in active avoidance responding. We have reported that the immediate behavioral suppression observed in another rat strain (Sprague-Dawley, Zivic Miller Laboratories), which exhibits inferior active avoidance performance, is similarly correlated with cholinergic activation in the dorsal hippocampus [17]. These data support the hypothesis that the dorsal-hippocampal cholinergic system is involved in the mediation of stress-induced behavioral suppression. Furthermore, strain differences in the temporal response of this system following exposure to stress may partially underlie previously observed strain differences in active avoidance performance. Such strain differences in neurochemical function provide a useful model for further investigations of the mechanisms involved in the effects of stress on motor-dependent behavior.

Picrotoxin-induced disruption of bidirectional active avoidance behavior and locomotor activity

The effects of picrotoxin (0.75 and 1.5 mg/kg), an antagonist of GABA mediated chloride ion conductance changes, were examined on the acquisition and performance of a bidirectional active avoidance (BAA) response and on locomotor activity. Treatment with this agent disrupted both the acquisition and performance of this task and decreased locomotor activity. This picrotoxin-induced suppression of BAA was reversed by pre-treatment with diazepam (2 mg/kg), d-amphetamine (d-AMP, 2.0 mg/kg) and lysergic acid diethylamide (LSD, 10 μmg/kg). Picrotoxin-induced activity decreases in locomotor activity were antagonized by d-AMP, were partially reversed by LSD but were not reversed by methysergide. It is proposed that picrotoxin disrupts bidirectional active avoidance behavior by increasing the response suppressive effects of aversive stimuli and by inducing a general depression of motility.

Effects of dopamine receptor blockade on avoidance performance: assessment of effects on cue—shock and response—outcome associations

Treatment with pimozide, a neuroleptic drug which blocks postsynaptic dopamine receptors, retarded active avoidance performance among naive mice. The performance deficit was eliminated among mice that were previously trained in the avoidance task. Like avoidance training, prior CS-shock pairings enhanced avoidance performance, but this treatment did not reduce the effects of pimozide on later avoidance performance. Likewise, treatment with pimozide prior to CS-shock pairings did not influence the performance enhancements evident in a later nondrug test of avoidance performance. Moreover, the drug did not influence the extinction of avoidance induced by response prevention (flooding). Together, these data suggest that pimozide does not influence S-S associations, but affects avoidance performance by disrupting response initiation processes.

Septal lesions and active avoidance performance in rats: Effects of differential intrabox cues

In two separate experiments, male rats received septal lesions and were compared to operated controls on the acquisition of a two-way active avoidance task. In both experiments, an automated active avoidance apparatus (Lafayette Instrument Co.) was used, and the animals were tested 10 trials each day, 6 days/week. The CS was a tone, and the US was a 0.7 mA shock; the CS-US interval was 7 seconds. In Experiment 1, the rats (N=6/group) were tested under conventional conditions. The two compartments of the avoidance apparatus were identical in all respects. In Experiment 2, the rats (N=6/group) were tested in the same apparatus, but with differential intrabox cues. The inside of the left compartment was lined with black contact paper, while the inside of the right compartment was lined with white contact paper. Irrespective of the conditions, the septal rats were facilitated in the acquisition of shuttle-avoidance. In both tasks, the septal subjects required fewer trials to reach criterion, and showed better orientation in the shuttle-box compared to controls. The response latencies of the septal subjects also tended to be faster, but neither septal nor control subjects showed differential response latencies related to the direction of the shuttle response. Previous findings have shown that the addition of external cues to purported spatial tasks can reduce the behavioral effects produced by damage to the septohippocampal axis on such tasks. The present results suggest that such a cue-addition procedure does not influence the behavioral effects produced by septal lesions in shuttle-avoidance.

“Coping” and gastric ulceration in rats after prolonged active avoidance performance

Rats performing an avoidance task involving conflict with massed trials exhibit severe gastric ulceration, and high post session levels of adrenocortical activity. At the same time, rats performing a two-way active avoidance task, which also involves conflict, with spaced trials are known to exhibit “coping,” i.e. de-activation of the adrenocortical system. In the present experiment, rats were made to perform a two way active avoidance task with massed trials for twenty hours. These animals exhibited more severe gastric ulceration than did shock-yoked or non-shock controls, but no differences were found between groups on adrenocortical activity. “Coping” as measured here was independent of gastric ulceration.

Schedule induced ethanol polydipsia in psychogenetically selected lines of rats

Schedule induced ethanol polydipsia was established in 28 male and female rats of two psychogenetically selected lines bred for extremes in active avoidance performance. These rats were maintained at 80% normal body weight and given 36 consecutive daily 45-min sessions with 3% (w/w) ethanol available. During the acquisition phase, food pellets were delivered intermittently on a FT-1 min schedule. Baseline tests preceded and followed the acquisition phase and involved presentation of 45 food pellets together at the start of a test. Roman High Avoidance (RHA/Verh) rats exhibited greater ethanol intake than Roman Low Avoidance (RLA/Verh) rats and female rats drank more ethanol (adjusted for body weight differences) than male rats during baseline and acquisition phases. Furthermore, baseline ethanol intake increased significantly from the initial block to the final block of sessions following acquisition testing, but remained significantly lower than ethanol intake during the final block of acquisition tests. In a second experiment, naive female rats of the two psychogenetic lines were given baseline tests or sessions with food intermittently delivered on a FT-2 min schedule following a period of free feeding or a 20-hr session 3% ethanol was continuously available. In the initial phase of acquisition, fasted RHA/Verh rats drank more ethanol than RLA/Verh rats. In the second phase, undeprived rats of these two lines did not differ in ethanol intake. In a final acquisition phase, fasted RHA/Verh and RLA/Verh rats did not differ significantly in ethanol consumption. Under both deprivation regimens, baseline ethanol intake increased from the initial to the final baseline test. The ethanol consumption of fasted rats in the final acquisition test was significantly greater than that in the final baseline test. Thus, although pronounced and relatively enduring differences in the schedule induced ethanol intake of these two rat lines were observed under the condition of chronically reduced body weight, this strain difference was relatively weak and observed only in the initial phase of acquisition when 20-hr fasted rats were tested.