Acquisition Of Avoidance Response Research Articles

Comparison of the effects of amitriptyline, melipramine and fluoxetine on acquisition and spatial alteration of avoidance responses in rats

The effects of amitriptyline (10 mg/kg), melipramine (10 mg/kg), and fluoxetine (5 mg/kg) on the acquisition of conditioned active avoidance responses and their spatial alteration in rats were studied. During the acquisition of avoidance, a passage in the partition was open, adjacent to the rear wall of the shuttle chamber. On the 5th experimental day after the end of the training, this distal opening was closed and the proximal one was opened, after which avoidance performance under changed conditions was tested for 20 trials. Melipramine and amitriptyline accelerated the acquisition of avoidance responses. Changing the location of the opening disrupted the learned skill, especially in the control animals. Melipramine and fluoxetine statistically significantly (in contrast to amitriptyline) accelerated the recovery of the level of avoidance. The positive effect of melipramine and fluoxetine is explained by a psychostimulating component in their spectrum. The inability of amitriptyline to produce a significant effect in this model is due to its psychosedative properties. The data obtained allow us to conclude that the acquisition of the active conditioned avoidance responses and their spatial modification can be used to analyze the antidepressant activity of pharmacological agents.

A-learning: A new formulation of associative learning theory.

We present a new mathematical formulation of associative learning focused on non-human animals, which we call A-learning. Building on current animal learning theory and machine learning, A-learning is composed of two learning equations, one for stimulus-response values and one for stimulus values (conditioned reinforcement). A third equation implements decision-making by mapping stimulus-response values to response probabilities. We show that A-learning can reproduce the main features of: instrumental acquisition, including the effects of signaled and unsignaled non-contingent reinforcement; Pavlovian acquisition, including higher-order conditioning, omission training, autoshaping, and differences in form between conditioned and unconditioned responses; acquisition of avoidance responses; acquisition and extinction of instrumental chains and Pavlovian higher-order conditioning; Pavlovian-to-instrumental transfer; Pavlovian and instrumental outcome revaluation effects, including insight into why these effects vary greatly with training procedures and with the proximity of a response to the reinforcer. We discuss the differences between current theory and A-learning, such as its lack of stimulus-stimulus and response-stimulus associations, and compare A-learning with other temporal-difference models from machine learning, such as Q-learning, SARSA, and the actor-critic model. We conclude that A-learning may offer a more convenient view of associative learning than current mathematical models, and point out areas that need further development.

White Environment Can Be Used as an Aversive Stimulus in Zebrafish Inhibitory Avoidance Learning.

The two-factor theory predicts that the acquisition of avoidance responses is dependent on fear reduction; as such, drugs that reduce or increase fear or anxiety states should alter inhibitory avoidance (IA) acquisition. The present experiment used white spaces as aversive unconditioned stimuli in IA in zebrafish. Adult zebrafishes were tested in three experiments: validation of white compartment as aversive in IA; open field test; and effect of antidepressant (fluoxetine, imipramine) and anxiolytic (diazepam, clonazepam). The data show the effectiveness of the white compartment as an aversive stimulus in IA. Antidepressant fluoxetine did not alter and imipramine impairs avoidance acquisition in higher doses. Imipramine also produced a sedative effect in lower doses. Anxiolytic and stimulant drugs facilitated learning at doses which did not impair locomotion, suggesting that pharmacological manipulation of other factors in addition to fear/anxiety can impact aversive learning in zebrafish.

Extinction of avoidance behavior by safety learning depends on endocannabinoid signaling in the hippocampus

