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Reaching tasks are commonly used in preclinical and clinical studies to assess the acquisition of fine motor skills and recovery of function following stroke. These tasks are often used to assess functional deficits in the absence of quantifying the quality of movement which requires kinematic analysis. To meet this need, this study uses a kinematic analysis in mice performing the Montoya staircase task at 5 and 14 days following a cortical photothrombosis-induced stroke. Following stroke, the mice had reaching impairments associated with sustained deficits including longer, unsmooth, and less individuated paw trajectories. Two weeks after stroke we also detected the emergence of abnormal elbow and shoulder angles, flexion/extensions, and stereotyped kinematic synergies. These data suggest that proximal and distal segments acting in concert is paramount during post-stroke reaching and encourage further analysis of synergies within the translational pipeline of preclinical to clinical studies.

Complex body movements require complex dynamics and coordination among neurons in motor cortex. Conversely, a long-standing theoretical notion supposes that if many neurons in motor cortex become excessively synchronized, they may lack the necessary complexity for healthy motor coding. However, direct experimental support for this idea is rare and underlying mechanisms are unclear. Here we recorded three-dimensional body movements and spiking activity of many single neurons in motor cortex of rats with enhanced synaptic inhibition and a transgenic rat model of Rett syndrome (RTT). For both cases, we found a collapse of complexity in the motor system. Reduced complexity was apparent in lower-dimensional, stereotyped brain-body interactions, neural synchrony, and simpler behavior. Our results demonstrate how imbalanced inhibition can cause excessive synchrony among movement-related neurons and, consequently, a stereotyped motor code. Excessive inhibition and synchrony may underlie abnormal motor function in RTT., Competing Interests: The authors declare no competing interest.

Stereotyped behavior is rhythmic, repetitive movement that is essentially invariant in form. Stereotypy is common in several clinical disorders, such as autism spectrum disorders (ASD), where it is considered maladaptive. However, it also occurs early in typical development (TD) where it is hypothesized to serve as the foundation on which complex, adaptive motor behavior develops. This transition from stereotyped to complex movement in TD is thought to be supported by sensorimotor integration. Stereotypy in clinical disorders may persist due to deficits in sensorimotor integration. The present study assessed whether differences in sensorimotor processing may limit the expression of complex motor behavior in individuals with ASD and contribute to the clinical stereotypy observed in this population. Adult participants with ASD and TD performed a computer-based stimulus-tracking task in the presence and absence of visual feedback. Electroencephalography was recorded during the task. Groups were compared on motor performance (root mean square error), motor complexity (sample entropy), and neural complexity (multiscale sample entropy of the electroencephalography signal) in the presence and absence of visual feedback. No group differences were found for motor performance or motor complexity. The ASD group demonstrated greater neural complexity and greater differences between feedback conditions than TD individuals, specifically in signals relevant to sensorimotor processing. Motor performance and motor complexity correlated with clinical stereotypy in the ASD group. These findings support the hypothesis that individuals with ASD have differences in sensorimotor processing when executing complex motor behavior and that stereotypy is associated with low motor complexity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

How animals adapt their behavior according to regular time intervals between events is not well understood, especially when intervals last several seconds. One possibility is that animals use disembodied internal neuronal representations of time to decide when to initiate a given action at the end of an interval. However, animals rarely remain immobile during time intervals but tend to perform stereotyped behaviors, raising the possibility that motor routines improve timing accuracy. To test this possibility, we used a task in which rats, freely moving on a motorized treadmill, could obtain a reward if they approached it after a fixed interval. Most animals took advantage of the treadmill length and its moving direction to develop, by trial-and-error, the same motor routine whose execution resulted in the precise timing of their reward approaches. Noticeably, when proficient animals did not follow this routine, their temporal accuracy decreased. Then, naïve animals were trained in modified versions of the task designed to prevent the development of this routine. Compared to rats trained in the first protocol, these animals didn't reach a comparable level of timing accuracy. Altogether, our results indicate that timing accuracy in rats is improved when the environment affords cues that animals can incorporate into motor routines., Competing Interests: The authors declare no competing interest.

One of the core diagnostic features of autism spectrum disorder (ASD) is engagement in stereotypical motor movements, although the etiology of this repetitive behavior is unknown. Since the 1960s, it has been hypothesized that stereotypical motor movements serve a homeostatic regulation function, and thereby a putative coupling mechanism to cardiovascular arousal. However, to date, surprisingly few reports explicitly assess cardio-somatic coupling and stereotypical motor movements. The present exploratory study investigates coupling of stereotypical body rocking and hand flapping to heart rate and heart rate variability (HRV) in a convenience sample (n = 10) of children and young adults with moderate to profound ASD. Motor movements were recorded via video and three-axis accelerometry, and simultaneous electrocardiographic signals were obtained to determine cardiovascular indices at or around the onset of naturalistically occurring stereotypy. Analysis of the heart rate revealed both repetitive body rocking and hand flapping in particular were found to associate with a strikingly similar cardiovascular pattern of acceleration and deceleration unrelated to physical demands associated with the movements themselves. Furthermore, neither type of stereotypical movement provoked directional change in heart rate variability. The implications of these results and opportunities for future research are discussed., (Copyright © 2019. Published by Elsevier B.V.)

Repetitive sensory motor behaviors are a direct target for clinical treatment and a potential treatment endpoint for individuals with intellectual or developmental disabilities. By removing the burden associated with video annotation or direct observation, automated detection of stereotypy would allow for longer term monitoring in ecologic settings. We report automated detection of common stereotypical motor movements using commercially available accelerometers affixed to the body and a generalizable detection algorithm. The method achieved a sensitivity of 80% for body rocking and 93% for hand flapping without individualized algorithm training or foreknowledge of subject's specific movements. This approach is well-suited for implementation in a continuous monitoring system outside of a clinical setting.

In fragile X syndrome (FXS), sensory hypersensitivity and impaired habituation is thought to result in attention overload and various behavioral abnormalities in reaction to the excessive and remanent salience of environment features that would normally be ignored. This phenomenon, termed sensory defensiveness, has been proposed as the potential cause of hyperactivity, hyperarousal, and negative reactions to changes in routine that are often deleterious for FXS patients. However, the lack of tools for manipulating sensory hypersensitivity has not allowed the experimental testing required to evaluate the relevance of this hypothesis. Recent work has shown that BMS-204352, a BK Ca channel agonist, was efficient to reverse cortical hyperexcitability and related sensory hypersensitivity in the Fmr1-KO mouse model of FXS. In the present study, we report that exposing Fmr1-KO mice to novel or unfamiliar environments resulted in multiple behavioral perturbations, such as hyperactivity, impaired nest building and excessive grooming of the back. Reversing sensory hypersensitivity with the BK Ca channel agonist BMS-204352 prevented these behavioral abnormalities in Fmr1-KO mice. These results are in support of the sensory defensiveness hypothesis, and confirm BK Ca as a potentially relevant molecular target for the development of drug medication against FXS/ASD.

