Rita B. Messing

Des-Gly-vasopressin improves acquisition and slows extinction of autoshaped behavior

The effects of a vasopressin analog (DGAVP) with minimal endocrinological activity, were assayed on acquisition and extinction of a discrete trial, food reinforced, autoshaped lever touch response. Magazine-trained rats, maintained at 80-85% of free-feeding body weights, were injected s.c. with saline, 5 or 10 micrograms/kg of DGAVP 1 h before each of two sessions in which they learned to touch a retractable lever, presented on a 45 s random interval (RI 45) schedule. Retracted lever contacts (nose-pokes) and unconditioned rearing activity were simultaneously monitored. After acquisition of the extended lever touch response, rats were reassigned to treatment groups, and again injected with saline, 5 or 10 micrograms/kg of DGAVP 1 h before each of two extinction sessions. DGAVP facilitated acquisition (5 micrograms/kg) and slowed extinction (5 and 10 micrograms/kg) of conditioned behavior, while having no effects on the other behaviors, thus demonstrating the specificity of the effect of a vasopressin-like compound on both tasks (enhanced acquisition and retarded extinction) used to study learning.

Greater task difficulty amplifies the facilitatory effect of des-glycinamide arginine vasopressin on appetitively motivated learning.

Rats were trained in a discrete-trial forward autoshaping paradigm to touch an extended lever to earn food pellets. Reinforcement was delivered either simultaneously with or 6 s after lever retraction which occurred either non-contingently after 15 s or when the animal touched the lever. Treatment with des-glycinamide arginine vasopressin (DGAVP; 15 micrograms/kg, sc) 1 hr before sessions increased the rate of acquisition of the extended-lever-touch response and also facilitated development of intertrial (adjunctive) nose poking. Effects of the peptide were more robust in the more difficult, delayed reinforcement task. DGAVP lacks the classical peripheral activity of vasopressin. In both experiments, peptide treatment was terminated before asymptotic levels of performance were attained; the continued facilitation of acquisition in treated groups suggests a specific enhancement of learning and/or enhanced memory retrieval.

Delaying reinforcement in an autoshaping task generates adjunctive and superstitious behaviors

Rats were autoshaped to touch a lever upon its insertion into an operant chamber on a 45 s random time schedule. Occurrence of a reinforced touch on each of 12 lever insertions per session and nose-pokes at the retracted lever were monitored, as was exploratory rearing activity. Delays of 2, 4 or 8 s interposed between the retraction of the lever, which occurred either after 15 s or after a touch response, and delivery of the food pellet reward, resulted in progressively slower acquisition of the extended lever touch response. However, if rats had already acquired the response under immediate reinforcement conditions, the delays subsequently introduced did not cause a decline in autoshaped touch responding. Nose-pokes at the retracted lever occurred during both intertrial and reinforcement delay intervals over the course of autoshaping. The appearance and frequency of these (adjunctive or superstitious) behaviors depended upon the reinforcement delay and behavioral history. These interval behaviors offer measurements of learning not based on arbitrary criteria; they thus provide information about effects on endpoints, or a more global approach to learning.

Selective learning impairment of delayed reinforcement autoshaped behavior caused by low doses of trimethyltin.

The organometal neurotoxin trimethyltin (TMT), induces impaired learning and memory for various tasks. However, administration is also associated with other “non-specific” behavioral changes which may be responsible for effects on conditioned behaviors. To determine if TMT treatment causes a specific learning impairment, three experiments were done using variations of a delay of reinforcement autoshaping task in which rats learn to associate the presentation and retraction of a lever with the delivery of a food pellet reinforcer. No significant effects of TMT treatment were found with a short (4 s) delay of reinforcement, indicating that rats were motivated and had the sensorimotor capacity for learning. When the delay was increased to 6 s, 3.0 or 6.0 mg TMT/kg produced dose-related reductions in behaviors directed towards the lever. Performance of a group given 7.5 mg TMT/kg, while still impaired relative to controls, appeared to be better than the performance of groups given lower doses. This paradoxical effect was investigated with a latent inhibition paradigm, in which rats were pre-exposed to the Skinner boxes for several sessions without delivery of food reinforcement. Control rats showed retardation of autoshaping when food reinforcement was subsequently introduced. Rats given 7.5 mg TMT/kg exhibited elevated levels of lever responding during pre-exposure and autoshaping sessions. The results indicate that 7.5 mg TMT/kg produces learning impairments which are confounded by hyperreactivity to the environment and an inability to suppress behavior toward irrelevant stimuli. In contrast, low doses of TMT cause learning impairments which are not confounded by hyperreactivity, and may prove to be useful models for studying specific associational dysfunctions.