The development of exaggerated avoidance behavior is largely responsible for the decreased quality of life in patients suffering from anxiety disorders. Studies using animal models have contributed to the understanding of the neural mechanisms underlying the acquisition of avoidance responses. However, much less is known about its extinction. Here we provide evidence in mice that learning about the safety of an environment (i.e., safety learning) rather than repeated execution of the avoided response in absence of negative consequences (i.e., response extinction) allowed the animals to overcome their avoidance behavior in a step-down avoidance task. This process was context-dependent and could be blocked by pharmacological (3 mg/kg, s.c.; SR141716) or genetic (lack of cannabinoid CB1 receptors in neurons expressing dopamine D1 receptors) inactivation of CB1 receptors. In turn, the endocannabinoid reuptake inhibitor AM404 (3 mg/kg, i.p.) facilitated safety learning in a CB1-dependent manner and attenuated the relapse of avoidance behavior 28 days after conditioning. Safety learning crucially depended on endocannabinoid signaling at level of the hippocampus, since intrahippocampal SR141716 treatment impaired, whereas AM404 facilitated safety learning. Other than AM404, treatment with diazepam (1 mg/kg, i.p.) impaired safety learning. Drug effects on behavior were directly mirrored by drug effects on evoked activity propagation through the hippocampal trisynaptic circuit in brain slices: As revealed by voltage-sensitive dye imaging, diazepam impaired whereas AM404 facilitated activity propagation to CA1 in a CB1-dependent manner. In line with this, systemic AM404 enhanced safety learning-induced expression of Egr1 at level of CA1. Together, our data render it likely that AM404 promotes safety learning by enhancing information flow through the trisynaptic circuit to CA1.

Behaviourally inhibited temperament and female sex, two vulnerability factors for anxiety disorders, facilitate conditioned avoidance (also) in humans

Acquisition and maintenance of avoidance behaviour is a key feature of all human anxiety disorders. Animal models have been useful in understanding how anxiety vulnerability could translate into avoidance learning. For example, behaviourally inhibited temperament and female sex, two vulnerability factors for clinical anxiety, are associated with faster acquisition of avoidance responses in rodents. However, to date, the translation of such empirical data to human populations has been limited since many features of animal avoidance paradigms are not typically captured in human research. Here, using a computer-based task that captures many features of rodent escape-avoidance learning paradigms, we investigated whether avoidance learning would be faster in humans with inhibited temperament and/or female sex and, if so, whether this facilitation would take the same form. Results showed that, as in rats, both vulnerability factors were associated with facilitated acquisition of avoidance behaviour in humans. Specifically, inhibited temperament was associated with higher rate of avoidance responding, while female sex was associated with longer avoidance duration. These findings strengthen the direct link between animal avoidance work and human anxiety vulnerability, further motivating the study of animal models while also providing a simple testbed for a direct human testing.

Effects of antibodies against S-100 antigen in ultralow doses (Proproten-100) on acquisition of avoidance response in rats

We studied the effect of potentiated antibodies against S-100 antigen on learning of avoidance responses of 2 types. Peroral administration of antibodies promoted inhibition of locomotor activity and feeding behavior, which was associated with electrical pain stimulation. Our results indicate that the preparation in ultralow doses modulates the mechanism of memory formation.

Improvement in brain function and oxidative damage of aged senescence-accelerated mice by green tea catechins

Learning and memory functions decline with aging. Oxidative damage has been considered to be a cause of age-associated brain dysfunction because the brain is believed to be particularly vulnerable to oxidative stress. We investigated the influence of green tea catechins (GT-catechin), which have been reported to have antioxidative effects, on learning and memory using senescence-accelerated mice (SAMP10). The learning time for acquisition of avoidance response and the ratio of working memory in a Y-maze indicated that GT-catechin intake was effective for improvement of learning and memory functions in aged SAMP10 mice. In addition, we found that GT-catechin intake was effective for the suppression of cerebral atrophy in SAMP10 of 12-month-old mice. Levels of 8-oxodeoxyguanosine (8-oxodG) were suppressed in rhinencephalon and in liver of SAMP10 mice that had drunk catechin water. These results suggest that intake of GT-catechin over a long term partially improves oxidative damage and morphologic and functional alterations of the brain in aged SAMP10.

Leverpress escape/avoidance conditioning in rats: safety signal length and avoidance performance.

Leverpress escape/avoidance is an excellent model for assessing coping in rats. Acquisition of the leverpress response is determined by the interstimulus (signal-shock) interval, as well as the type and duration of the aversive event. One factor that has received less research attention is the safety or feedback signal. The safety signal presumably negatively reinforces leverpress responding through fear reduction. Here, we present a parametric manipulation of safety signal length and avoidance performance. All rats were trained with a 60-s tone conditioned stimulus and an intermittent 1-s, 1.0-mA footshock. Training was further accomplished with a 1-, 2-, 4-, or 6-min safety signal. Acquisition of the avoidance response was comparable at all safety signal durations. Rats trained with the shortest safety signal (1 min) exhibited more leverpresses during the safe period, a measure of anxiety. Thus, acquisition of the leverpress avoidance response was efficient regardless of safety signal duration, even though shorter periods were associated with greater anxiety.