Autism spectrum disorders (ASDs) are a heterogeneous group of psychiatric illness characterized by common core symptoms including sociability deficits and stereotyped behaviors. ASD is caused by various genetic and non-genetic factors. The genetic effects of autism-related genes are usually global and are presented with multiple symptoms, which hamper understanding of the mechanism through which the diverse causes of ASD produce common symptoms. In the present study, we demonstrate that genetic or molecular disruption of an array of molecular networks centered on adenylyl cyclase type-5 (AC5 or ADCY5) in the dorsal striatum produces autistic-like behaviors. AC5 knockout (KO) mice exhibit increased repetitive behaviors and sociability deficits, the two core domains of ASD, and that siRNA-mediated suppression of AC5 within the dorsal striatum is sufficient to replicate these behavioral phenotypes. Notably, the autistic-like behaviors of AC5 KO mice are rescued by blocking mGluR5 glutamate receptors within the dorsal striatum. Furthermore, pharmacological or siRNA-mediated inhibition of mGluR3, GluA and GluN glutamate receptors in the dorsal striatum in wildtype mice also induces autistic-like behaviors. Optogenetic inhibition of the prelimbic cortical neurons projecting to the dorsal striatum in AC5 KO mice rescues the deficits in social and object novelty preferences. Our results suggest that AC5 mutation produces autistic-like symptoms through the upregulation of mGluR5 functions in the dorsal striatum and that the dorsal striatum regulated by AC5 is a neural correlate responsible for core ASD symptoms.

High-speed video analysis was used to quantify two aspects of gait in 10 zoo-housed polar bears. These two variables were then examined as to how they differed in the conditions of pacing versus locomoting for each bear. Percent difference calculations measured the difference between pacing and locomoting data for each bear. We inferred that the higher the percent difference between pacing and locomoting in a given subject, the more intense the pacing may be. The percent difference values were analyzed alongside caregiver survey data defining the locations, frequency, and anticipatory nature of pacing in each bear, as well as each bear's age and sex, to determine whether any variables were correlated. The frequency and intensity of pacing behavior were not correlated. However, location of pacing was significantly correlated both with the subjects' age and whether or not the subject was classified as an anticipatory pacer. Bears appeared to select specific spots within their exhibits to pace, and the location therefore seemed tied to underlying motivation for the behavior. Additionally, bears that were classified in the survey as pacing anticipatorily displayed significantly more intense pacing behavior as quantified by gait analysis., (© 2017 Wiley Periodicals, Inc.)

Little is known about the mechanisms mediating the development of repetitive behaviors in human or animals. Deer mice reared with environmental enrichment (EE) exhibit fewer repetitive behaviors and greater indirect basal ganglia pathway activation as adults than those reared in standard cages. The developmental progression of these behavioral and neural circuitry changes has not been characterized. We assessed the development of repetitive behavior in deer mice using both a longitudinal and cohort design. Repeated testing negated the expected effect of EE, but cohort analyses showed that progression of repetitive behavior was arrested after 1 week of EE and differed significantly from controls after 3 weeks. Moreover, EE reductions in repetitive behavior were associated with increasing activation of indirect pathway nuclei in males across adolescence, but not females. These findings provide the first assessment of developmental trajectories within EE and support indirect pathway mediation of repetitive behavior in male deer mice., (© 2017 Wiley Periodicals, Inc.)

Animal model studies using equal numbers of males and females are sparse in psychiatry research. Given the marked sex differences observed in psychiatric disorders, such as schizophrenia, using both males and females in research studies is an important requirement. Thus the aim of this study was to examine sex differences in psychotomimetic-induced behavioural deficits relevant to psychosis. We therefore compared the acute effect of amphetamine or phencyclidine on locomotor activity and prepulse inhibition in adult male and female Sprague-Dawley rats. The results of this study were that: (1) amphetamine-induced distance travelled was greater in female rats than in male rats, (2) phencyclidine-induced locomotor hyperactivity was similar in male and female rats; (3) there were no sex differences in amphetamine- or phencyclidine-induced disruption of prepulse inhibition; (4) male rats had an increased startle response after amphetamine. These findings suggest that sensitivity to amphetamine, but not phencyclidine, differs between male and female rats, and that this sex difference is selective to locomotor hyperactivity and startle, but not prepulse inhibition. This study used two widely-used, validated preclinical assays relevant to psychosis; the results of this study have implications for psychiatry research, particularly for disorders where marked sex differences in onset and symptomology are observed., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Numerous environmental and genetic factors can contribute significantly to behavioral and cardiorespiratory variability observed experimentally. Affordable technologies that allow for noninvasive home cage capture of physio-behavioral variables should enhance understanding of inter-animal variability including after experimental interventions., New Method: We assessed whether EPIC electric field sensors (Plessey Semiconductors) embedded within or attached externally to a rodent's home cage could accurately record respiration, heart rate, and motor behaviors., Comparison With Existing Methods: Current systems for quantification of behavioral variables require expensive specialty equipment, while measures of respiratory and heart rate are often provided by surgically implanted or chronically affixed devices., Results: Sensors accurately encoded imposed sinusoidal changes in electric field tested at frequencies ranging from 0.5-100Hz. Mini-metronome arm movements were easily detected, but response magnitude was highly distance dependent. Sensors accurately reported respiration during whole-body plethysmography. In anesthetized rodents, PVC tube-embedded sensors provided accurate mechanical detection of both respiratory and heart rate. Comparable success was seen in naturally behaving animals at rest or sleeping when sensors were attached externally. Video-verified motor behaviors (sniffing, grooming, chewing, and rearing) were detectable and largely separable by their characteristic voltage fluctuations. Larger movement-related events had comparably larger voltage dynamics that easily allowed for a broad approximation of overall motor activity. Spectrograms were used to quickly depict characteristic frequencies in long-lasting recordings, while filtering and thresholding software allowed for detection and quantification of movement-related physio-behavioral events., Conclusions: EPIC electric field sensors provide a means for affordable non-contact home cage detection of physio-behavioral variables., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Beneficial effects of voluntary wheel running on hippocampal neurogenesis, morphology and hippocampal-dependent behavior have widely been studied in rodents, but also serious side effects and similarities to stereotypy have been reported. Some mouse strains run excessively when equipped with running wheels, complicating the comparability to human exercise regimes. Here, we investigated how exercise restriction to 6h/day affects hippocampal morphology and metabolism, stereotypic and basal behaviors, as well as the endocannabinoid system in wheel running C57BL/6 mice; the strain most commonly used for behavioral analyses and psychiatric disease models. Restricted and unrestricted wheel running had similar effects on immature hippocampal neuron numbers, thermoregulatory nest building and basal home-cage behaviors. Surprisingly, hippocampal gray matter volume, assessed with magnetic resonance (MR) imaging at 9.4 Tesla, was only increased in unrestricted but not in restricted runners. Moreover, unrestricted runners showed less stereotypic behavior than restricted runners did. However, after blockage of running wheels for 24h stereotypic behavior also increased in unrestricted runners, arguing against a long-term effect of wheel running on stereotypic behavior. Stereotypic behaviors correlated with frontal glutamate and glucose levels assessed by 1 H-MR spectroscopy. While acute running increased plasma levels of the endocannabinoid anandamide in former studies in mice and humans, we found an inverse correlation of anandamide with the daily running distance after long-term running. In conclusion, although there are some diverging effects of restricted and unrestricted running on brain and behavior, restricted running does not per se seem to be a better animal model for aerobic exercise in mice., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Prolonged wakefulness is thought to gradually increase 'sleep need' and influence subsequent sleep duration and intensity, but the role of specific waking behaviours remains unclear. Here we report the effect of voluntary wheel running during wakefulness on neuronal activity in the motor and somatosensory cortex in mice. We find that stereotypic wheel running is associated with a substantial reduction in firing rates among a large subpopulation of cortical neurons, especially at high speeds. Wheel running also has longer-term effects on spiking activity across periods of wakefulness. Specifically, cortical firing rates are significantly higher towards the end of a spontaneous prolonged waking period. However, this increase is abolished when wakefulness is dominated by running wheel activity. These findings indicate that wake-related changes in firing rates are determined not only by wake duration, but also by specific waking behaviours.

