Repeated Acquisition Procedure Research Articles

Examination of clozapine and haloperidol in improving ketamine-induced deficits in an incremental repeated acquisition procedure in BALB/c mice.

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, causes locomotor hyperactivity, aberrant prepulse inhibition and impaired reversal learning among other deficits. There are numerous clinical and pre-clinically uses of NMDAR antagonists and a growing need to characterize their neurobehavioral effects. The present study was designed to characterize 1) ketamine's effect on incremental repeated acquisition (IRA), a procedure that taps multiple neurobehavioral functions and has performance measures correlated with IQ in humans, and 2) the extent to which clozapine (CLZ) and haloperidol (HAL) block ketamine's detrimental effects. In experiment 1 (Exp. 1), BALB/c mice nose-poked under an IRA procedure for sucrose pellets. Systemic ketamine (1-30 mg/kg) dose-dependently decreased measures of cognitive and motor function. CLZ pretreatment (CLZ 0.1-4.0 mg/kg) dose-dependently attenuated ketamine-induced (30 mg/kg) deficits; the effective dose range of CLZ was 0.3-1.0 mg/kg. HAL pretreatment (0.01-0.1 mg/kg) did not attenuate any ketamine-induced deficits. In experiment 2 (Exp. 2), BALB/c mice lever-pressed under an IRA procedure for sweetened condensed milk. Ketamine (30 mg/kg) produced a global impairment in the IRA procedure and CLZ pretreatment (0.3-1.0 mg/kg) dose-dependently attenuated that impairment; motor-based performance recovered to a greater extent than cognitive performance. When tested alone, these doses of CLZ had little effect on IRA performance. These findings support the notion that CLZ is more effective than HAL at blocking ketamine-induced deficits. The IRA procedure may be beneficial for distinguishing the efficacy of drugs that seek to alleviate deficits in complex behavior that result from acute NMDAR antagonism.

Effect of Dextromethorphan on Reference Memory Assessed in Rats by a Three-panel Runway Task

The effects of dextromethorphan (DM, CAS 6700-34-1), a common over-the-counter cough suppressant, on the reference memory have been investigated by a three-panel runway setup in rats. This study was designed by using a repeated acquisition procedure such as a radialarm maze task or a water maze task. DM (20-40 mg/kg i.p.) produced a significant decrease in the number of errors (pushes made on the two incorrect panels of the three panel gates at four choice points) and latency. Systemically administered scopolamine (CAS 114-49-8) (1 mg/kg i.p.) impaired the performance on both parameters. DM (40 mg/kg i.p.) was effective in reversing the reference memory deficit induced by administration of scopolamine. DM acts as a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptors. Our results suggest that inhibition of NMDA receptors by DM supports its potential positive properties. This finding might present an oppurtunity for the evaluation of this old antitussive drug.

Mechanisms and performance measures in mastery-based incremental repeated acquisition: behavioral and pharmacological analyses

Low doses of D: -amphetamine may enhance learning, depending on the conditions under which learning is studied. The objective of this study is to evaluate the sensitivity of procedural variations of an incremental repeated acquisition procedure to very low-dose D: -amphetamine administration. A 60-min session began with a one-link chain (single lever press) that incremented to a maximum of a four-link chain using three levers: left (L), right (R), and back (B). Backward (five rats) and forward (five rats) training procedures were used to build the chain. In pseudo-randomized presentations, a performance session (same chain every session) and a learning session (chain differed from session to session) were imposed. Some learning chains had an embedded repeated response (e.g., LRRB), and others had no such repeat (e.g., LRLB). The product of chain length and number of reinforcers divided by total reinforcers was the primary marker of progress during a session (i.e., progress quotient (PQ)). After behavior stabilized, D: -amphetamine (0.01-3.0 mg/kg, i.p.) was administered. Acquisition was superior for the backward training group during non-repeating learning sessions, across all but the highest doses of D: -amphetamine. Very low, clinically relevant, doses of D: -amphetamine improved acquisition for the backward training group during repeating learning sessions. Under some conditions, low doses of D: -amphetamine enhanced learning for one training procedure group. A novel dependent measure ("PQ") was a superior marker of progress on this mastery-based learning task.

