Impulsivity and motor activity in aged, male Ts65Dn mice.

Attention deficit/hyperactivity disorder (ADHD) is more prevalent in children with Down syndrome than in typically developing children. The defining characteristics of ADHD include inattention, impulsivity, and hyperactivity. The main purpose of this study was to determine whether a mouse model of Down syndrome exhibited higher levels of impulsivity than controls. A secondary aim was to examine the effects of d-amphetamine (0.1-10 mg/kg) and fenfluramine (0.3-10 mg/kg) on impulsivity. Seven male Ts65Dn and 9 male littermate control (LC) mice were trained under a response inhibition schedule of reinforcement; the main measure of impulsivity under this schedule is the mean wait time. After behavior stabilized, the mean wait time for the Ts65Dn mice was indistinguishable from that of the LC mice. Administration of 1 mg/kg d-amphetamine increased the mean wait time in both Ts65Dn and LC, though it was statistically significant only for the LC. However, no dose of fenfluramine altered the mean wait time in Ts65Dn or LC mice. An additional aim of these studies was to determine whether Ts65Dn mice displayed higher levels of motor activity than LC mice. A comparison of running wheel activity revealed no difference between Ts65Dn and LC mice. Thus, the results of the current studies suggest that aged, male Ts65Dn mice are no different from age-matched LC mice in terms of impulsivity or motor activity.

Low bone turnover and low BMD in Down syndrome: effect of intermittent PTH treatment.

Trisomy 21 affects virtually every organ system and results in the complex clinical presentation of Down syndrome (DS). Patterns of differences are now being recognized as patients' age and these patterns bring about new opportunities for disease prevention and treatment. Low bone mineral density (BMD) has been reported in many studies of males and females with DS yet the specific effects of trisomy 21 on the skeleton remain poorly defined. Therefore we determined the bone phenotype and measured bone turnover markers in the murine DS model Ts65Dn. Male Ts65Dn DS mice are infertile and display a profound low bone mass phenotype that deteriorates with age. The low bone mass was correlated with significantly decreased osteoblast and osteoclast development, decreased bone biochemical markers, a diminished bone formation rate and reduced mechanical strength. The low bone mass observed in 3 month old Ts65Dn mice was significantly increased after 4 weeks of intermittent PTH treatment. These studies provide novel insight into the cause of the profound bone fragility in DS and identify PTH as a potential anabolic agent in the adult low bone mass DS population.

Working memory in the aged Ts65Dn mouse, a model for Down syndrome.

The Ts65Dn mouse displays several phenotypic abnormalities that parallel characteristics found in Down syndrome. One important characteristic associated with Down syndrome is an increased incidence of early-onset Alzheimer's disease. Since Alzheimer's disease is characterized largely by progressive memory loss, it is of interest to study working memory in the Ts65Dn mouse. Previous research in our lab using a titrating, delayed matching-to-position schedule of reinforcement has demonstrated that young, adult male Ts65Dn mice do not display a working memory deficit when compared to age-matched littermate controls. However, there have been no studies examining the working memory of these mice as they age. Due to the correlation between Down syndrome and Alzheimer's disease, and as part of a larger effort to further characterize the phenotype of the Ts65Dn mouse, the purpose of this study was to determine whether aged Ts65Dn mice possess a working memory deficit when compared to age-matched littermate controls. In order to study working memory, two groups of mice were trained under a titrating, delayed matching-to-position schedule of reinforcement. The first group was trained beginning at 3 months of age, and the second group began training at 15 months of age. Both groups were studied to 24 months of age. Initially, both groups of Ts65Dn mice performed at a lower level of accuracy than the control mice; however, this difference disappeared with further practice. The results from these lifespan studies indicate that the aged Ts65Dn mouse does not possess a working memory deficit when compared to age-matched controls.

Human behavioral pharmacology, past, present, and future: symposium presented at the 50th annual meeting of the Behavioral Pharmacology Society.