Impairments in acoustically cued repetitive finger movement often emerge at rates near to and above 2Hz in persons with Parkinson's Disease (PD) in which some patients move faster (hastening) and others move slower (bradykinetic). The clinical features impacting this differential performance of repetitive finger movement remain unknown. The purpose of this study was to compare repetitive finger movement performance between the more and less affected side, and the difference in clinical ratings among performance groups. Forty-one participants diagnosed with idiopathic PD completed an acoustically cued repetitive finger movement task while "on" medication. Eighteen participants moved faster, 10 moved slower, and 13 were able to maintain the appropriate rate at rates above 2Hz. Clinical measures of laterality, disease severity, and the UPDRS were obtained. There were no significant differences between the more and less affected sides regardless of performance group. Comparison of disease severity, tremor, and rigidity among performance groups revealed no significant differences. Comparison of posture and postural instability scores revealed that the participants that demonstrated hastening had worse posture and postural instability scores. Consideration of movement rate during the clinical evaluation of repetitive finger movement may provide additional insight into varying disease features in persons with PD., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The favorable consequences of environmental enrichment (EE) on brain and behavior development are well documented. Much less is known, however, about transgenerational benefits of EE on non-enriched offspring. We explored whether transgenerational effects of EE might extend to the development of repetitive motor behaviors in deer mice. Repetitive motor behaviors are invariant patterns of movement that, across species, can be reduced by EE. We found that EE not only attenuated the development of repetitive behavior in dams, but also in their non-enriched offspring. Moreover, maternal behavior did not seem to mediate the transgenerational effect we found, although repetitive behavior was affected by reproductive experience. These data support a beneficial transgenerational effect of EE on repetitive behavior development and suggest a novel benefit of reproductive experience., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Response interruption and redirection (RIRD), a procedure in which demands are delivered contingent on stereotypy, has been shown to reduce vocal and motor stereotypy maintained by automatic reinforcement. However, RIRD can be time consuming and can interrupt ongoing activities and access to reinforcement for appropriate behavior. We attempted to address these limitations by comparing the effectiveness of RIRD using the standard 3-demand procedure to RIRD using just 1 demand. Results showed that RIRD with 1 demand was effective in reducing stereotypy for all participants, required fewer demands overall, and resulted in shorter implementation time. In addition, 2 participants showed an increase in appropriate play during RIRD. These results suggest RIRD with 1 demand may be an effective and less intrusive procedure for reducing stereotypy., (© Society for the Experimental Analysis of Behavior.)

Daily physical activity shows substantial inter-individual variation, and low physical activity is associated with obesity and weight gain. Elevated physical activity is also associated with high intrinsic aerobic capacity, which confers considerable metabolic health benefits. Rats artificially selected for high intrinsic aerobic capacity (high-capacity runners, HCR) are more physically active than their low-capacity counterparts (low-capacity runners, LCR). To test the hypothesis that physical activity counters metabolic thriftiness, we measured physical activity and weight loss during three weeks of 50% calorie restriction (CR) in the HCR and LCR rat lines. At baseline, HCR ate more and were more active than LCR; this was seen in male rats, where LCR are considerably heavier than HCR, as well as in a set of female rats where body weight did not differ between the lines, demonstrating that this effect is consistent across sex and not secondary to body weight. We show for the first time that HCR lose more weight than LCR relative to baseline. Physical activity levels declined throughout CR, and this was more pronounced in HCR than in LCR, yet some aspects of activity remained elevated in HCR relative to LCR even during CR. This is consistent with the idea that low physical activity contributes to metabolic thriftiness during food restriction, allowing LCR to defend body mass, particularly lean mass. This has implications for physical activity during diet-induced weight loss, the genetic underpinnings of individual differences in weight loss during a diet, and the potential evolutionary opposition between metabolic thriftiness and aerobic capacity., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The preclinical study of human disorders associated with comorbidities and for which the aetiology is still unclear may substantially benefit from multi-strain studies conducted in mice. The latter can help isolating experimental populations (strains) exhibiting distinct facets in the parameters isomorphic to the symptoms of a given disorder. Through a reverse-translation approach, multi-strain studies can inform both natural predisposing factors and environmental modulators. Thus, mouse strains selected for a particular trait may be leveraged to generate hypothesis-driven studies aimed at clarifying the potential role played by the environment in modulating the exhibition of the symptoms of interest. Tourette's syndrome (TS) constitutes a paradigmatic example whereby: it is characterized by a core symptom (tics) often associated with comorbidities (attention-deficit-hyperactivity and obsessive-compulsive symptoms); it has a clear genetic origin though specific genes are, as yet, unidentified; its course (exacerbations and remissions) is under the influence of environmental factors. Based on these considerations, we tested four mouse strains (ABH, C57, CD1, and SJL) - varying along a plethora of behavioural, neurochemical, and immunological parameters - on a test battery tailored to address the following domains: tics (through the i.p. administration of the selective 5-HT2 receptor agonist DOI, 5mg/kg); locomotion (spontaneous locomotion in the home-cage); perseverative responding in an attentional set shifting task; and behavioural stereotypies in response to a single amphetamine (10mg/kg, i.p.) injection. Present data demonstrate that while ABH and SJL mice respectively exhibit selective increments in amphetamine-induced sniffing behaviour and DOI-induced tic-like behaviours, C57 and CD1 mice show a distinct phenotype, compared to other strains, in several parameters., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Schizophrenia is a complex constellation of positive, negative and cognitive symptoms. Acute administration of the non-competitive antagonist of the N-methyl-d-aspartate receptor (NMDAR) dizocilpine (MK801) in rats is one of few preclinical animal models of this disorder that has both face and/or construct validity for these multiple at-risk behavioral domains and predictive power for the efficacy of therapeutic drugs in treating them. This study asked whether and to what extent the rat NMDAR hypofunction model also embodies the sex differences that distinguish the symptoms of schizophrenia and their treatment. Thus, we compared the effects of acute MK801, with and without pretreatment with haloperidol or clozapine, on seven discrete spontaneous open-field activities in adult male and female rats. These analyses revealed that MK801 was more effective in stimulating ataxia and locomotion and inhibiting stationary behavior in females while more potently stimulating stereotypy and thigmotaxis and inhibiting rearing and grooming in males. Haloperidol and clozapine pretreatments had markedly different efficacies in terms of behaviors but strong similarities in their effectiveness in male and female subjects. These results bear intriguing relationships with the complex male/female differences that characterize the symptoms of schizophrenia and suggest possible applications for acute NMDAR hypofunction as a preclinical model for investigating the neurobiology that underlies them., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