Does vasopressin really facilitate memory processes

Department of Pharmacology. Medical School University of Minne~ota. Mimwapoli.~. .%,t,% 55455. I S.4. Background In numerous experiments published since the mid-196(Is, De Wied and Bohus and their colleagues have found that very small quantities of vasopressin or several analogs (picograms when adminis- tered into the CNS; micrograms system- ically) can increase resistance to extinction of shock-motivated active avoidance (pole-jumping) behavior, and enhance memory-related performance (retention and retrieval) in standard passive avoid- ance tests ~-3. Others have found that vasopressin also has the capacity to attenuate deficits in avoidance retention performance produced by a variety of treatments, which have been adminis- tered after training as models to study amnesia 23. From such observations, the Dutch researchers have advanced the hypothesis that vasopressin plays a direct, fadlitatory role in memory consolida- tion and retrieval processes 3. Recent advances in our understanding of the metabolism and distribution of endogenous neuroactive peptides in general, and the neurohypophyseal pep- tides vasopressin and ox3tocin in parti- cular, have led to a more widespread interest in their possible functions as neurohumoral agents. This interest has been accompanied by a renewed clinical and basic research effort to test the hypothesis that vasopressin can indeed improve memory. The clinical research to date contains mostly equivocal results. In general, vasopressin has been found to be ineffec- tive in patients with severe memory deficits (e.g. advanced Aizheimers patients, severely impaired Korsakoffs patients) ¢-6. However, in the few cases in which the compound, or its analogs, desglycinamide-9-arginine-8-vasopressin (DGAVP) or 1-des-amino-8-o-arginine-. vasopressin (DDAVP) have been tried with less severely impaired amnesic, aged or cognitively deficient patients, the results have been somewhat more positive t9. Thus, the limited clinical research has been sufficiently encourag- ing to generate interest in animal experi- mentation to re-examine several un- resolved issues. Interpretive

Learning enhancement and behavioral arousal induced by yohimbine

Learning of a food motivated delayed reinforcement autoshaping task was investigated in rats treated with water vehicle or the prototypical anxiogenic agent and alpha 2-adrenergic antagonist yohimbine (0.5 or 1.5 mg/kg, i.p. 30 min before behavioral testing). Unconditioned exploratory rearing activity was monitored concomitantly with acquisition of a lever touch response. The low dose of yohimbine enhanced learning, but it also increased unconditioned behavioral arousal. The high dose retarded acquisition, but when it was withdrawn the animals learned but exploratory activity increased beyond control levels prior to acquisition. Learning thus appeared to be related to the behavioral arousal produced by yohimbine, suggesting that learning enhancement by anxiogenic substances is not due to a direct effect on processes intrinsic to information storage and retrieval; rather, anxiogenic substances may be important modulators of vigilance and performance variables.