Effects of MDMA, methamphetamine and methylphenidate on repeated acquisition and performance in rats

Repeated-acquisition procedures that include performance controls for effects not specific to acquisition permit the assessment of drug effects on learning on a within-subject, within-session basis. Despite the advantages of this methodology, few studies have examined effects of psychomotor stimulants on repeated acquisition in rodents. The purpose of the present study was to investigate the effects of methylenedioxymethamphetamine (MDMA, 0.3–10 mg/kg), methamphetamine (MA, 0.1–3 mg/kg) and methylphenidate (MPD,1–17 mg/kg) using repeated-acquisition procedures with performance controls in rats using a touch-screen apparatus. Rats were presented a 2 × 3 array of stimuli using a computer touch-screen and nose-pokes to target locations within the array were reinforced. In the acquisition component, the correct location changed across sessions, whereas during the performance component, the correct location was constant across sessions. All three drugs reduced accuracy of responding to target locations in a dose-dependent fashion. None of the compounds enhanced learning at any dose. MPD and MA produced significant disruptions of acquisition accuracy only at doses that also disrupted performance, but the 3 mg/kg dose of MDMA impaired acquisition of target responding without affecting performance. The selective impairment of acquisition found in the present study adds to the evidence of learning and memory disruption produced by acute MDMA administration and raise questions about the mechanisms for these actions.

EFFECTS OF RESPONSE SPACING ON ACQUISITION AND RETENTION OF CONDITIONAL DISCRIMINATIONS

Pigeons were exposed to a repeated acquisition procedure in which no delays were imposed and rate of responding was relatively high. They also were exposed to conditions in which delays were arranged between trials within chains or between completed chains, and rates of responding were lower. Number of trials, rate of reinforcement, difficulty of the discrimination, and motivating operations were held constant. Terminal accuracy was highest under the no-delay condition, in which rate of responding was highest. Effects of trial spacing on retention were mixed and depended on whether delays were imposed between trials within chains or between completed chains. These findings provide basic-research support for the rapid presentation of trials in direct instruction and for rate building in precision teaching.

Oral haloperidol or risperidone treatment in rats: Temporal effects on nerve growth factor receptors, cholinergic neurons, and memory performance

First and second generation antipsychotics (FGAs and SGAs) ameliorate psychotic symptoms of schizophrenia, however, their chronic effects on information processing and memory function (i.e. key determinants of long term functional outcome) are largely unknown. In this rodent study the effects of different time periods (ranging from 2 weeks to 6 months) of oral treatment with the FGA, haloperidol (2.0 mg/kg/day), or the SGA, risperidone (2.5 mg/kg/day) on a water maze repeated acquisition procedure, the levels of nerve growth factor receptors, and two important cholinergic proteins, the vesicular acetylcholine transporter and the high affinity choline transporter were evaluated. The effects of the antipsychotics on a spontaneous novel object recognition procedure were also assessed during days 8–14 and 31–38 of treatment. Haloperidol (but not risperidone) was associated with impairments in water maze hidden platform trial performance at each of the time periods evaluated up to 45 days, but not when tested during days 83–90. In contrast, risperidone did not impair water maze task performance at the early time periods and it was actually associated with improved performance during the 83–90 day period. Both antipsychotics, however, were associated with significant water maze impairments during the 174–180 day period. Further, haloperidol was associated with decrements in short delay performance in the spontaneous novel object recognition task during both the 8–14 and 31–38 day periods of treatment, while risperidone was associated with short delay impairment during the 31–38 day time period. Both antipsychotics were also associated with time dependent alterations in the vesicular acetylcholine transporter, the high affinity choline transporter, as well as tyrosine kinase A, and p75 neurotrophin receptors in specific brain regions. These data from rats support the notion that while risperidone may hold some advantages over haloperidol, both antipsychotics can produce time-dependent alterations in neurotrophin receptors and cholinergic proteins as well as impairments in the performance of tasks designed to assess spatial learning and episodic memory.