Rationale: Drug use during adolescence is associated with an increased propensity for drug dependency during adulthood. Therefore, the effects of adolescent exposure to nicotine on adult behavioral responsiveness to nicotine are of particular importance., Objectives: The objective of the current study was to determine if adolescent nicotine exposure would enhance behavioral sensitivity and development of sensitization to nicotine during adulthood., Materials and Methods: Male Wistar rats were assigned to one of three groups that received subcutaneous (s.c.) injections of nicotine (0, 0.25, or 0.5mg/kg) in the home cage for 12 consecutive days during adolescence, PD 31-42. Starting on PD 80, distance traveled, rearing, and stereotypy were recorded in locomotor activity chambers each day for 10 days, following s.c. injections of 0, 0.25, or 0.5mg/kg nicotine. One week later, a final challenge session took place during which rats were injected with 0.5mg/kg nicotine., Results: Rats exposed to nicotine during adolescence displayed a greater locomotor response to a novel environment than saline-treated rats. Adolescent nicotine treatment also resulted in context-independent sensitization to the acute locomotor activating properties of nicotine, including distance traveled and stereotypy, as measured on the first day of adulthood nicotine exposure. Adolescent nicotine-treated rats displayed increased sensitivity to repeated nicotine exposures during adulthood, compared to adolescent saline-treated rats, as measured by distance traveled, rearing, and stereotypic behaviors. Finally, rats treated with nicotine only during adolescence were more sensitive to a final nicotine challenge during adulthood than rats treated with nicotine only previously during adulthood., Conclusions: Overall, the results suggest that adolescent nicotine treatment predisposes adult rats to develop increased behavioral sensitivity to chronic nicotine treatment and to be more sensitive to the initial effects of nicotine., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Dopaminergic compounds often affect the unlearned behaviors of preweanling and adult rats differently, although the brain regions underlying these age-dependent behavioral effects have not been specified. A candidate brain region is the dorsal caudate-putamen (CPu); thus, a goal of the present study was to determine whether D1 and D2 receptors in the dorsal CPu are capable of modulating the unlearned behaviors of preweanling rats. In Experiments 1 and 2, selective and nonselective dopamine agonists were bilaterally microinjected into the dorsal CPu on postnatal day (PD) 18 and both locomotor activity and stereotypy were measured. In Experiment 3, the functional coupling of D1 and D2 receptors was assessed by microinjecting the D1 agonist SKF-82958 and the D₂/D₃ agonist quinpirole either alone or in combination. In Experiments 4 and 5, quinpirole and the D1 receptor antagonist SCH-23390, or SKF-82958 and the D2 receptor antagonist raclopride, were co-administered into the dorsal CPu to further assess whether a functional D1 or D2 receptor system is necessary for the expression of quinpirole- or SKF-82958-induced behaviors. Results showed that selective stimulation of D1 or D2 receptors in the dorsal CPu increased both the locomotor activity and stereotypy of preweanling rats. Receptor coupling was evident on PD 18 because co-administration of a subthreshold dose of SKF-82958 and quinpirole produced more locomotor activity than either agonist alone. Lastly, the dopamine antagonist experiments showed that both D1 and D2 receptor systems must be functional for SKF-82958- or quinpirole-induced locomotor activity to be fully manifested. When the present data are compared to results from non-ontogenetic studies, it appears that pharmacological manipulation of D1 and D2 receptors in the dorsal CPu affects the behavior of preweanling and adult rats in a generally similar manner, although some important age-dependent differences are apparent. For example, D1 and/or D2 agonists preferentially induce locomotor activity, and not intense stereotypy, in younger animals., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

Sensation seeking and early life stress are both risk factors for developing substance use disorders. Neural adaptations resulting from early life stress may mediate individual differences in novelty responsiveness, and, in turn, contribute to drug abuse vulnerability. Animal models also demonstrate associations between novelty responsiveness or early life stress and increased sensitivity to psychostimulants. We investigated whether repeated maternal separation affects responses to novelty during adolescence and to amphetamine during adulthood, and whether maternal separation alters the relationship between these behavioral variables. Rat pups underwent separation (180 min/day) or control procedures (15 min/day) on postnatal days (PND) 2-8. Novel object exploration and amphetamine response were tested at PND 38 and 60, respectively. Adolescent males were less active in a novel environment and approached novel objects more frequently than females, but adult females showed greater amphetamine-induced locomotion. Maternal separation did not affect novelty responsiveness or amphetamine sensitivity. Locomotor activity in an inescapable, novel environment during adolescence predicted amphetamine-induced locomotor activity during adulthood in maternally separated rats, but not in controls. The results of this study suggest that adolescent responses to novelty may be particularly predictive of future substance abuse among survivors of early life trauma. Furthermore, sex differences in novelty and amphetamine responsiveness may complicate the relationship between these behavioral variables., (Copyright © 2010 Wiley Periodicals, Inc.)

The effects of 2 forms of response interruption and redirection (RIRD)-motor RIRD and vocal RIRD-were examined with 4 boys with autism to evaluate further the effects of this intervention and its potential underlying mechanisms. In Experiment 1, the effects of motor RIRD and vocal RIRD on vocal stereotypy and appropriate vocalizations were compared for 2 participants. In Experiment 2, the effects of both RIRD procedures on both vocal and motor stereotypy and appropriate vocalizations were compared with 2 additional participants. Results suggested that RIRD was effective regardless of the procedural variation or topography of stereotypy and that vocal RIRD functioned as a punisher. This mechanism was further explored with 1 participant by manipulating the schedule of RIRD in Experiment 3. Results were consistent with the punishment interpretation.

The psychostimulant methylphenidate (MPD, Ritalin) is the prescribed drug of choice for treatment of ADHD. In recent years, the diagnosis rate of ADHD has increased dramatically, as have the number of MPD prescriptions. Repeated exposure to psychostimulants produces behavioral sensitization in rats, an experimental indicator of a drug's potential liability. In studies on cocaine and amphetamine, this effect has been reported to involve the nucleus accumbens (NAc), one of the nuclei belonging to the motive circuit. The aim of this study was to investigate the role of the NAc on the expression of behavioral sensitization as a response to MPD exposure. In the present study, 20 male Sprague-Dawley rats were divided randomly into three groups: an intact control group, a sham-operated group, and a NAc bilateral electrical lesion group. Locomotor activity was assessed for the first 2h following 2.5mg/kg MPD injection, using open field monitoring systems. Recordings were made during 6 days of continuous MPD administration, and then upon re-challenge with the same dose following 3 days of washout. Acute MPD exposure elicited an increase in locomotor activity in all three groups. However, the NAc lesion group exhibited significantly increased locomotor activity in comparison to sham and control groups. Chronic MPD did not elicit sensitization in the NAc lesion group, while both sham and control groups did exhibit behavioral sensitization to repetitive MPD administration. These findings suggest that the NAc plays a significant role in eliciting locomotor activity as an acute effect of MPD, and in the expression of sensitization due to chronic MPD exposure., (Copyright 2010 Elsevier Inc. All rights reserved.)