Naloxone administration impairs autoshaped learning

Effects of naloxone on acquisition of autoshaped behavior were investigated. Rats deprived to 85% of free-feeding weights were trained to touch a retractable lever; delivery of a food pellet occurred on every trial following lever retraction. The lever was retracted immediately if a touch occurred within 15 s, or automatically after 15 s. Analyses were conducted on number and latencies of touches of the extended lever, nose-pokes (touches) directed at the retracted lever during intertrial intervals (a measure less constrained by ceiling effects than extended lever touches), and unconditioned exploratory rearing activity, measured as touches of a metal strip mounted above the grid floor of the apparatus. In an initial experiment, male Sprague-Dawley rats were given saline or naloxone (2.0 mg/kg, ip) 5 min before a training session of 12 trials. Two days later they were tested, in the absence of drug, in a session of 36 (three blocks of 12) trials. Naloxone depressed training levels of lever responding, in addition to slowing acquisition rate. No effect of naloxone was observed on rearing activity. Previous work showed that injection of saline 5 min before behavioral testing increases the rate of autoshaping compared to injections 30 min before (Messing & Sparber, 1984). Thus, effects of naloxone on acquisition of lever-directed behaviors may have been confounded by behavioral depressant effects and/or by an injection effect such a short time before testing. In a second experiment naloxone (0.5 or 2.0 mg/kg) was injected after five of seven training sessions (12 trials each) to male and female rats. A 6-s delay of reinforcement was inserted between lever retraction and food delivery, slowing acquisition rates and providing the opportunity to test the effects of naloxone throughout a multiple-session task. The low dose retarded acquisition of extended lever touching in both sexes; both doses retarded acquisition of interim lever touching in males. Thus, in some circumstances, post-training naloxone administration may impair learning. The results support the notion that low doses of naloxone may have agonist activity.

Food deprivation enhances both autoshaping and autoshaping impairment by a latent inhibition procedure

The influence of food deprivation on acquisition of autoshaped operant behavior was measured. In one study separate groups of young, male rats that were deprived to 75%, 80%, 85%, 90%, and 95% of ad lib weight were subjected to an autoshaping procedure in which a 6 s delay was interposed between lever retraction (which occurred when rats made a lever touch, or automatically after 15 s) and food pellet delivery. In a second study, groups of rats were deprived to 80% or 90% of ad lib weight prior to testing in a latent inhibition variation of the same autoshaping procedure. This was done to determine if greater food deprivation would enhance learning which, because of the latent inhibition manipulation, is manifest as less lever-directed behavior. Greater food deprivation was associated both with fast acquisition of autoshaped lever responding and with more reliable failure to increase lever responding in the latent inhibition paradigm. Thus, increasing food deprivation was associated with enhanced acquisition regardless of whether the required performance was an increase or a failure to increase the same behavior, indicating a specific effect on learning.

Limbic forebrain toxin trimethyltin reduces behavioral suppression by clonidine

Trimethyltin (TMT) at moderate doses selectively damages hippocampus and related olfactory cortex and produces learning and memory impairments. TMT also increases forebrain beta-adrenergic ligand binding; this could be ancillary to reduced noradrenergic neurotransmission, which in turn could be involved in the cognitive deficit caused by TMT. If this hypothesis is correct, then the alpha 1-adrenergic agonist clonidine, which inhibits noradrenergic neurotransmission in normal subjects, should be less behaviourally effective after TMT poisoning. Thus, rats treated with water vehicle or TMT (6 mg/kg, PO) were given saline or clonidine IP (5, 10, or 20 micrograms/kg) 30 min before placement in a hole-board apparatus. Exploratory activity was reduced in controls by 10 or 20 micrograms/kg. Clonidine at 10 micrograms/kg was ineffective in rats given TMT. At 20 micrograms/kg, an apparent reduction in exploratory activity was not significant because variability of responding was higher after TMT treatment. The results suggest an impairment in noradrenergic neurotransmission following TMT poisoning.

Increased forebrain β-adrenergic ligand binding induced by trimethyltin

Abstract Systemic injection of the organometal neurotoxin trimethyltin (TMT) into rats causes impairments in learning and memory. However, there is a discontinuity in dose-response functions, such that the deficit which emerges with a higher, acutely toxic dose, is qualitatively different from the impairment induced after lower doses. To investigate synaptic receptor changes associated with behavioral deficits, neurotransmitter-receptor ligand binding assays were done in forebrain areas of rats given TMT (3,6 or 7.5 mg/kg). Binding of the β-adrenergic ligand, dihydroalprenol in frontal cortex and amygdala/pyriform cortex was an inverted U-shaped function of TMT dose, with rats given the median dose exhibiting increased binding. The curvilinear dose-response functions in behavioral and biochemical assays suggest that altered forebrain noradrenergic neurotransmission could play a role in behavioral deficits.