Contriving establishing operations: Responses of individuals with developmental disabilities during a learning task

The field of applied behavior analysis has utilized the ability to capture and contrive establishing operations in treating aberrant behavior in individuals with developmental disabilities. However, research on the use of establishing operations in the teaching of appropriate behavior is not as systematic. This study examined the effects of establishing operations on the responses of three males with mild to moderate intellectual disability during an incremental repeated acquisition procedure. Individuals responded more frequently and accurately during periods of longer deprivation (1 day and 2–3 days) than during shorter periods (15 min and 2 h). These results have implications for conducting preference assessments, scheduling daily activities, maximizing responding and teaching new skills.

Response sequence difficulty in an incremental repeated acquisition (learning) procedure

Incremental repeated acquisition (IRA) procedures require subjects to learn a different sequence of behavioral responses during each experimental session with required response sequences increasing incrementally in length as subjects demonstrate mastery of shorter response chains. The purpose of this study was to investigate whether some response sequences are more or less difficult to acquire than others. If true, then sequence difficulty must be considered as a potential confound when attempting to assess the effects of drugs and other experimental manipulations on learning. Accuracy for each response sequence was assessed using control data from two large rodent studies, and each sequence was classified as easy, moderate or hard. Sequences that required responses on adjacent levers were easier (characterized by higher accuracies) to acquire than those that required responses on non-adjacent levers. In addition, sequences that required responses on only two of three response levers were easier to acquire than those that required responses on all three levers. These results provide strong evidence for differing levels of response sequence difficulty in IRA procedures with sequence difficulty seeming to be dependent on whether or not responses are required on adjacent levers.

Low-dose mecamylamine improves learning of rats in the radial-arm maze repeated acquisition procedure

The nicotinic antagonist mecamylamine has been widely shown to cause cognitive impairment. However, these effects are mainly seen with high doses. There have been scattered findings that low doses of mecamylamine can have the opposite effect. This may be due to opposite effects of low doses of mecamylamine. In the current study, an extensive dose–effect function of mecamylamine was characterized in the low-dose range. Adult female Sprague–Dawley rats were trained on a repeated acquisition procedure on an automated 8-arm radial maze. Three of the eight arms were designated as correct for any particular session. Five trials per session were run. The number of errors per trial to find the three correct arms was determined. The rats were trained on the repeated acquisition procedure for at least 18 sessions at which time they showed reliable learning each session. Then, the effect of low doses of mecamylamine between 0 and 1 mg/kg were assessed in a repeated measures counterbalanced design. This dose range of mecamylamine did not affect performance on the first trial when the rats were naïve to the array to be learned. On trials 2–5 a significant ( p < .025) quadratic dose–effect function was seen over this dose range. The most substantial effect was seen with 0.125 mg/kg of mecamylamine, which caused a significant ( p < .05) improvement relative to the saline control condition. The effect diminished with increasing mecamylamine doses and with the 1 mg/kg dose choice accuracy was back to control levels. This study showed that low doses of mecamylamine can effectively improve learning. A U-shaped dose–effect curve was documented. This suggests possible low-dose nicotinic antagonist lines of treatment for cognitive impairment.

Effects of Partial Hippocampal Lesions by IbotenicAcid on Repeated Acquisition of Spatial Discrimination in Pigeons

Pigeons were trained on a spatial discrimination task using a repeated acquisition procedure. In this procedure, the pigeons were trained to discriminate between the positions of three keys. One of them was designated the correct key. When the subjects reached the criterion, the discrimination task was changed, with one of two previously incorrect keys now being made the correct key. This procedure was repeated at least 15 times. Then, lesions to the whole hippocampus, the medial hippocampus or to the lateral hippocampus were made by injections of ibotenic acid (Experiment 1). Only the subjects with damage to the whole hippocampus showed deficits in learning after the lesions. The deficits were similar to those caused by aspiration lesions /37/. Knife cuts separating the medial and lateral hippocampi were made in Experiment 2. The subjects did not show deficits in the spatial discrimination task after the sections. Although studies of the connectivity in the avian hippocampus suggested functional differences between the medial and lateral hippocampi, the present results show that pigeons can learn spatial discrimination with the medial and lateral parts of hippocampus separated.

