Role of learning of open arm avoidance in the phenomenon of one-trial tolerance to the anxiolytic effect of chlordiazepoxide in mice

A single exposure to the elevated plus-maze (EPM) test of anxiety reduces or abolishes the anxiolytic efficacy of benzodiazepines on a second trial. Some possible explanations to the occurrence of this phenomenon (one-trial tolerance-OTT) involve behavioral modifications thought to be consequence of some kind of learning in the first trial. In the present study, the influence of learning-impairing situations on the effects of the benzodiazepine chlordiazepoxide on mice re-tested in the EPM is investigated. The results showed that: (1) as expected, the administration of chlordiazepoxide to mice re-tested in the EPM- under the same conditions of the first trial- failed to induce anxiolysis; (2) a decreased percent time in the open arms was observed on the second trial of mice exposed to both trials under the same experimental conditions; (3) neither the increase in open arm avoidance by mice re-exposed to the EPM nor the OTT to chlordiazepoxide effect were modified by administration of the amnestic agent scopolamine; (4) the decrement of the duration of the first trial to 1 min or the change in light and noise conditions in both trials counteracted the increase in open arm avoidance on trial 2; (5) none of the later procedures modified the phenomenon of OTT. Although not discarding the modulation exerted by other memory processes in the OTT phenomenon, the results indicate that situations that impair the learned avoidance response to the open arms in the EPM do not modify the phenomenon of OTT.     

Performance of mice in an automated olfactometer: odor detection, discrimination and odor memory

Mice were trained on a variety of odor detection and discrimination tasks in 100- or 200-trial sessions using a go, no-go discrete trials operant conditioning procedure. Odors, presented for 1 s on each trial, were generated by an air dilution olfactometer (for threshold tests) and an easily constructed eight-channel liquid dilution unit (for two- and multiple-odor discrimination tasks). Mice rapidly acquired the operant task and demonstrated excellent stimulus control by odor vapors. Their absolute detection threshold for ethyl acetate was similar to that obtained with rats using similar methods. They readily acquired four separate two-odor discrimination tasks and continued to perform well when all eight odors were presented in random order in the same session and when reinforcement probability for correct responding was decreased from 1 to 0.5. Memory for these eight odors, assessed under extinction after a 32 day rest period, was essentially perfect. Time spent sampling the odor on S+ and S- trials was highly correlated with response accuracy. When accuracy was at chance levels (e.g. initial trials on a novel task), stimulus sampling time on both S+ and S- trials was approximately 0.5-0.7 s. As response accuracy increased, sampling time on S+ trials tended to increase and remain higher than sampling time on S- trials.     

Some effects of a discrete trial procedure on differentiation learning by Japanese monkeys

Employing newly developed equipment, which permitted presentation of discriminative stimuli and the response manipulandum separately, the present study reexamined the results ofMcClearn's (1957) study on differentiation learning. When a discrete trial procedure analogous toMcClearn's was used, the subjects (two Japanese monkeys;Macaca fuscata fuscata) persisted in responding on S- trials, replicatingMcClearn's results. However, when a free operant procedure was used, in which the response manipulandum was continually available, the subjects made few responses during S- trials and showed almost complete differentiation. It was concluded that the discrete presentation of the manipulandum itself has some obstructive effects on differentiation, or successive discrimination learning.     

How rats combine temporal cues

The procedures for classical and operant conditioning, and for many timing procedures, involve the delivery of reinforcers that may be related to the time of previous reinforcers and responses, and to the time of onsets and terminations of stimuli. The behavior resulting from such procedures can be described as bouts of responding that occur in some pattern at some rate. A packet theory of timing and conditioning is described that accounts for such behavior under a wide range of procedures. Applications include the food searching by rats in Skinner boxes under conditions of fixed and random reinforcement, brief and sustained stimuli, and several response-food contingencies. The approach is used to describe how multiple cues from reinforcers and stimuli combine to determine the rate and pattern of response bouts.     