A symposium held at the 50th annual meeting of the Behavioral Pharmacology Society in May 2007 reviewed progress in the human behavioral pharmacology of drug abuse. Studies on drug self-administration in humans are reviewed that assessed reinforcing and subjective effects of drugs of abuse. The close parallels observed between studies in humans and laboratory animals using similar behavioral techniques have broadened our understanding of the complex nature of the pharmacological and behavioral factors controlling drug self-administration. The symposium also addressed the role that individual differences, such as sex, personality, and genotype play in determining the extent of self-administration of illicit drugs in human populations. Knowledge of how these factors influence human drug self-administration has helped validate similar differences observed in laboratory animals. In recognition that drug self-administration is but one of many choices available in the lives of humans, the symposium addressed the ways in which choice behavior can be studied in humans. These choice studies in human drug abusers have opened up new and exciting avenues of research in laboratory animals. Finally, the symposium reviewed behavioral pharmacology studies conducted in drug abuse treatment settings and the therapeutic benefits that have emerged from these studies.

Rats selectively bred for ethanol preference or nonpreference have altered working memory.

To examine whether the cognitive deficit observed in chronic alcoholics is because of the chronic exposure to alcohol or to a factor that contributes to the chronic alcohol use, working memory was evaluated under a delayed matching-to-position task in rats selectively bred for ethanol preference or nonpreference (iP/iNP, iHAD1/iLAD1, and iHAD2/iLAD2). Before the study on working memory, rats were studied under a progressive ratio schedule of food presentation to determine whether differences in motivation to respond for food existed between the alcohol-preferring and -nonpreferring strains. No such differences were observed. Under the delayed matching-to-position schedule, the length of the delay was titrated such that accuracy was maintained at approximately 80%, and the mean length of the delay for each experimental session provided a measure of working memory function. In two (iP/iNP and iHAD1/iLAD1) of the three pairs of selectively bred rats, nonpreference to ethanol was associated with better working memory performance. In the third pair of selectively bred rats (iHAD2/iLAD2), the relationship was reversed, with increased ethanol preference associated with better working memory function after saline administration. After ethanol administration, both the mean delay and the rate of responding were decreased in all six strains. Based upon an ED50 analysis, there was little evidence of strain difference in sensitivity to ethanol on either parameter. Additional studies are needed to better understand the relationship between working memory and ethanol preference in these rats.

Does the learning deficit observed under an incremental repeated acquisition schedule of reinforcement in Ts65Dn mice, a model for Down syndrome, change as they age?

The Ts65Dn mouse is partly trisomic at chromosome 16 and is considered to be a valid mouse model of human Down syndrome. Prior research using an incremental repeated acquisition (IRA) schedule of reinforcement has revealed that there is a significant learning deficit in young, adult Ts65Dn mice compared to littermate controls. The purpose of this study was to examine whether this deficit changes during the life-span of these mice. In order to determine if changes in the deficit were caused by motoric or motivational deficiencies, a second group of mice was trained to respond under a performance version of the task (IRA-P). The IRA-P task required the same motor responses to produce the reinforcer, but no learning or acquisition was required. Data collected under the IRA task demonstrated that there was a significant learning impairment that persisted up to 24 months of age in the Ts65Dn mice compared to littermate controls. There was a significant decrease in the rate of responding and the number of milk presentations earned by the Ts65Dn mice after 19 months of age. However, during this time, response accuracy, which is independent of mobility and possibly motivation, did not decrease. Under the IRA-P schedule, there was no decrease observed in the number of milk presentations of either line as they aged, but the trend in the rate of responding of the Ts65Dn mice was similarly declining as the rate of responding observed in the Ts65Dn mice under the IRA task. These data indicate that the ability to learn in Ts65Dn mice does not decline with age as measured by the IRA task and suggests that perhaps Ts65Dn mice do not exhibit the same early onset Alzheimer's disease phenotype that is typically seen in human patients.