The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates PCP-induced cognitive deficits in rats.

Recent studies have shown that metabotropic glutamate receptor 5 (mGluR5) can modulate N-methyl-D-aspartate (NMDA) receptor function in vivo. For example, the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP) can potentiate PCP (phencyclidine)-evoked hyperactivity and PCP-induced disruptions in pre-pulse inhibition (PPI) in rats. To extend these previous behavioral findings and determine whether the mGluR5 antagonist MPEP can modulate the disruptions in learning and memory induced by PCP in rats. The effects of MPEP, alone and in combination with PCP, were evaluated in rats trained to perform a repeated acquisition procedure (learning) or a delayed non-matching to position (DNMTP) radial maze task (spatial memory). In the repeated acquisition task, MPEP (0-10 mg/kg, IP) dose-dependently decreased response rates but had no effect on response accuracy. In contrast, PCP (0.625-1.25 mg/kg, SC) reduced response rate and response accuracy in a dose-dependent manner. Although MPEP (10 mg/kg, IP) had no effect when administered alone, the mGluR5 antagonist potentiated the disruptions in learning induced by a low dose of PCP (0.625 mg/kg, SC). In the DNMTP maze task, MPEP (0-10 mg/kg, IP) had no effect on spatial memory, whereas PCP (1.25-2.5 mg/kg, SC) produced a dose-dependent disruption. MPEP (10 mg/kg, IP) potentiated the impairments in memory induced by PCP (1.25 mg/kg, SC). The mGluR5 antagonist, MPEP, potentiated the disruptions in learning and memory induced by PCP. These behavioral data extend previous behavioral findings and further suggest that mGluR5 can modulate NMDA receptor function in vivo.

Lobeline-induced learning improvement of rats in the radial-arm maze

Lobeline is a nicotinic ligand with some nicotine-like effects, but with some atypical effects as well, including actions as a nicotinic antagonist. Lobeline, like nicotine, has been found to significantly improve memory function as well as provide anxiolytic-like effects in the elevated plus maze. Lobeline effects on learning remain to be fully characterized. Nicotine has been found to improve learning of shock avoidance tasks. Other nicotinic agonists also have been shown to improve learning performance. However, this effect is limited. In some tasks, nicotine has been found to cause deficits. In the current study, effects of lobeline and nicotine injections were assessed in a repeated acquisition procedure in the radial-arm maze for 3 weeks of drug administration. Lobeline (0.3 and 0.9 mg/kg) improved learning on the radial-arm maze. Neither nicotine dose (0.1 and 0.3 mg/kg) improved learning. This nicotine dose range was previously found to improve post-acquisition working memory performance in the radial-arm maze. The atypical effects of lobeline may underlie its greater efficacy than nicotine for improving repeated acquisition. The effect of lobeline improving learning may be useful in the development of novel treatments for learning deficits.

Learning impairment caused by a toxin produced by Pfiesteria piscicida infused into the hippocampus of rats

Pfiesteria piscicida, an estuarine dinoflagellate, which has been shown to kill fish, has also been associated with neurocognitive deficits in humans. With a rat model, we have demonstrated the cause-and-effect relationship between Pfiesteria exposure and learning impairment. In several studies, we have replicated the finding in Sprague–Dawley rats that exposure to fixed acute doses of Pfiesteria cells or filtrates caused radial-arm maze learning impairment. Recently, this finding of Pfiesteria-induced learning impairment in rats has been independently replicated in another laboratory as well. We have demonstrated significant Pfiesteria-induced learning impairment in both the win-shift and repeated-acquisition tasks in the radial-arm maze and in reversal learning in a visual operant signal detection task. These learning impairments have been seen as long as 10 weeks after a single acute exposure to Pfiesteria. In the current study, we used a hydrophilic toxin isolated from clonal P. piscicida cultures (PfTx) and tested its effect when applied locally to the ventral hippocampus on repeated acquisition of rats in the radial-arm maze. Toxin exposure impaired choice accuracy in the radial-arm maze repeated acquisition procedure. The PfTx-induced impairment was seen at the beginning of the session and the early learning deficit was persistent across 6 weeks of testing after a single administration of the toxin. Eventually, with enough practice, in each session, the PfTx-exposed rats did learn that session's problem as did control rats. This model has demonstrated the cause-and-effect relationship between exposure to a hydrophilic toxin produced by P. piscicida and learning impairment, and specifically that the ventral hippocampus was critically involved.