A general method for evaluating incubation of sucrose craving in rats

For someone on a food-restricted diet, food craving in response to food-paired cues may serve as a key behavioral transition point between abstinence and relapse to food taking. Food craving conceptualized in this way is akin to drug craving in response to drug-paired cues. A rich literature has been developed around understanding the behavioral and neurobiological determinants of drug craving; we and others have been focusing recently on translating techniques from basic addiction research to better understand addiction-like behaviors related to food. As done in previous studies of drug craving, we examine sucrose craving behavior by utilizing a rat model of relapse. In this model, rats self-administer either drug or food in sessions over several days. In a session, lever responding delivers the reward along with a tone+light stimulus. Craving behavior is then operationally defined as responding in a subsequent session where the reward is not available. Rats will reliably respond for the tone+light stimulus, likely due to its acquired conditioned reinforcing properties. This behavior is sometimes referred to as sucrose seeking or cue reactivity. In the present discussion we will use the term "sucrose craving" to subsume both of these constructs. In the past decade, we have focused on how the length of time following reward self-administration influences reward craving. Interestingly, rats increase responding for the reward-paired cue over the course of several weeks of a period of forced-abstinence. This "incubation of craving" is observed in rats that have self-administered either food or drugs of abuse. This time-dependent increase in craving we have identified in the animal model may have great potential relevance to human drug and food addiction behaviors. Here we present a protocol for assessing incubation of sucrose craving in rats. Variants of the procedure will be indicated where craving is assessed as responding for a discrete sucrose-paired cue following extinction of lever pressing within the sucrose self-administration context (Extinction without cues) or as responding for sucrose-paired cues in a general extinction context (Extinction with cues).     

Effects of auditory frequency-shifts on zero and below-zero SCR habituation

The purpose of the present experiment was to test a procedure for the measurement of effects of zero- and below-zero habituation (BZH) on responding to frequency shifts in auditory stimuli. The present procedure avoided some of the drawbacks of other procedures, that is, long duration, ambiguity in the definition of BZH, and inadequate control procedures. Two groups received 18 stimulus presentations each; group 1 received first a tone of 1000 Hz 12 times, then 1400 Hz (test stimulus 1) 3 times, and 1850 Hz (test stimulus 2) 3 times. Group 2 received the same stimuli, but 3, 12, and 3 times, respectively. The procedure had the advantages of short duration of the experiment, zero habituation and BZH were operationally defined (as 3 and 12 stimulus presentations, respectively), and there were adequate control conditions since a control group that did not receive stimulus change on the relevant trial was employed. The results showed no effects of stimulus shifts on responding to the test stimuli. Group 2 responded significantly less than group 1 across trials, though, and this may be explained by an inhibitory process elicited by changes in weak stimulation during the habituation process.     

Estrus synchronization and superovulation with a subcutaneous gestagen implant (Norgestomet, Intervet) in suckler cows and heifers

Four trials were conducted to investigate the suitability of a gestagen implant (Norgestomet, Intervet) for estrus synchronization and superovulation in suckler cows and heifers kept under field conditions in Germany. In trial 1 out of 17 heifers treated 12 responded with one ovulation each. In trial 2 57 suckler cows were treated at the University experimental farm. Of 23 cows treated sooner and 34 cows treated later than 50 days post partum one (4 %) and 16 (47 %) respectively calved at the expected time. Trial 3 was a field trial involving 126 suckler cows and 21 heifers. Of 24 cows treated sooner and 102 cows treated later than 50 days post partum 17 % and 52 % respectively calved at the expected time. Of the 21 heifers only 19 % calved at the expected time. In trial 4 superovulation of 13 cows and 17 heifers resulted in 62 % and 94 % responding with 10.0 +/- 2.5 and 11.1 +/- 3.0 (x +/- SD ) ovulations per animal respectively.     