5-HT(1A) Receptor Null Mutant Mice Responding Under a Differential-Reinforcement-of-Low-Rate 72-Second Schedule of Reinforcement.

Over the last two decades, our ever-increasing ability to manipulate the mouse genome has resulted in a variety of genetically defined mouse models of depression and other psychiatric and neurological disorders. However, it is still the case that some relevant rodent models for depression and antidepressant action have been validated experimentally in rats only and not in mice. An important example of such models is the operant model of antidepressant action known as differential-reinforcement-of-low-rates 72-second (DRL 72-s). A specific set of drug-induced changes on the performance of rats responding under a DRL 72-s schedule of reinforcement has been shown to be a highly reliable predictor of antidepressant activity in human depressive disorders. The aim of this study is to validate the use of the DRL 72-s schedule in mice by both genetic and pharmacological means. We have analyzed the actions of the specific serotonin reuptake inhibitor (SSRI) fluoxetine and the tricyclic agent desipramine (DMI) on wild-type and 5-hydroxytryptamine 1A receptor-null mutant (5-HT(1A)R KO) mice. In agreement with the literature on rats, we found that fluoxetine produced an acute antidepressant-like effect in 5-HT(1A)R KO mice but not in wild-type (Wt) mice. Additionally, an antidepressant-like effect was observed when DMI was administered to both 5-HT(1A)R KO and Wt mice. In conclusion: through the use of both genetic and pharmacological strategies, this study validates the extension of a protocol involving the DRL 72-s operant schedule of reinforcement as a behavioral model for the action of antidepressants in mice.

Working memory in the Ts65Dn mouse, a model for Down syndrome.

This study used a matching-to-position schedule of reinforcement to examine working memory in Ts65Dn and littermate control mice. Initially there appeared to be a memory deficit in the Ts65Dn mice, which disappeared with extended practice. Thus, what appeared as a memory deficit may actually be the result of a delay in learning the concept of matching. These results suggest that delayed learning may be an important factor in other procedures examining working memory in Ts65Dn mice and have important implications for clinical treatment of Down syndrome patients.

Operant conditioning in the Ts65Dn mouse: learning.

Ts65Dn and littermate controls were trained to respond (nose-poke) under operant schedules of reinforcement. A small difference was observed in the initial operant training of the Ts65Dn mouse that disappeared with training under a fixed-ratio 15 schedule of milk presentation. No difference was observed in a position reversal task in which mice initially trained to respond upon one photocell had to learn to respond on a previously inactive photocell. Under an incremental repeated acquisition of behavioral chains schedule, no difference was observed when one or two responses were required to complete the sequence. However, when three or four responses were required to complete the sequence, a marked deficit was observed in the Ts65Dn mice. These results show that both Ts65Dn and littermate controls can be trained to respond under operant schedules of reinforcement, but that Ts65Dn mice have a learning deficit that is correlated with task difficulty.

Behavioral training increases local astrocytic metabolic activity but does not alter outcome of mild transient ischemia.

Functional neurological outcome after transient ischemia might be improved by timely therapeutic intervention. To determine if restorative behavioral therapy influences damage, improves task learning, or alters astrocyte metabolic activity after ischemia, rats (food-restricted to 85% of free-feeding weight) were (a) first trained to respond on one of two levers under a fixed-ratio 20 schedule of food presentation (FR20), then (b) subjected to sham manipulation of carotid arteries or 10 min ischemia by four-vessel occlusion, followed by (c) 4 days of operant testing or inactivity, (d) then all rats were tested under a FR20 lever reversal task for 4 weeks, and (e) 3 days after the last behavioral session astrocyte metabolism was assayed by local uptake of [2-14C]acetate. Mild loss of hippocampal neurons occurred in ischemic rats with or without training after ischemia. Glial fibrillary acidic protein-positive astrocytes were present in similar numbers throughout brains of sham control and ischemic rats. Mild ischemia did not impair learning, and no changes in FR20 reversal learning were detected in sham vs. ischemic rats. Net [14C]acetate uptake was unaffected by ischemia but [14C]acetate uptake increased 15-24% (P<0.05; n=12-15/group) in specific structures (caudate, primary motor and sensorimotor cortex, CA1 hippocampus, subcortical white matter) in the pooled groups of rats that had 4 days FR20 testing vs. inactivity before reversal learning. 'Behavioral therapy' (operant testing on the 4 days immediately following either sham manipulation or ischemia) did not alter ischemic outcome, but was associated with higher acetate utilization in regions involved in motor activities.