SR 141716A prevents Δ 9-tetrahydrocannabinol-induced spatial learning deficit in a Morris-type water maze in mice

This study reports a series of spatial discrimination procedures in a Morris-type maze to investigate the effects of Δ 9-tetrahydrocannabinol (Δ 9-THC) on different phases of learning and memory in mice. Adult male mice were given training trails to find the submerged platform at a fixed location in the water maze adapted for mice. In additional experiments, mice were trained with the repeated acquisition procedure to test the working memory. Results indicate that Δ 9-THC (8 mg/kg ip) 30 min pretest impaired specifically the acquisition of spatial learning and the performance of mice in the working memory task, while consolidation and retrieval of a previously learned task were not affected. There was no evidence of motoric difficulty, as the number of quadrant line crossings was not decreased and no visible sign of sensorimotor disturbance was observed during swimming. Pretreatment with SR 141716A (1 mg/kg ip), a CB1 cannabinoid receptor antagonist, significantly prevented the learning deficits in the water maze. These findings show that Δ 9-THC impairs spatial discrimination learning in a selective way in the water maze in mice and that these deficits may be mediated by cannabinoid receptors.

Effects of hippocampal lesions on repeated acquisition of spatial discrimination in pigeons

Anatomical studies of avian hippocampus suggest this structure is a counterpart of that of mammals, and allometric studies of food storing birds support the idea that the avian hippocampus has spatial cognitive functions. In the present study, the spatial cognitive function of hippocampus in pigeons was examined by lesion experiments. Pigeons were trained on either a spatial discrimination, or a spatial discrimination with an added color cue, using a repeated acquisition procedure. In the spatial task, the pigeons were trained to discriminate the position of three keys. Each time the subjects reached the criterion, they were trained on different discriminations in which one out of two previously incorrect keys became the correct key. In the task with color added, each key had its own color, so the subject had both spatial and color cues for the discrimination. The hippocampal lesions disturbed the acquisition of the spatial discrimination, but not in the task in which color cues were added. These results suggest that the avian hippocampus have a crucial role in acquisition of spatial discriminations.

Effects of Lobus parolfactorius Lesions on Repeated Acquisition of Spatial Discrimination in Pigeons

The basal part of the avian telencephalon can be divided into the paleostriatum augmentatum, paleostriatum primitivum and lobus parolfactorius (LPO). In the present experiments, the cognitive functions of the LPO in pigeons were examined. Pigeons were trained on spatial discrimination with or without added color cues using a repeated acquisition procedure. The discrimination task was a choice of three keys in an operant chamber. Every time the subjects reached the criterion, they were trained on a different discrimination in which one of two previously incorrect keys became the correct key. In the task with added color each key had a unique color (i.e., color discrimination). The LPO lesions disrupted the acquisition of both the spatial discrimination and the discrimination with added color. Birds with LPO damage emitted many errors in the first trial indicating the preservation of a previously correct response. Thus, the LPO lesions caused cognitive rigidity. These results are consistent with clinical observations of patients with basal ganglia disorders.

