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Activity changes and marked stereotypic behavior precede Abeta pathology in TgCRND8 Alzheimer mice.

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.

Adrenal Medulla↗

Self-injurious and stereotypic behavior of noninstitutionalized mentally retarded people: prevalence and classification.

A nationwide mail survey on self-injurious behavior (SIB) and stereotypies was carried out among noninstitutionalized mentally retarded people in the Federal Republic of Germany. The estimated SIB prevalence among 25,872 retarded persons from 294 service facilities was 1.7%, which is considerably lower than earlier estimates based on samples of institutionalized persons. Prevalence of stereotypic behavior among individuals with SIB was 65%, compared to 62% in a control sample of persons without SIB. A cluster analysis distinguished three SIB clusters. Different types of stereotypic behavior were found to be differentially related to different types of SIB.

Female↗

Mixed D2/5-HT2 antagonism differentially affects apomorphine- and amphetamine-induced stereotyped behavior.

Evidence supports the hypothesis that psychostimulant stereotypy is mediated through postsynaptic dopamine receptors. Given the recent findings of behavioral, neurochemical and electrophysiological studies showing 5-HT2 modulation of dopamine systems, a series of experiments were undertaken to assess the ability of D2 and 5-HT2 antagonists to reverse apomorphine and amphetamine stereotypy in the rat. Haloperidol reduced stereotyped behavior induced by d-amphetamine (50% reduction with 0.162 mg/kg) and apomorphine (50% reduction with 0.112 mg/kg) MDL 28,133A, a mixed D2/5-HT2 antagonist, also reduced stereotypy in the apomorphine group (50% reduction with 3.89 mg/kg) but was much less effective in antagonizing the effects of d-amphetamine (not even a 25% reduction with 9.0 mg/kg). MDL 100,907, a selective 5-HT2 antagonist, was ineffective at reducing stereotyped behavior induced by either stimulant. Thus, 5-HT2 modulation of dopaminergic activity was not demonstrated in the case of psychostimulant stereotypy. Furthermore, 5-HT2 antagonism did not induce stereotypy, as has been proposed in some models. These findings provide further support for the hypothesis that antipsychotic medications with high affinity for 5-HT2 receptors do not interfere with the regulation of the nigrostriatal dopaminergic system and, therefore, would be less likely to produce extrapyramidal side effects.

Amphetamine↗

Digiscan activity: automated measurement of thigmotactic and stereotypic behavior in rats.

Visual measures of stereotypy, margin time (thigmotaxis or wall-hugging), and center time were correlated with automated measures using a revised 16 beam version of the Digiscan Animal Activity Monitor System. Rats were injected with d-amphetamine (1.25, 2.5, 5.0 and 10.0 mg/kg), scopolamine (1.25 and 2.5 mg/kg) or saline and drugs were found to increase center time and decrease margin time in a dose-dependent manner, with the maximum effect occurring with 1.25 and 2.5 mg/kg, respectively. At higher doses, an opposite effect was observed. Extremely high correlations between visual and automated recordings of both margin time and center time were found. Since thigmotaxic or wall-hugging behavior has been used as an indicator of emotionality in rats, the results of the present study suggest that these two locomotor variables may be useful additions to the Digiscan multivariate analysis of locomotor behavior. It was also found that a redefinition of stereotypic behavior improved its correlation with visual measurements compared to earlier studies.

Animals↗

Cytidine(5')diphosphocholine enhances the ability of haloperidol to increase dopamine metabolites in the striatum of the rat and to diminish stereotyped behavior induced by apomorphine.

Experiments were performed to determine whether exogenous cytidine(5')diphosphocholine (CDP-choline) could modify release of dopamine in the striatum and behavior dependent on dopamine, perhaps by providing supplemental choline for synthesis of acetylcholine. Rats received water (control) or CDP-choline orally (100 mg/kg per day, for 5 days), either alone or before injection with haloperidol (1 mg/kg, i.p.), apomorphine (0.15 mg/kg, s.c.), or both. Stereotyped behavior was measured during the hour after administration of apomorphine; levels of the dopamine metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum were assessed at the end of this period (2 hr after administration of haloperidol). In rats receiving the CDP-choline, the stereotyped behavior observed after injection of apomorphine alone (P less than 0.01), or after haloperidol plus apomorphine (P less than 0.01), was attenuated. The pretreatment with CDP-choline also significantly increased levels of HVA (by 24%) and DOPAC (by 23%) in the striatum over appropriate controls in animals receiving haloperidol, or by 29 and 59% (averaging data for all time points), respectively, in animals receiving haloperidol plus apomorphine. One mechanism by which CDP-choline may affect behavior involves contributing choline to enhance synthesis of acetylcholine.