Effect of pentobarbital, d-amphetamine, and nicotine on two models of sustained attention in pigeons.

RATIONALE: The animal literature examining the effects of drugs of abuse on sustained attention has provided conflicting results. One reason for these inconsistencies could be the different type of tasks used to measure sustained attention. OBJECTIVE: Acute effects of pentobarbital (0.3, 1, 3, 5.6, 10, and 13 mg/kg), d-amphetamine (0.03, 0.1, 0.3, 1, 3, and 5.6 mg/kg), and nicotine (0.03, 0.1, 0.3, 1, and 3 mg/kg) were compared in two models of sustained attention. METHODS: Dose-response curves were compared in eight male, white Carneaux pigeons trained under a continuous-trial attention procedure and in six male, white Carneaux pigeons trained under a discrete-trial attention procedure. Both procedures required subjects to respond to a variable and brief signal presentation (signal was presented on average every 6.5 s). RESULTS: Under the continuous-trial procedure, pentobarbital decreased hits as well as increased the number of false alarms and misses at doses that did not impair the ability of the animals to respond. d-Amphetamine and nicotine dose dependently decreased hits and increased misses at doses that did not impair rates of responding. However, neither psychomotor stimulant caused a significant increase in false alarms. Under the discrete-trial procedure, pentobarbital, d-amphetamine, and nicotine decreased hits and correct rejections and increased misses and errors of omission. For the most part, these drug effects occurred at doses that increased the latencies of the animals to respond. When comparing drug effects between the continuous- and discrete-trial procedures, a difference in the false alarm rate was observed. CONCLUSIONS: The present study shows that the continuous-trial procedure was able to detect differences between drug classes that were not apparent under the discrete-trial procedure. Although the lack of a true measure of a false alarm rate continues to be a problem with the continuous-trial procedure, it may be an important procedure for studying the effects of pharmacological agents.

A single dose of monoclonal anti-phencyclidine IgG offers long-term reductions in phencyclidine behavioral effects in rats.

These studies tested the hypothesis that a single dose of high-affinity anti-phencyclidine monoclonal antibody (anti-PCP mAb) provides long-term protection against behavioral effects of repeated PCP administration in rats. Rats were treated with saline, nonspecific bovine IgG (NS-IgG), or anti-PCP mAb (1.0 g/kg). The next morning, the rats were challenged with escalating i.v. doses of PCP (0.32, 0.56, and 1.0 mg/kg) at 90-min intervals. This regimen was repeated every 3 days for 2 weeks. In the saline and NS-IgG control groups, PCP yielded reproducible and linear dose-dependent effects that remained constant during the experiment. In contrast, the anti-PCP mAb treatment blocked PCP effects on day 1, and sustained significant (P < 0.05) reductions in drug effects for the entire 2-week experiment. Brain PCP concentrations (determined at study termination) were reduced by ~55%, whereas serum concentrations were increased over 4000% compared with controls. Thus, a single dose of antibody medication provided long-term reductions in drug effects and brain concentrations, beyond the expected capacity of the drug-antibody interaction. These data challenge current concepts about in vivo dose dependence and unimolecular interaction between antibody binding sites and small molecules and establish that neuroprotection by mAbs may have an unique mechanism of action.