Effects of histamine precursor and (R)-α-methylhistamine on the avoidance response in rats

The aim of this work is to clarify the role of histamine in learning and memory processes. In order to do this, the effect of administration of the histamine precursor, l-histidine (HIS) and of the agonist of the H 3 receptor, (R)-α-methylhistamine (RAMH), on active avoidance response in rats is studied. Treatment with RAMH (10 mg/kg i.p.) increased the number of avoidance responses produced during acquisition and retention of the learning. In contrast, administration of l-his (500 mg/kg i.p.) impairs performance in the shuttle-box. These results are consistent with a role for histamine in cognitive processes and suggest that a increase in cerebral histamine levels impair the acquisition of avoidance response, whereas reduced levels facilitate this acquisition.

Effect of cyproheptadine treatment on conditioned avoidance response in female rats

1. 1. The percentage of conditioned avoidance response was higher during proestrus compared to diestrus. 2. 2. Cyproheptadine (CPH) significantly enhanced avoidance behavior during diestrus. 3. 3. On the other hand, CPH treatment did not alter avoidance behavior during proestrus. 4. 4. Serum progesterone and testosterone levels were determined at the end of 60 trials for acquisition of conditioned avoidance response after prolonged (12–15 days) CPH treatment (0.5 mg/kg for 24 h per os (p.o.). 5. 5. Prolonged CPH treatment lowered adrenal testosterone levels, and rats with impaired avoidance had higher testosterone and progesterone levels. 6. 6. The results of this study indicate a positive role for CPH in the acquisition of avoidance response during diestrus, and a negative effect of progesterone and adrenal testosterone on the avoidance response.

Similar effects of ethanol and flumazenil on acquisition of a shuttle‐box avoidance response during withdrawal from chronic ethanol treatment

1. Acquisition of a two-way shuttle-box avoidance response is facilitated by ethanol. This facilitated acquisition of an avoidance response to ethanol was attenuated during withdrawal from chronic-ethanol diet intake (i.e. tolerance developed by ethanol). The deficit in the avoidance task after chronic ethanol treatment could be overcome by increasing the dose of ethanol. 2. Flumazenil, a benzodiazepine antagonist, also facilitated acquisition of the avoidance response in control rats. This response to flumazenil was significantly reduced during withdrawal from chronic-ethanol treatment. This reduced avoidance responding during withdrawal also could be overcome by increasing the dose of flumazenil. 3. The benzodiazepine-inverse agonist, RO 15-4513, produced a deficit in avoidance responding that was antagonized by both ethanol and flumazenil in a dose-related manner. 4. To determine whether flumazenil has the properties of a benzodiazepine agonist, it was established that, unlike the benzodiazepine chlordiazepoxide, flumazenil did not enhance the ethanol-induced deficit in the aerial righting reflex. Additionally, flumazenil blocked the action of chlordiazepoxide in this procedure, consistent with the benzodiazepine antagonist action of flumazenil. 5. Data collected are consistent with the hypothesis that an endogenous substance with the properties of a benzodiazepine-inverse agonist antagonizes the anticonflict actions of acutely administered ethanol during withdrawal from chronic-ethanol exposure.

Cocaine administration prior to reactivation facilitates later acquisition of an avoidance response in rats.

The effect of cocaine administered prior to memory reactivation on the subsequent acquisition of an avoidance response was investigated. Two noncontingent footshocks were administered to rats in the black compartment of a one-way avoidance chamber. Twenty-four hours later, cocaine or saline was administered 5 min prior to a 30-s reactivation treatment consisting of re-exposure to selected stimuli present during the initial conditioning. Subjects were trained 24 h later to move from the chamber's black compartment to its white compartment in order to avoid a footshock. Intermediate (5.0 or 7.5 mg/kg IP), but not low (3.3 mg/kg IP) or high (11.25 or 16.88 mg/kg IP), doses of cocaine given prior to the reactivation treatment enhanced later acquisition of the one-way avoidance response. These results suggest that cocaine administered prior to the reintroduction of cues associated with a conditioning episode can modulate memory processes, and that the dose-response function for this effect is U-shaped. The avoidance performance of rats that received cocaine (5.0 mg/kg IP) 3 h after the reactivation treatment did not differ from that of saline-treated control subjects, suggesting that the conjoint neural activity elicited by cocaine and exogenous retrieval cues is necessary for potentiation of memory retrieval or reconstruction processes.