Repeated acquisition and the assessment of centrally acting compounds

Repeated acquisition (RA) procedures are behavioral preparations in which subjects learn new sequences of responses during each experimental session. They have been used with great success to assess the effects of drugs and other compounds on learning processes. As learning can be measured over many sessions in individual subjects, RA procedures can prove invaluable when conducting studies of the effects of chronic drug administration, aging and the long-term effects of exposure to toxic compounds. Analyzing the patterns of responding during acquisition can provide insights into the behavioral mechanisms underlying the effects of drugs and other centrally acting compounds on learning. Systematic comparisons are needed on the influence of many procedural variables on RA and the extent to which they may modulate the effects of chemicals.

Repeated acquisition of response sequences: The analysis of behavior in transition

Repeated acquisition (RA) procedures are behavioral preparations in which subjects are required to learn new response sequences within each experimental session. Such procedures avoid problems inherent in nonRA learning procedures. For example, as the subject masters nonRA tasks, one begins to measure performance of a learned response rather than learning itself. Advantages to using RA procedures include (a) the strength of the within-subjects design, including the ability to establish dose effect curves within individual subjects; (b) the ability to assess learning phenomena over extended periods of time; (c) the ability to use chronic dosing regimens; and 9d) the ability to assess treatments with permanent or long-lasting effects. In addition, analysis of the response patterns committed during acquisition allows for a description of how behavioral strategies may change in response to experimental manipulation. Difficulties include the relatively long training period often preceding attainment of a stable baseline of acquisition. This review examines the history of RA paradigms, with an emphasis on procedural comparisons.

The effects of delta(9)-tetrahydrocannabinol on repeated acquisition and performance of response sequences and on self-reports in humans.

This study assessed the acute effects of delta(9)-tetrahydrocannabinol (THC) on learning and performance, using a repeated acquisition and performance paradigm, in eight healthy adult humans. Subjective ratings of drug effects were also collected. In each component of a multiple schedule, subjects completed a different sequence of 10 responses using three keys of a numeric keypad. In the acquisition component, subjects learned a new sequence with each series of 20 trials. In the performance component, the sequence remained constant throughout the study. The multiple schedule and rating scales were presented pre-drug, post-drug and at 30min intervals thereafter for 5h. THC (10-20mg, p.o.) increased the peak percentage of errors during the acquisition component from 7.0% to 9.3% but responding during the performance component was unchanged. THC decreased Digit Symbol Substitution Test performance, increased Profile of Mood State ratings of confusion, depression and general mood disturbance and Visual Analog Scale ratings of strength of drug effect, good and bad effects, but did not alter Addiction Research Center Inventory ratings. In summary, THC in humans caused a slight learning deficit at behaviorally active doses under the repeated acquisition procedure.

Effects of sublethal doses of ionizing radiation on repeated acquisition in rats

To extend previous research on the effects of ionizing radiation on learning, dose-effect data with 60Co γ-rays were collected for individual rats responding under a repeated-acquisition procedure. Under this procedure, subjects acquired a different three-response chain each session by responding (nose push) on one of three transilluminated response keys in the presence of each of three sequentially ordered colors. The response chain was maintained under a second-order fixed ratio (FR) 2 schedule of food presentation. An error produced a 5-s timeout but did not reset the three-response chain. Acquisition of each response chain was defined by a decrease in errors as the session progressed (i.e., within-session error reduction). Each session ended after 200 reinforcements or 90 min, whichever occurred first. When day-to-day acquisition for all four subjects reached a steady state, the effects of three or four doses of γ-rays were assessed. In general, radiation doses of 1, 3, 4.5, and 8 Gy of gamma radiation delivered at a dose rate of 2.5 Gy/min produced a dose-dependent decrease in the overall response rate for 24–72 h after exposure in all four subjects. Radiation exposure also produced an increase in percent errors but only at doses that substantially decreased overall rate of responding. Unlike the effects on response rate, which were relatively consistent over a 72-h period, the effects on accuracy were greater at 72 h than at 24 h in three of four subjects. The results indicate that the repeated-acquisition procedure may be particularly useful for quantifying the effects of ionizing radiation on acquisition behavior or learning and that γ-rays can differentially affect behavioral measures of rate and accuracy over a 72-h period following exposure.