Stepping outside the box in considering the C/T ratio

Rate expectancy theory (RET) predicts that in Pavlovian procedures conditioned responding will be directly related to the ratio of time spent in the experimental context (C) relative to the trial time (T) or duration of the conditioned stimulus (CS). This prediction was discussed in the context of three experiments. The first and third experiments involved sexual conditioning in quail [Learn Motiv 31 (2000) 211; J Exp Psychol Anim Behav Processes 27 (2001) 269]; the second experiment involved conditioning rats with food as the unconditioned stimulus (US) [Learn Motiv 28(1997) 465]. In each experiment, one type of conditioned response was directly related to the C/T ratio (as predicted by RET) but another conditioned response was inversely related. In addition, the conditioned behavior that occurred with low C/T ratios was controlled by contextual cues rather than the putative CS. The implications of these findings for possible boundary conditions of RET were discussed. The discussion revealed serious shortcomings in the characterization of context conditioning by RET.     

Effects of retention interval on performance in a numerical reproduction task

The retention interval (RI) between the sample and production phase in a numerical reproduction task was varied to determine whether a "produce-small" effect would be obtained with increased delays. Four pigeons were trained with a retention interval of 2s, and then tested with intervals of 0.5s and 8s. Results showed a number-dependent, "produce-large" effect-response number increased when RI was increased-analyses of average response number and accuracy suggested RI affected responding most on the 2-flash trials with an 8-s RI. Additionally, discrimination between trial types decreased as RI increased. Existing explanations for the "choose-short/small" effect appear unable to account for these results; however the "produce-large" effect may be attributed to a disruption in stimulus control over responding.     

Fast odor learning improves reliability of odor responses in the locust antennal lobe

Recordings in the locust antennal lobe (AL) reveal activity-dependent, stimulus-specific changes in projection neuron (PN) and local neuron response patterns over repeated odor trials. During the first few trials, PN response intensity decreases, while spike time precision increases, and coherent oscillations, absent at first, quickly emerge. We examined this "fast odor learning" with a realistic computational model of the AL. Activity-dependent facilitation of AL inhibitory synapses was sufficient to simulate physiological recordings of fast learning. In addition, in experiments with noisy inputs, a network including synaptic facilitation of both inhibition and excitation responded with reliable spatiotemporal patterns from trial to trial despite the noise. A network lacking fast plasticity, however, responded with patterns that varied across trials, reflecting the input variability. Thus, our study suggests that fast olfactory learning results from stimulus-specific, activity-dependent synaptic facilitation and may improve the signal-to-noise ratio for repeatedly encountered odor stimuli.     

Bioresponsive matrices in drug delivery

For years, the field of drug delivery has focused on (1) controlling the release of a therapeutic and (2) targeting the therapeutic to a specific cell type. These research endeavors have concentrated mainly on the development of new degradable polymers and molecule-labeled drug delivery vehicles. Recent interest in biomaterials that respond to their environment have opened new methods to trigger the release of drugs and localize the therapeutic within a particular site. These novel biomaterials, usually termed "smart" or "intelligent", are able to deliver a therapeutic agent based on either environmental cues or a remote stimulus. Stimuli-responsive materials could potentially elicit a therapeutically effective dose without adverse side effects. Polymers responding to different stimuli, such as pH, light, temperature, ultrasound, magnetism, or biomolecules have been investigated as potential drug delivery vehicles. This review describes the most recent advances in "smart" drug delivery systems that respond to one or multiple stimuli.     

Nefiracetam (DM-9384) Preserves Hippocampal Neural Cell Adhesion Molecule-Mediated Memory Consolidation Processes During Scopolamine Disruption of Passive Avoidance Training in the Rat

Abstract: Scopolamine (0.15 mg/kg), a muscarinic antagonist, when administered during training or at a discrete 6-h posttraining time point, is demonstrated to inhibit the recall of a step-down passive avoidance response when tested at 24 and 48 h after task acquisition. Nefiracetam (3 mg/ kg), a piracetam-related nootropic, when given with scopolamine during training tended to improve task recall, and this effect was more pronounced when given at the 6-h posttraining time. Co-administration of nefiracetam with scopolamine was not necessary to achieve the antiamnesic action, as nefiracetam given during training significantly improved the memory deficits produced by scopolamine at the 6-h posttraining time. The paradigm-specific increase in hippocampal neural cell adhesion molecule sialylation, which is observed during consolidation of a passive avoidance response, was attenuated by the presence of scopolamine during training and at the 6-h posttraining time, and this effect was reversed by co-administration of nefiracetam, albeit in a paradigm-independent manner. These results suggest nefiracetam exerts a neurotrophic action that protects memory consolidation from drug inter- ventive insults.     