D-Pen 2-[ d-Pen 5]Enkephalin impairs acquisition and enhances retention of a one-way active avoidance response in rats

We reported previously that d-Pen 2-[ d-Pen 5]enkephalin (DPDPE), a δ-opioid receptor selective analog of Leu-enkephalin, impairs acquisition of an automated jump-up avoidance response in rats and acquisition of a one-way active avoidance response in mice. In the present study we investigated the effects of DPDPE on one-way avoidance conditioning in rats. The rats received two escape-only trials on day 1 and eight additional training trials on day 2. DPDPE (1.16 μg/kg IP) administered prior to training on day 2 impaired acquisition of the avoidance response. On the other hand, DPDPE (0.332 μg/kg IP) administered following presentation of the two escape-only trials on day 1 significantly enhanced retention, as measured by improved one-way active avoidance performance on day 2. These results indicate that activation of δ-opioid receptors by DPDPE has a modulatory effect on acquisition and retention of aversively motivated performance.

Only tyrosine-containing metabolites of [Leu]Enkephalin impair active avoidance conditioning in mice

The effects of the enkephalin metabolites, Tyr, des-Tyr-[Leu]enkephalin (GGFL), and Tyr-Gly-Gly (YGG), on acquisition of an active avoidance task following their IP administration to mice were determined. Neither free Tyr (3.9-390.0 micrograms/kg) nor GGFL (7.1-710.0 micrograms/kg) altered acquisition of the avoidance response. In contrast, 53, but not 16 micrograms/kg, of YGG significantly impaired response acquisition. A 390.0, but not 39.0 micrograms/kg, dose of Tyr decreased locomotor activity levels measured in an open field. Together with previous findings that the enkephalin metabolites Tyr-Gly and Tyr-Gly-Gly-Phe also impair avoidance acquisition, these data indicate that the dipeptide Tyr-Gly is the minimum sequence needed to intefere with acquisition of an active avoidance response. Because the various enkephalin metabolites do not bind to opioid receptors, it is likely that their effects on avoidance acquisition represent a separate class of pharmacological agents whose effects are mediated by a nonopioid receptor mechanism. These results are important to the interpretation of behavioral studies involving peripheral administration of the opioid peptide, [Leu]enkephalin (LE).

Limbic networks and associative learning: I. Entorhinal contributions to instrumental conditioning

The hippocampal formation is a highly delineated brain structure that is believed to play a prominent role in learning and memory. The present experiment evaluated the contributions of medial and lateral perforant path input to bar press-conditioning under (a) continuous and (b) differential reinforcement of low rates of responding (DRL) schedules, and (c) shuttlebox avoidance conditioning. Bilateral deafferentation of either pathway had no effect on the acquisition of bar press responses or on performance under the DRL schedule. Deafferentation of the medial pathway facilitated acquisition of avoidance responses in a manner much like the effects seen in hippocampectomized animals. It is suggested that the medial perforant path participates in the expression of correlated patterns of neuronal discharge known to develop within the hippocampus and that this “model” serves to modulate the temporal characteristics of simple conditioned reflexes. Loss of the modulatory influence of the model may affect acquisition and extinction rates. Contributions of other hippocampal circuits are discussed in relation to established deficits.

Two Metabolites of [Leu]enkephalin, Tyr-Gly and Tyr-Gly-Gly-Phe, Impair Acquisition of an Active Avoidance Response in Mice

Two tyrosine-containing enkephalin metabolites, Tyr-Gly and Tyr-Gly-Gly-Phe, were found to impair acquisition of a one-way active avoidance response when administered intraperitoneally to mice. Prior studies demonstrated that the enkephalin metabolite Tyr-Gly-Gly also impairs avoidance acquisition, but that the tetrapeptide Gly-Gly-Phe-Leu is without similar effects. Since [leu]enkephalin also impairs acquisition of the avoidance response, these data are consistent with the suggestion that enkephalin metabolites containing an N-terminal tyrosine may be the active principals for the behavioral effects produced by [leu]enkephalin. Alternatively, these metabolites may represent a separate class of pharmacological agents that shares some behavioral effects with the enkephalins, but that produces effects on learning through a different mechanism.