5-HT(1A) receptors mediate some effects of atypical antipsychotic drugs, such as the increase in cortical dopaminergic function, an effect likely related to the superior efficacy of these drugs on negative symptoms and cognitive deficits of schizophrenia. To examine whether 5-HT(1A) receptors are involved in the therapeutic action of clozapine (Clz) on positive symptoms, here we examined the ability of Clz to antagonize the behavioural syndrome induced by the non-competitive N-methyl-d-aspartate receptor antagonist, MK-801 in wild-type (WT) and 5-HT(1A)-receptor knockout (KO(1A)) mice. MK-801 administration induced hyperlocomotion, ataxia, stereotypies and an alteration of the locomotor pattern in both genotypes. However, some symptoms of the behavioural syndrome induced by MK-801 were less intense in KO(1A) mice compared with wild-type mice. Clz antagonized the majority of MK-801-induced effects in both strains of mice. No differences between genotypes were noted for the ability of Clz to antagonize the hyperlocomotion, yet Clz was more effective in preventing the increased activation time, short movements, circling behaviour and hind-limb abduction in KO(1A) mice. The present results indicate that 5-HT(1A) receptors do not play a critical role in Clz-induced antagonism of the main hyperactivity signs evoked by MK-801, suggesting that 5-HT(1A) receptors are not involved in the therapeutic action of Clz on positive symptoms of schizophrenia., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Occlusion of middle cerebral artery (MCAo) is commonly used to generate stroke in experimental animals. Different behavioral assays have been used to evaluate the severity of lesions or recovery after treatment in this model. In this study, we examined the correlation between the size of infarction and locomotor activity after transient MCAo in adult Sprague-Dawley rats. The right middle cerebral artery was occluded for 30-90-min by ligation with a 10-O suture. At 2 days after MCAo, animals were individually placed in a 3-D infrared activity chamber for 1h to measure their horizontal, vertical, stereotypic and rotational activity. Body asymmetry was examined using an elevated body swing test. Volume of infarction was measured by triphenyltetrazolium chloride staining. We found that there is a significant correlation between the volume of infarction and vertical movement, such as vertical activity, vertical movement number and vertical movement time. There is also a significant correlation between the infarction volume and body asymmetry. In conclusion, our data suggest that vertical locomotor activity and body asymmetry are useful behavioral indices to estimate the size of lesioning in rodents after MCAo., (Copyright 2009 Elsevier B.V. All rights reserved.)

The comparative study of expression of early c-fos-gene (marker of neuronal activation) and NADPH-diaphorase reactivity (NADPH-dr) was performed in the cervical spinal cord of rats in the control (intact) animal, in the state of starvation and after realization of long-lasting (repeated 4 to 12 times per minute for 30 min) motivated stereotyped food-procuring forelimb movements. In comparison with control rats; in the starving rats or rats showed forelimb movement to reach-to-grasp the food, the number of Fos-immunoreactive (Fos-ir) cells in the dorsal and ventral horns of a 40-microm-thick slice was significantly greater (P < 0.05). The number of Fosir neurons in the starving state clearly exceeded that in the most layers after realization of movements. Increase of Fos immunoreactivity in the superficial (2i, 3) and deeper (4, 5) layers of the dorsal horn was initiated, evidently, by signals from peripheral and supraspinal structures. We also found labelled cells within layers 6-8, and 9 demonstrating the activity of interneurons and motoneurons directly involved into generation of operant forelimb movements. According to our data, high density of NADPH-dr/NO-generating neurons in the C6/C7 segments are observed in the substance gelatinosa (layer 2i) and layers 7 and 10. NADPH-dr cells and Fos-ir neurons were intermixed within the layers but did not demonstrate double-labelling. It is possible to suggest that NADPH-dr/NO-generating cells of the spinal cord did not operate under realization of the studied operant reflexes, which did not include nociceptive component.

The high prevalence of psychostimulant abuse observed in schizophrenic patients may be related to the development of mesolimbic dopaminergic supersensitivity (MDS) or nigrostriatal dopaminergic supersensitivity (NDS) in response to the chronic blockade of dopamine receptors produced by typical neuroleptic treatment. We compared the effects of withdrawal from long-term administration of the typical neuroleptic haloperidol (Hal) and/or the atypical agent risperidone (Ris) on MDS and NDS, behaviorally evaluated by amphetamine-induced locomotor stimulation (AILS) and apomorphine-induced stereotypy (AIS) in mice, respectively. We further evaluated the duration of MDS and investigated the specific role of dopamine D2 receptors in this phenomenon by administering the D2 agonist quinpirole (Quin) to mice withdrawn from long-term treatment with these neuroleptics. Withdrawal (48 hours) from long-term (20 days) Hal (0.5 mg/kg i.p.) (but not 0.5 mg/kg Ris i.p.) treatment potentiated both AILS and AIS. Ris co-administration abolished the potentiation of AILS and AIS observed in Hal-withdrawn mice. Ten days after withdrawal from long-term treatment with Hal (but not with Ris or Ris + Hal), a potentiation in AILS was still observed. Only Hal-withdrawn mice presented an attenuation of locomotor inhibition produced by Quin. Our data suggest that the atypical neuroleptic Ris has a pharmacological property that counteracts the compensatory MDS and NDS developed in response to the chronic blockade of dopamine receptors imposed by Ris itself or by typical neuroleptics such as Hal. They also indicate that MDS may be long lasting and suggest that an upregulation of dopamine D2 receptors in response to long-term treatment with the typical neuroleptic is involved in this phenomenon.

Activity budgets were studied in eight Asian elephants (Elephas maximus) at Chester Zoo (UK) for 35 days, between January and November 1999. Recordings were made between 10:00 and 16:00 hr (with most behavior frequencies calculated between 10:00 and 14:00 hr). The elephants exhibited variation in activity depending on their age, sex, the time of day and the time of year. Only the five adult cows exhibited stereotypic behavior, with frequencies ranging from 3.9 to 29.4% of all observations. These elephants exhibited individual, diurnal and seasonal variation in stereotypic behavior. This has implications for studies that use short sampling periods and may make comparisons of data collected at different times of the day or year invalid. The six adult elephants spent 27.4-41.4% of the time feeding (between 10:00 and 14:00 hr), 22.9-42.0% standing still, 6.1-19.2% walking and 3.9-9.6% dusting. The hypothesis that the frequency of stereotypic behavior in adult cow elephants was negatively correlated with the frequency of feeding behavior was tested and was found to be true. Stereotypic behavior increased in frequency toward the end of the day-while waiting to return to the elephant house for food--and elephants spent more time stereotyping during the winter months than during the summer months. Elephants were inactive (i.e. exhibited behaviors other than locomotion) for between 70.1 and 93.9% of the time. Creating more opportunities for elephants to exhibit foraging behavior and the introduction of greater unpredictability into management regimes, especially feeding times, may reduce the frequency of stereotypic behavior and increase general activity levels.