Slowing after Observed Error Transfers across Tasks

After committing an error, participants tend to perform more slowly. This phenomenon is called post-error slowing (PES). Although previous studies have explored the PES effect in the context of observed errors, the issue as to whether the slowing effect generalizes across tasksets remains unclear. Further, the generation mechanisms of PES following observed errors must be examined. To address the above issues, we employed an observation-execution task in three experiments. During each trial, participants were required to mentally observe the outcomes of their partners in the observation task and then to perform their own key-press according to the mapping rules in the execution task. In Experiment 1, the same tasksets were utilized in the observation task and the execution task, and three error rate conditions (20%, 50% and 80%) were established in the observation task. The results revealed that the PES effect after observed errors was obtained in all three error rate conditions, replicating and extending previous studies. In Experiment 2, distinct stimuli and response rules were utilized in the observation task and the execution task. The result pattern was the same as that in Experiment 1, suggesting that the PES effect after observed errors was a generic adjustment process. In Experiment 3, the response deadline was shortened in the execution task to rule out the ceiling effect, and two error rate conditions (50% and 80%) were established in the observation task. The PES effect after observed errors was still obtained in the 50% and 80% error rate conditions. However, the accuracy in the post-observed error trials was comparable to that in the post-observed correct trials, suggesting that the slowing effect and improved accuracy did not rely on the same underlying mechanism. Current findings indicate that the occurrence of PES after observed errors is not dependent on the probability of observed errors, consistent with the assumption of cognitive control account. Moreover, the PES effect appears across tasksets with distinct stimuli and response rules in the context of observed errors, reflecting a generic process. Additionally, the slowing effect and improved accuracy in the post-observed error trial do not occur together, suggesting that they are independent behavioral adjustments in the context of observed errors.     

Disentangling the nature of the nicotine stimulus

Learning involving interoceptive stimuli likely plays an important role in many diseases and psychopathologies. Within this area, there has been extensive research investigating the interoceptive stimulus effects of abused drugs. In this pursuit, behavioral pharmacologists have taken advantage of what is known about learning processes and adapted the techniques to investigate the behavioral and receptor mechanisms of drug stimuli. Of particular interest is the nicotine stimulus and the use of the two-lever operant drug discrimination task and the Pavlovian drug discriminated goal-tracking task. There is strong concordance between the two methods when using "standard" testing protocols that minimize learning on test days. For example, ABT-418, nornicotine, and varenicline all fully evoked nicotine-appropriate responding. Notably, research from our laboratory with the discriminated goal-tracking task has used an alternative testing protocol. This protocol assesses stimulus substitution based on how well extinction learning using a non-nicotine ligand transfers back to the nicotine stimulus. These findings challenge conclusions based on more "standard" testing procedures (e.g., ABT-418 is not nicotine-like). As a starting point, we propose Thurstone scaling as a quantitative method for more precisely comparing transfer of extinction across doses, experiments, and investigators. We close with a discussion of future research directions and potential implications of the research for understanding interoceptive stimuli.     