Age-related changes in learning and memory in the senescence-accelerated mouse (SAM)

Age-related changes in learning ability were studied in senescence-accelerated mice (SAM) reared under specific pathogen-free (SPF) conditions. SAM-P/8/Ta (SAM-P/8, senescence-prone substrain) showed an age-associated increase in spontaneous motor activity (SMA) compared with SAM-R/1/Ta (SAM-R/1, senescence-resistant substrain) in a novel environment when the activity was measured in the light period, although there was no significant difference in the dark period. In observations of the circadian rhythm of SMA, SAM-P/8 showed a significant increase in diurnal SMA. In SAM-P/8 mice, the acquisition of passive avoidance response was slightly but significantly impaired even at 2 months of age, compared with SAM-R/1 control; the impairment became obvious with aging. In a one-way active avoidance task, SAM-P/8 did not show any impairment in the acquisition of avoidance response at 2 and 4 months of age. However, significant impairment was observed in SAM-P/8 at 12 months of age. The impairments of avoidance tasks were not due to a decrease in shock sensitivity, as indicated by no significant change in the flinch-jump threshold. In a water-filled multiple T-maze task, there was no difference in the number of errors between the two groups. With regard to the performance time to reach the goal, however, SAM-P/8 showed a mild prolongation at 2 months of age, and the prolongation became marked with advancing age. Furthermore, SAM-P/8 showed an age-related increase in the latency to escape onto the hidden platform in the Morris water task as compared with the control mice, whereas a slight but significant impairment was observed even at 2 months of age. These results indicate that SAM-P/8 shows age-related deterioration of ability in learning and memory, and the two factors of genetic strain difference and acceleration of aging are likely to be involved in the deterioration observed in SAM-P/8. Also, it is suggested that SAM-P/8 may be useful as an experimental animal model for senile memory impairment in humans.

Central versus peripheral actions of Leu-enkephalin on acquisition of a one-way active avoidance response in rats

A comparison was carried out of the effectiveness of intracerebroventricular or intraperitoneal administration of Leu-enkephalin to affect acquisition of a one-way active avoidance response, locomotor activity or shock sensitivity. Leu-enkephalin impaired acquisition of the avoidance response only when administered peripherally. In contrast, either central or peripheral administration of Leu-enkephalin increased locomotor activity in the open field, and Leu-enkephalin also produced analgesia when administered directly into the brain. The pattern of results suggests that Leu-enkephalin acts at a peripheral site to influence avoidance conditioning.

Classical conditioning of an “avoidance” response in goldfish using a linear presentation procedure

The present study examined the nature of the “avoidance” response in goldfish under the linear presentation procedure (Zerbolio, 1981). With this procedure, shuttling behavior occurring during the presentation of the trial stimulus produces either CS− or CS+, and further occurrence of shuttling within the trial interval (10 sec) changes the value of CS from negative to positive, or vice versa. If the fish remains in the compartment when the prevailing cue state is CS− at the end of the interval, shock can be avoided. With this procedure fish responded to the CS+ more than to the CS− and avoided shock. But fish in one of two control groups, in which responses had no effect in changing the cue state from CS+ to CS−, or vice versa, also showed a clear differentiation. The results were generally in line with the view that the “avoidance” response in fish is acquired through classical conditioning. The contribution of classical conditioning to the acquisition of avoidance response is discussed.

Effect of high doses of naloxone on shuttle avoidance acquisition in rats

Administration of high doses of naloxone intraperitoneally (2.5 – 0.0 mg/kg) resulted in a dose-related impairment of avoidance response acquisition in a shuttle avoidance paradigm in rats. Naloxone in this dose range produced a significant decrease in the number of intertrial responses but did not result in a significant dose-response. Escape latencies were not affected by naloxone administration at any dose tested. The effect of naloxone on activity and nociception are implicated as possible causes of the observed behavior. The results are discussed as behavioral evidence supporting theories postulating multiple opiate receptors.