3,4-Dihydroxyphenylacetic Acid↗

Environmental enrichment: effects on stereotyped behavior and regional neuronal metabolic activity.

The present study evaluated whether environmental enrichment-related effects on the development of stereotyped behavior in deer mice were associated with alterations in neuronal metabolic activity. Deer mice were reared under either enriched or standard housing conditions for 60 days following weaning. All mice were then placed in automated photocell detectors and classified as either stereotypic or non-stereotypic. Neuronal metabolic activity was then assessed using cytochrome oxidase (CO) histochemistry. The results demonstrated that environmental enrichment significantly increased neuronal metabolic activity in the motor cortex. Furthermore, non-stereotypic mice exhibited significantly more CO activity than stereotypic mice in the cortex, striatum, nucleus accumbens, thalamus, hippocampus and amygdala. This latter effect was due to the enriched mice as evidenced by a significant interaction between housing condition and behavioral status in the cortex, striatum, nucleus accumbens, thalamus and hippocampus. Thus, the observed increase in CO activity reflected increased neuronal metabolic activity in non-stereotypic enriched mice relative to stereotypic enriched mice. These results suggest that, in a developmental model of spontaneous stereotypy, the enrichment-related prevention of stereotyped behavior is associated with increased CO activity.

Animals↗

Septo-hypothalamic organization of a stereotyped behavior controlled by vasopressin in golden hamsters.

In golden hamsters, microinjections of arginine vasopressin (AVP) within the anterior hypothalamus (AH) and lateral septum (LS) elicit the display of a stereotyped behavior: flank marking. As these areas are reciprocally connected, we tested whether AVP-sensitive sites constitute an organized network. Flank marking was recorded in animals with ibotenic acid lesions within the AH or LS after AVP injections within the LS or AH. While AVP injections in the AH and LS induced high flank-marking scores, certain lesions blocked the behavior. Lesions of the LS failed to affect flank marking induced by injections within the AH. In contrast, unilateral AH lesions blocked flank marking induced either by LS injections or AH injections in the contralateral side. These results suggest that the bilateral integrity of the AH is critical for the activation of flank-marking behavior by AVP. Together, these data suggest that the AH is an important relay of the neural network controlling flank-marking behavior.

Animals↗

Differential nigral expression of Bcl-2 protein family in chronically haloperidol and clozapine-treated rats: role in neurotoxicity and stereotyped behavior.

Tardive dyskinesia (TD) is a syndrome characterized by repetitive involuntary movements induced by the administration of typical neuroleptics such as haloperidol. TD generally persists after haloperidol withdrawal indicating that haloperidol produces long-lasting changes in brain function. In contrast to the typicals, atypical medications, such as clozapine, have very low rates of TD. The mechanisms underlying drug-induced TD are poorly understood. We have investigated the role of nigral expression of the bcl-2 family of proteins on haloperidol-induced neurotoxicity. Rats were treated for 21 days with the following drugs: haloperidol (1 mg/kg), clozapine (1 mg/kg) or saline. After a 3-day washout period, apomorphine-induced stereotyped behavior was scored. Western blotting was performed to evaluate the nigral expression of the dopamine transporter (DAT), bax, bcl-x(L) and bcl-2 proteins. Haloperidol administration, but not clozapine, increased stereotyped behavior (p<0.01) in association with a decrease in striatal DAT expression (p<0.05). Haloperidol and clozapine treatment significantly decreased the nigral expression of bax (p<0.05, p<0.01, respectively). Neither treatment modified bcx(L) expression. Haloperidol increased (p<0.05), whereas clozapine did not significantly modify the nigral expression of bcl-2. Our results suggest that the increase in bcl-2 expression in the haloperidol-treated animals might be a compensatory mechanism that may reflect cellular damage induced by haloperidol in the dopaminergic neurons in the pars compacta of the substantia nigra.