Isolated effects of number of acquisition trials on extinction of rat conditioned approach behavior

Four conditioned approach experiments with rats assessed for effects of number of acquisition trials on extinction of conditioned responding, when number of acquisition sessions and total acquisition time were held constant. In Experiment 1, 32 trials per acquisition session led to more extinction responding than did 1 or 2 trials per session but less than did 4 trials per session. In Experiment 2, 2 trials per acquisition session led to more spontaneous recovery than did 32 trials per session. These latter findings are reminiscent of the overtraining extinction effect (OEE). Experiment 3 attempted to reduce the OEE with a preconditioning phase of partial reinforcement. Experiment 4 attempted to reduce the beneficial within-subject effects of increasing the number of acquisition trials on extinction observed by Gottlieb and Rescorla (2010) by extinguishing stimuli in different sessions. Overall, results suggest a procedural asymmetry: between-subject, increasing the number of trials between any pair of trials does not lead to greater persistence of responding during extinction; within-subject, it does. Results are discussed from an associative perspective, with a focus on explanations involving either frustration or comparator mechanisms, and from an information processing perspective, with a focus on Rate Estimation Theory.     

Amphetamine affects the start of responding in the peak interval timing task

In this paper we investigate how amphetamine affects performance in a PI task by comparing two analyses of responding during peak trials. After training on 24 s fixed interval (FI-24) with 96 s peak trials, rats were given amphetamine for 4 consecutive days at doses of .5 and 1.0 mg/kg. Responses during peak trials were fitted with a Gaussian distribution to estimate the expected time of reinforcement from the peak time. A single trials analysis was also performed to determine the start time and stop time of the transition into and out of a high rate of responding on each peak trial. Amphetamine significantly decreased peak times as measured with the Gaussian curve fitting. However, in the single trials analysis, animals initiated responding significantly earlier, but did not stop responding earlier. Thus, fitting a Gaussian to the average performance across trials sometimes provides a different characterization of the timing process than does analyzing the start and stop of responding on individual trials. In the current experiment, the latter approach provided a more precise characterization of the effects of amphetamine on response timing.     

Effects of partial reinforcement and time between reinforced trials on terminal response rate in pigeon autoshaping

Partial reinforcement often leads to asymptotically higher rates of responding and number of trials with a response than does continuous reinforcement in pigeon autoshaping. However, comparisons typically involve a partial reinforcement schedule that differs from the continuous reinforcement schedule in both time between reinforced trials and probability of reinforcement. Two experiments examined the relative contributions of these two manipulations to asymptotic response rate. Results suggest that the greater responding previously seen with partial reinforcement is primarily due to differential probability of reinforcement and not differential time between reinforced trials. Further, once established, differences in responding are resistant to a change in stimulus and contingency. Secondary response theories of autoshaped responding (theories that posit additional response-augmenting or response-attenuating mechanisms specific to partial or continuous reinforcement) cannot fully accommodate the current body of data. It is suggested that researchers who study pigeon autoshaping train animals on a common task prior to training them under different conditions.     

Galantamine reverses scopolamine-induced behavioral alterations in Dugesia tigrina

In planaria (Dugesia tigrina), scopolamine, a nonselective muscarinic receptor antagonist, induced distinct behaviors of attenuated motility and C-like hyperactivity. Planarian locomotor velocity (pLMV) displayed a dose-dependent negative correlation with scopolamine concentrations from 0.001 to 1.0 mM, and a further increase in scopolamine concentration to 2.25 mM did not further decrease pLMV. Planarian hyperactivity counts was dose-dependently increased following pretreatment with scopolamine concentrations from 0.001 to 0.5 mM and then decreased for scopolamine concentrations ≥1 mM. Planarian learning and memory investigated using classical Pavlovian conditioning experiments demonstrated that scopolamine (1 mM) negatively influenced associative learning indicated by a significant decrease in % positive behaviors from 86 % (control) to 14 % (1 mM scopolamine) and similarly altered memory retention, which is indicated by a decrease in % positive behaviors from 69 % (control) to 27 % (1 mM scopolamine). Galantamine demonstrated a complex behavior in planarian motility experiments since co-application of low concentrations of galantamine (0.001 and 0.01 mM) protected planaria against 1 mM scopolamine-induced motility impairments; however, pLMV was significantly decreased when planaria were tested in the presence of 0.1 mM galantamine alone. Effects of co-treatment of scopolamine and galantamine on memory retention in planaria via classical Pavlovian conditioning experiments showed that galantamine (0.01 mM) partially reversed scopolamine (1 mM)-induced memory deficits in planaria as the % positive behaviors increased from 27 to 63 %. The results demonstrate, for the first time in planaria, scopolamine’s effects in causing learning and memory impairments and galantamine’s ability in reversing scopolamine-induced memory impairments.     