This study investigated behavioral differences between neonatal rats with vasopressin AVP deficiency (di/di) and those with little (+/di) or no deficiency (+/+) using a number of open field metrics. Infant rats (pups) at days 7 and 10 postpartum were videotaped in individual and group trials in a temperature-controlled arena for 12min. Pups were tracked every 5s for tip-of-the-nose and base-of-the-tail coordinate positions. These positional data were transformed, using computer algorithms, into measures of activity, change in orientation, distance moved, cells occupied, wall contact, number of corners visited, and degree of aggregation. Analysis of these data revealed some phenotypic differences among genotypes for 7-day-old pups in individual trials, but there was no clear pattern of genotypic differences. By day 10, however, there were dramatic differences. AVP deficient pups differed significantly from both +/+ and +/di pups on most individual and group metrics. As measured by effect size, group effects were especially large. The behavioral results were consistent with previous findings in adult di/di rats and indicated that 10-day-old di/di pups were hyperactive and had social deficits. AVP deficient pups also appeared to have accelerated locomotor development and to exhibit stereotypic behavior. These results suggest that Brattleboro, di/di, pups are a potentially important animal model for investigating the role of AVP in early locomoter and social development. These behavioral metrics are generalizable to infants of other rodent species and thus may allow early behavioral phenotyping and the assessment of behavioral deficits.

How the captive environment influences the behavior of animals is relevant to the well-being of captive animals. Captivity diverges from the natural environment in many ways, and one goal of enrichment practices is to encourage species-typical behavior in these unnatural environments. This study investigated the influence of grass vs. gravel substrate on activity budgets and degree of hair loss in seven groups of captive rhesus macaques housed in outdoor enclosures at the California National Primate Research Center. Groups having grass substrate spent a greater proportion of their time foraging and a smaller proportion of time grooming compared with groups having gravel substrate. Increased time spent grooming in gravel enclosures may have contributed to significantly greater hair loss in those enclosures. A causal relationship between ground substrate on foraging and grooming, and therefore hair loss, is strengthened by similar changes in activity budgets and hair loss in a single group that was moved from gravel to grass substrate halfway through the study. These results add to growing evidence that substrate type in captivity is important to consider because it affects animal well-being. In particular, these results reveal that grass substrate is more effective than gravel in stimulating foraging and reducing allo-grooming to levels that are comparable to wild populations, and enable animals to maintain healthier coats.

Rationale: Serotonin 1A receptor (5-HT1AR) agonists reduce L-DOPA-induced dyskinesia and enhance motor function in experimental and clinical investigations of Parkinson's disease (PD). While the mechanism(s) by which these effects occur are unclear, recent research suggests that modulation of glutamate neurotransmission contributes., Objective: To further delineate the relationship between 5-HT1A receptors and glutamate, the current study examined the effects of the 5-HT1AR agonist, +/-8-OH-DPAT and the N-methyl-D-aspartic acid receptor (NMDAR) antagonist, MK-801, on L-DOPA-induced motor behavior., Materials and Methods: Unilateral 6-hydroxydopamine lesioned male Sprague-Dawley rats were rendered dyskinetic with 1 week of daily L-DOPA (12 mg/kg, i.p.) + benserazide (15 mg/kg, i.p.). On test days, one group of rats received pretreatments of: +/-8-OH-DPAT (0, 0.03, 0.1, 0.3 mg/kg, i.p.) or MK-801 (0, 0.03, 0.1, 0.3 mg/kg, i.p.). A second group was administered combined +/-8-OH-DPAT (0, 0.03 or 0.1 mg/kg, i.p.) + MK-801 (0, 0.1 mg/kg, i.p.). Pretreatments were followed by L-DOPA administration, after which, abnormal involuntary movements (AIMs) and rotations were monitored. To investigate effects on motor performance, subthreshold doses of +/-8-OH-DPAT (0.03 mg/kg, i.p.) + MK-801 (0.1 mg/kg, i.p.) were administered to L-DOPA-naïve hemiparkinsonian rats before the forepaw adjusting steps test., Results: Individually, both +/-8-OH-DPAT and MK-801 dose-dependently decreased L-DOPA-induced AIMs without affecting rotations. Combined subthreshold doses of +/-8-OH-DPAT+MK-801 reduced L-DOPA-induced AIMs and potently enhanced contralateral rotations without altering L-DOPA-induced motor improvements., Conclusions: The current results indicate a functional interaction between 5-HT1AR and NMDAR that may improve pharmacological treatment of PD patients.

Health professionals recognize the benefits of moderate physical activity and encourage clients to engage in some form of activity on a regular basis. In spite of these recognized benefits, there are growing concerns that some may exercise at levels detrimental to health. The term exercise dependence refers to those individuals whose extreme exercise schedules interfere with their social, occupational, and family lives. The purpose of this study was to examine the relationship between weekly exercise habits and scores on the Exercise Dependence Questionnaire in a sample of undergraduate students (213 women and 79 men). Overall, participants who reported high activity scored higher than those reporting low activity on subscales measuring interference with family and social life, positive reward, withdrawal, exercise for social reasons, exercise for health reasons, and stereotyped behavior.

Amphetamine-induced motor behaviors, i.e., locomotor and stereotypic activities, were simultaneously characterized in C57BL/6 mice, a strain commonly used for genetic studies. Our findings show relatively high levels of focused activities in drug-naive C57BL/6 mice, confirming the lively nature of this mouse strain. Acute amphetamine induced a dose-dependent, bimodal response: locomotion predominated at lower doses of amphetamine and was gradually displaced by stereotypic behavior as dose and time increased. The sum total of both behavioral activities increased with amphetamine dose, supporting the notion that amphetamine-induced locomotion and stereotypy form a continuum. These data provide a basis for using C57BL/6 mice as a strain to study the molecular and cellular mechanisms underlying psychostimulant effects, drug addiction and psychotic disorders.

Serotonin 1A receptor (5-HT(1A)R) agonists have emerged as valuable supplements to l-DOPA therapy, demonstrating that they can decrease side effects and enhance motor function in animal models of Parkinson's disease (PD) and human PD patients. The precise mechanism by which these receptors act remains unknown and there is limited information on how 5-HT(1A)R stimulation impacts striatal dopamine (DA) D1 receptor (D1R) and D2 receptor (D2R) function. The current study examined the effects of 5-HT(1A)R stimulation on DA receptor-mediated behaviors. Male Sprague-Dawley rats were rendered hemiparkinsonian by unilateral 6-OHDA lesions and primed with the D1R agonist SKF81297 (0.8 mg/kg, i.p.) in order to sensitize DA receptors. Using a randomized within subjects design, rats received a first injection of: Vehicle (dH(2)O) or the 5-HT(1A)R agonist +/-8-OH-DPAT (0.1 or 1.0 mg/kg, i.p.), followed by a second injection of: Vehicle (dimethyl sulfoxide), the D1R agonist SKF81297 (0.8 mg/kg, i.p.), the D2R agonist quinpirole (0.2 mg/kg, i.p.), or l-DOPA (12 mg/kg+benserazide, 15 mg/kg, i.p.). On test days, rats were monitored over a 2-h period immediately following the second injection for abnormal involuntary movements (AIMs), analogous to dyskinesia observed in PD patients, and contralateral rotations. The present findings indicate that 5-HT(1A)R stimulation reduces AIMs induced by D1R, D2R and l-DOPA administration while its effects on DA agonist-induced rotations were receptor-dependent, suggesting that direct 5-HT(1A)R and DA receptor interactions may contribute to the unique profile of 5-HT(1A)R agonists for the improvement of PD treatment.