Animals↗

Role of nigral NFkappaB p50 and p65 subunit expression in haloperidol-induced neurotoxicity and stereotyped behavior in rats.

Long-term use of typical neuroleptics such as haloperidol may be limited by unwanted motor side effects like tardive dyskinesia (TD) characterized by repetitive involuntary movements, involving the mouth, face and tongue. TD generally persists after haloperidol withdrawal indicating long lasting changes in brain function that are no longer related to the presence of the drug. The precise mechanisms of the neuronal toxicity induced by haloperidol are poorly understood. Haloperidol has been shown to induce the expression of the transcription factor nuclear factor-kappaB (NFkappaB). NFkappaB resembles a heterodimer protein composed of a 50 and a 65 kDa subunits and the role of the NFkappaB subunits on haloperidol-induced toxicity remains still unknown. The aim of the present study is to investigate the role of the p65 and p50 subunits of NFkappaB on the toxicity induced by chronic haloperidol administration in an experimental model of TD. Rats were treated for 21 days with: haloperidol (1mg/kg), clozapine (1mg/kg) or saline. Apomorphine-induced stereotyped behavior was evaluated. Striatal expression of the dopamine transporter (DAT) and the nigral expression of the NFkappaB p65 and p50 subunits were measured by Western Blot. Haloperidol, but not clozapine, increased stereotyped behavior associated to a decreased striatal DAT expression (p<0.01). Haloperidol did not modify the nigral expression of the p65 subunit whereas clozapine decreased it (p<0.01). Both drugs induced a significant decrease in the nigral expression of the NFkappaB p50 (p<0.05 and p<0.01, respectively). The decrease in nigral expression of the p50 subunit may increase the vulnerability of the dopaminergic neurons to a possible neurotoxic effect of p65 subunits in the haloperidol-treated rats.

Animals↗

A single gene encodes multiple neuropeptides mediating a stereotyped behavior.

Egg laying in Aplysia is characterized by a stereotyped behavioral array which is mediated by several neuroactive peptides. We have sequenced two genes encoding the A and B peptides thought to initiate the egg-laying process, as well as a gene encoding egg-laying hormone (ELH) which directly mediates the behavioral array. The three genes share 90% sequence homology and are representatives of a small multigene family. Each gene encodes a protein precursor in which the active peptides are flanked by internal cleavage sites providing the potential to generate multiple small peptides. Each of the three genes consists of sequences homologous to A or B peptide as well as ELH. Although these genes share significant nucleotide homology, they have diverged such that different member genes express functionally related but nonoverlapping sets of neuroactive peptides in different tissues.

Animals↗

The competition of autistic stereotyped behavior with usual and specially assessed reinforcers.

This study was conducted to empirically assess a reinforcement theory of stereotyped behavior. Six students with autism were first presented with tasks, and no contingent reinforcers were provided for correct responding. Then, contingent reinforcers that were typically used with the students (usual reinforcers) were presented in a multiple baseline across subjects design. Three of the students evidenced decreases in stereotypy and increases in responding in the presence of usual reinforcers. The other three students required external suppression of stereotypy before increases in responding were shown. For these students, usual reinforcers and specially assessed reinforcers were then compared. The specially assessed reinforcers resulted in decreases in stereotypy and increases in responding and subjective measures of responsiveness. The results were discussed in terms of supporting a competing reinforcement hypothesis, such that powerful external reinforcers will successfully compete with and suppress reinforcers provided by stereotypy.

Adolescent↗

Effects of thioridazine on apomorphine-elicited stereotypic behavior and motor activity.

Bilaterally injected thioridazine (10 micrograms) into the striata of rats augmented the stereotypic behavior elicited by apomorphine. The enhancing effect was attenuated by pretreatment with alpha-methyl-p-tyrosine. At 48 hr postinjection of thioridazine (1.0 mg/kg, IP), motor suppression from a low dose of apomorphine (0.2 mg/kg, IP) was enhanced; however, motor response to a high dose of apomorphine (1 mg/kg, SC) was not affected. Possible mechanisms of action of thioridazine are discussed.