Cologne as a pungency control in tests of chemical discrimination: effects of concentration,brand, and simultaneous and sequential presentation

Cologne has been used extensively as a pungency control in experiments on chemosensory behavior to assess responses to an odorous, readily detectable stimulus that is irrelevant to the adaptive response being studied. However, undiluted cologne may be aversive, its effects might differ among brands, it might suppress responses to simultaneously presented chemical stimuli, and might affect subsequent responsiveness to other stimuli. We present experimental data showing that undiluted cologne can be aversive, but that aversion can be eliminated by dilution. We also show that the utility of cologne as a pungency control varies among brands, that cologne does not suppress responses to food chemicals in some species, but does in others, and that prior exposure to cologne does not affect later response to food chemicals. In 60 s swab trials with the Balearic lizard (Podarcis lilfordi), the main chemosensory responses were unaffected by cologne concentration. However, one-fourth of lizards exhibited slight to moderate aversion to undiluted cologne and 3:1 water:cologne, but not to a readily detected lower concentration (9:1). Two cologne brands did not affect responses, but a third brand induced increased tongue-flick rates. Colognes that stimulate increased tongue-flicking might mask real experimental effects. Cologne presented simultaneously with cricket chemicals did not affect tongue-flicking and biting responses in two species, but caused increased tongue-flicking in a third species and weaker response to cricket chemicals in a fourth. Prior testing with cologne did not affect responsiveness to cricket chemicals in a subsequent trial. Although cologne is a useful pungency control, pilot tests are needed to verify its utility for unstudied cologne types and animal species. Electronic Publication     

A method for estimating dry forage intake by sheep using polyethylene glycol as a faecal marker measured with NIRS

In experiments based on ruminants’ individual dry matter intake (DMI) assessment, several external markers can be used to estimate faecal output when total faeces collection is not possible. However, preparation of the markers to be administered and analytical procedures used for marker content determination are time-consuming thus strongly limiting the number of animals involved in the experiments. In this paper, polyethylene glycol (PEG, molecular weight 6000 da) was tested as a faecal marker. Four trials were conducted on dry, non-lactating ewes kept in digestibility crates that allowed individual measurements. The overall experiment was designed to assess the major factors that could lessen the effectiveness of this method, assuming that the use of grab samples of faeces is sufficient. Trial 1 was designed to test two levels of PEG (20 and 40 g/day) administered in two equal amounts. Trial 2 was designed to test the effect of either a single morning (0800 h) dose (20 g/day) or a twice daily administration (0800 and 1600 h) of the same fractionated dose. Trial 3 was designed to test a 20 g/day dose of PEG administered once daily to ewes fed with hays of different qualities: medium (MH) and low (LH). In trial 4, a lower dose of PEG (10 g/day) was administered once a day to ewes fed with fresh oat–vetch forage. It was demonstrated that PEG could be precisely estimated (average prediction error = 3.47 g/kg) with near-infrared reflectance spectroscopy (NIRS). On the basis of the four trials, it has been proved that PEG administration (20 and 40 g/day) did not significantly affect the DMI of ewes fed dry diets (trials 1, 2 and 3), whereas there was an unexpected increase of DMI for ewes fed exclusively with green feed (trial 4) without DM digestibility modification. Providing PEG as a single dose (0800 h) or split into two equal parts (0800 and 1600 h) did not alter the estimated DMI. Considering the interest of grab sampling, there were clear variations of PEG in faeces with higher concentrations observed at 0800 and 1600 h and lower concentrations at 1400 h. Consequently, with PEG (measured with NIRS) administered once and using the grab sampling procedure (morning collection), it is possible to estimate the DMI of dry feeds with good accuracy. For green feeds, more research is needed as the estimated results are still highly variable.