In sheep, neither the in vivo effect of vasopressin administered by a method other than systemic infusion nor the central effects on behavior from the perspective of stress regulation has been fully elucidated in an intact animal. We examined changes in behavioral, adrenocorticotropic, and autonomic nervous functions after intracerebroventricular infusions of arginine vasopressin (AVP) to elucidate its central role. Intracerebroventricular infusions of AVP (0, 0.12, 1.2 and 12 microg/500 microl/30 min) evoked a dose-related increase in plasma cortisol concentration. There were significant treatment-related effects on the total duration of sham-chewing (Friedman's test, X2=12.75, p=.0052), on the total duration of bar-biting (Friedman's test, X2=15.0, p=.0018), and on the total duration of rubbing (Friedman's test, X2=12.0, p=.0074). AVP 12 microg treatment induced a greater degree of sham-chewing and bar-biting than the other three treatments did (Nemenyi multiple comparisons: p<0.1). These findings indicate, together with our previous findings, that AVP has the same corticotropic potential as corticotropin-releasing hormone infused intracerebroventricularly in equal molar concentrations. Although the degree to which central stress signaling pathways are involved in these responses remains speculative, the relationships between stereotypies and central AVP are of particular interest.

Strategies of cell therapy for the treatment of Parkinson's disease (PD) are focused on replacing damaged neurons with cells to restore or improve function that is impaired due to cell population damage. In our studies, we used mesenchymal stromal cells (MSCs) from mouse bone marrow. Following our novel neuronal differentiation method, we found that the basic cellular phenotype changed to cells with neural morphology that express specific markers including those characteristic for dopaminergic neurons, such as tyrosine hydroxylase (TH). Intrastriatal transplantation of the differentiated MSCs in 6-hydroxydopamine-lesioned mice led to marked reduction in the amphetamine-induced rotations. Immunohistological analysis of the mice brains four months post transplantation, demonstrated that most of the transplanted cells survived in the striatum and expressed TH. Some of the TH positive cells migrated toward the substantia nigra. In conclusion, transplantation of bone marrow derived stem cells differentiated to dopaminergic-like cells, successfully improved behavior in an animal model of PD suggesting an accessible source of cells that may be used for autotransplantation in patient with PD.

In addition to morphological changes, global cerebral ischemia leads to functional changes that can be assessed by behavioral examination. The purpose of this study was to investigate the impact of the duration of global cerebral ischemia on the time course of a comprehensive set of motor behaviors in Mongolian gerbils. The common carotid arteries of gerbils were occluded either for 5 min, 10 min, or 15 min. Gerbil motor behavior was recorded in the open field at 24 h, 48 h, 4 days, 7 days, 14 days, 21 days, and 28 days after reperfusion. Each session lasted for 60 min and was composed of six intervals of 10 min. Our results revealed that ischemic gerbils quickly develop locomotor and stereotypic hyperactivity, with the expected decrease of resting time. The most evident effect was observed in gerbils submitted to a 15 min ischemia, whose locomotor activity returned to nearly normal values after 7 days. In contrast, the duration of global cerebral ischemia had no effects on rearing, clockwise, or counter-clockwise rotation. These findings indicate that exposure to global cerebral ischemia induces changes in locomotion, stereotypy, and resting time. The magnitude and duration of these effects depend on the duration of ischemia.

Object: The purpose of this study was to determine whether subthalamic nucleus (STN) ablation caused by kainic acid can restore dopaminergic neurotransmission and improve motor deficits in a 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian model., Methods: The authors investigated behavioral changes in rats displaying parkinsonian symptoms (6-OHDA-lesioned rats) after an STN lesion was created using kainic acid. They also measured levels of dopamine and its metabolites following tissue dissection. The results of this study showed that STN ablation led to behavioral improvement in parkinsonian motor deficits. Increased levels of dopamine were also observed in the striatum and globus pallidus externus (GPE)., Conclusions: The results indicate that creation of an STN lesion in this hemiparkinsonian rat model may counteract some of the neurochemical changes within the striatum and GPE caused by the 6-OHDA, and influence striatal dopaminergic metabolism.

Alzheimer's disease (AD) is not only characterized by cognitive decline and neuropathological changes, but also by non-cognitive behavioral symptoms like restlessness, sleep disturbance, and wandering. These symptoms are categorized in the "Behavioral and Psychological Symptoms of Dementia" (BPSD). We investigated transgenic and wildtype mice of an APP transgenic mouse model of AD (TgCRND8) with respect to 24 h activity and spontaneous home cage behavior at 30, 60, 90 and 120 days of age. At all test days, transgenic and wildtype animals differed significantly with respect to activity patterns. In addition, activity rhythms changed distinctly in transgenic mice with increasing age. Transgenic mice also clearly showed more stereotypic behavior, which correlated significantly at 90 and 120 days of age with elevated corticosterone metabolite concentrations in fecal samples. Activity patterns in TgCRND8 mice resemble altered rhythms of activity in AD patients. Stereotypic behaviors may be caused by the same mechanisms as non-cognitive behavioral symptoms of AD. Thus, it is likely that analogies to BPSD that precede Abeta pathology are found in APP-overexpressing TgCRND8 mice.

Asymmetrical turning behavior is an established indicator of asymmetrical dopaminergic activity and thought to be a manifestation of hemispatial neglect. We set out to find converging support for the hypothesis that cortisol modulates frontal dopaminergic asymmetrical activity, and hence dopaminergically mediated approach behaviors, by studying the effect of cortisol administration on turning behavior in healthy subjects. Both when our subjects attempted to rotate through a target angle (twice 360 degrees) in a clockwise or anticlockwise direction with reduced sensory input, cortisol induced a relative clockwise turning bias. Furthermore, this effect interacted with scores on novelty seeking, a putative indicator of individual differences in dopaminergic function: subjects scoring higher on novelty seeking demonstrated a smaller or no increase after cortisol administration in their clockwise turning bias. The results provide converging support for the hypothesis that cortisol modulates frontal dopaminergic asymmetrical activity. As we discuss, they further point to the possible involvement of the insula in cortisol effects.

Genes and environment are both essential and interdependent determinants of behavioral responses. Behavioral genetics focuses on the role of genes on behavior. In this article, we aim to provide a succinct, but comprehensive, overview of the different means through which behavioral analysis may be performed in rodents. We give general recommendations for planning and performing behavioral experiments in rats and mice, followed by brief descriptions of experimental paradigms most commonly used for the analysis of reflexes, sensory function, motor function and exploratory, social, emotional and cognitive behavior. We end with a discussion of some of the shortcomings of current concepts of genetic determinism and argue that the genetic basis of behavior should be analyzed in the context of environmental factors.

Rodent models of schizophrenia provide powerful experimental tools for elucidating certain manifestations of the brain disease. The chakragati (ckr) mouse mutant, for instance, reproduces aberrant neuroanatomical and behavioral phenotypes observed in the corresponding human condition. To further investigate the utility of this mouse in the context of social behavior, we compared spontaneous behavioral activity and social interactions recorded during the subjective night among wild-type, heterozygous, and homozygous ckr mice. We found that both heterozygous and homozygous ckr animals failed to show appropriate norms of social behavior, including proximity, approach, huddling, and anogenital investigation in response to novel conspecifics. We further found that the anatomical distribution, topography, and connectivity of the neuropeptides oxytocin and vasopressin in the anterior hypothalamus did not differ among wild-type, heterozygous, or homozygous ckr animals. These latter findings suggest that although oxytocin and vasopressin influence social behavior, connectivity of such cells may not be phenotypically relevant for the observed social deficits seen in heterozygous and homozygous ckr mice. Collectively, ckr mice and their heterozygote kin are valuable experimental tools for pre-clinical studies involving disruptions of social behavior (e.g., social withdrawal).

Pretreatment with a single dose of ribavirin (10, 20, and 30 mg/kg b.w., i.p.) decreased amphetamine (1.5 mg/kg b.w., i.p.)-induced total locomotor activity (distance traveled) compared to amphetamine alone, but the most significant effect was observed with 30 mg/kg dose. In contrast, total stereotypic activities (such as sniffing, self-grooming, licking, and head weaving) of these animals were unchanged. These findings demonstrate the ability of ribavirin to modulate in a different way central regulation of locomotor and stereotypic activities that in the future could have a practical application in target therapy of some movement disorders.

Objective: This study probed the ability of people with chronic schizophrenia to control their behavior in time by requiring them to deliberately vary responses within the temporal domain (i.e., to avoid regular inter-response intervals)., Methods: Thirteen schizophrenia patients performed single finger movements (at moments of their own choosing) in an event-related functional magnetic resonance imaging paradigm. Their performance was computed using the coefficient of variation of inter-response interval duration., Results: Task performance was positively correlated with activation of left lateral prefrontal cortex. Post hoc analyses revealed an inverse correlation between activation in this region and severity of attentional impairment., Conclusion: These findings implicate left lateral prefrontal cortex in the modulation of the temporal response space in schizophrenia and imply greater attentional (executive) impairment among those who fail to modulate their behavior in time.

These studies examined the role of (+)-methamphetamine ((+)METH) administration route on spontaneous behavioral activity vs. time relationships, and pharmacokinetic mechanisms for differences in effects. Male Sprague-Dawley rats (n=6 per administration route) received saline and three doses (0.3, 1.0 and 3.0 mg/kg) of (+)METH in a mixed-sequence design by intravenous (iv), subcutaneous (sc) or intraperitoneal (ip) administration. Locomotion and stereotypy were quantified by video-tracking analysis. The effects of (+)METH on spontaneous behavior were dose- and route-dependent. In particular, total locomotor activity was greatest following 3.0 mg/kg intraperitoneally (P<0.05) and stereotypy ratings were greatest following 3.0 mg/kg subcutaneously (P<0.05). In addition, the duration of locomotor effects was greatest after 3.0 mg/kg subcutaneously (P<0.05). Serum pharmacokinetic parameters were determined in separate rats given 3.0 mg/kg by subcutaneous and intraperitoneal administration (n=4 per administration route). The (+)METH elimination half-life was not different between the routes, but the (+)METH AUC was greater (P<0.05), and the (+)METH and (+)-amphetamine (AMP) maximum concentrations occurred later following subcutaneous than after intraperitoneal dosing (P<0.05), increasing and prolonging drug exposure. In conclusion, the overall pattern of (+)METH effects on locomotor activity depend on dose and the route of administration, which affects serum concentration and the time course of behavioral effects.

The neuropeptide neurotensin (NT) is highly sensitive to changes in dopaminergic signaling in the striatum, and is thought to modulate dopamine-mediated behaviors. To explore the interaction of NT with the dopamine system, we utilized mice with a targeted deletion of dopamine synthesis specifically in dopaminergic neurons. Dopamine levels in dopamine-deficient (DD) mice are less than 1% of control mice, and they require daily administration of the dopamine precursor L-dihydroxyphenylalanine (L-DOPA) for survival. DD mice are supersensitive to the effects of dopamine, becoming hyperactive relative to control mice in the presence of L-DOPA. We show that 24 h after L-DOPA treatment, when DD mice are in a "dopamine-depleted" state, Nt mRNA levels in the striatum of DD mice are similar to those in control mice. Administration of L-DOPA or L-DOPA plus the L-amino acid decarboxylase inhibitor, carbidopa, (C/L-DOPA) induced Nt expression in the striatum of DD mice. The dopamine D1 receptor antagonist, SCH23390, blocked C/L-DOPA-induced Nt. To test the hypothesis that this striatal Nt expression modulated dopamine-mediated behavior in DD mice, we administered SR 48692, an antagonist of the high affinity NT receptor, together with L-DOPA or C/L-DOPA. L-DOPA-induced hyperlocomotion and C/L-DOPA-induced stereotypy were potentiated by peripheral administration of SR 48692. Furthermore, intrastriatal microinjections of SR 48692 augmented L-DOPA-induced hyperlocomotion. These results demonstrate a dynamic regulation of striatal Nt expression by dopamine via D1 receptors in DD mice, and point to a physiological role for endogenous striatal NT in counteracting motor behaviors induced by an overactive dopamine system.

Gene expression studies have suggested that dopamine (DA) depletion increases the sensitivity of striatal direct pathway neurons to the effects of serotonin (5-HT) via the 5-HT(2) receptor. The present study examined the possible influence(s) of 5-HT(2A) or 5-HT(2C) receptor-mediated signaling locally within the striatum on motor behavior triggered by 5-HT(2) receptor agonism in the neonatal DA-depleted rat. Male Sprague-Dawley rats were treated with 6-hydroxydopamine (6-OHDA; 60 microg in 5 microl per lateral ventricle) on postnatal day 3 to achieve near-total DA depletion bilaterally. Sixty days later, sham-operated (saline-injected) or 6-OHDA-treated rats were challenged with the 5-HT(2A/2C) agonist DOI [(+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane] or saline either by systemic treatment or bilateral intrastriatal infusion. Motor behavior was quantified for 60 min after agonist injection using computerized activity monitors. Systemic DOI treatment (0.2 or 2.0 mg/kg i.p.) was more effective in inducing motor activity in the DA-depleted group compared with intact controls. Intrastriatal DOI infusion (1.0 or 10.0 microg/side) also produced a significant rise in motor activity in the DA-depleted group during the 30- to 60-min period of behavioral analysis but did not influence behavior in intact animals. The effects of intrastriatal DOI infusion were blocked by intrastriatal coinfusion of the 5-HT(2) antagonist ketanserin (1.0 microg) and the 5-HT(2A)-preferring antagonist M100907 [(R)(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol; 1.0 microg] but not the 5-HT(2C)-preferring antagonist RS102221 [8-[5-(2,4-dimethoxy-5-(4-trifluoromethylsulfo-amido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione; 1.0 microg]. Such results support the hypothesis that 5-HT(2A) receptor-mediated signaling events are strengthened within the striatum under conditions of DA depletion to provide a more potent regulation of motor activity.