Animals↗

The stereotypy analysis: an instrument for examining environmental variables associated with differential rates of stereotypic behavior.

The Stereotypy Analysis, a means of analyzing environmental variables associated with differential rates of stereotypic behavior, was conducted with five persons having moderate to profound developmental disabilities. The process involves partial-interval recording of the occurrence of targeted behaviors and the presence/absence of specific environmental events. The Stereotypy Analysis was able to detect environmental events associated with stereotypic responding for 3 of the 5 subjects. Based on the results of the Stereotypy Analysis, indicated and not-indicated interventions were implemented for two subjects. The data obtained using the Stereotypy Analysis were useful in determining effective interventions for those subjects. Providing activities and prompts every 15 s, later faded to every 30 s, reduced handmouthing from a mean of 40% of intervals to 13% for one subject. Providing prompts every 30 s to engage in an activity decreased body rocking from 60% to 15% for the other. Effects for both interventions were replicated using A-B-A-B designs. The not-indicated intervention was unsuccessful for one subject; it suggested multiple control of the behavior for the other. Implications for behavioral theory and practice are discussed.

Adult↗

Intracerebroventricular injection of kynurenic acid, but not kynurenine, induces ataxia and stereotyped behavior in rats.

In the present studies the behavioral-pharmacological effects of kynurenine and its metabolite kynurenic acid were investigated after intracerebroventricular (ICV) microinjection in rats. Kynurenine (0.1 and 0.2 mumol ICV) produced slight behavioral changes, but its metabolite kynurenic acid (0.2 mumol ICV) induced marked ataxia, stereotyped behavior and muscular hypotonia in a dose-dependent manner. The kynurenic acid-induced neurological symptoms were partially inhibited but not eliminated by ICV pretreatment with D-serine (0.5, 2.5, 5 mumol), which is a selective agonist at the strychnine-insensitive glycine binding site of the NMDA-receptor complex. Our results support the following conclusions: 1) kynurenine (0.1 or 0.2 mumol, ICV) results in slight stereotypy and ataxia, but the speed of its metabolism to kynurenic acid in this paradigm is not sufficient to produce concentrations of kynurenic acid, which are able to elicit marked ataxia and stereotypy; 2) the duration of kynurenic acid-induced behavioral abnormalities is correlated with the length of disappearance of micro-injected kynurenic acid from brain tissue; 3) D-serine which is an agonist at the glycine site linked to the NMDA complex, partially antagonizes but does not eliminate the neurological disturbances induced by ICV kynurenic acid injection.

Animals↗

Comparison of structural and stereoisomers of apomorphine on stereotyped behavior of the rat.

N-n-propylnorapomorphine (NPA) is 35 times more potent than apomorphine (APO) in producing stereotyped behavior in rats. The effect of NPA is blocked by perphenazine but unaltered by alpha-methyltyrosine pretreatment and is accompanied by a decrease in central dopamine turnover. The activity of APO and NPA appears to be primarily in the (-)-isomer, and is diminished but not lost by removal of either hydroxyl group from the catechol ring system.

Animals↗

A review of behavioral factors involved in the development and continued performance of stereotypic behaviors in pigs.

Environmentally induced stereotypies, commonly observed in farm and zoo animals, are behaviors that are relatively invariant, that are regularly repeated, and that serve no obvious function. However, there is as yet no accepted means of discriminating between normal and abnormal behavior, and the assumption that stereotypies are abnormal may mask the fact that they arise in part through processes that "normally" control behavior. There is growing evidence that stereotypies in sows and broiler breeders are strongly related to feeding motivation. For example, sows only develop oral stereotypies if their feed intake is restricted, and operant conditioning experiments have shown commercial levels of feed restriction to give rise to high levels of feeding motivation. Stereotypies in animals whose feed intake is restricted largely occur in the postprandial period, and ingestion of food has specifically been shown to elicit stereotypies in sows. These observations suggest that positive feedback from feeding produces a short-term increase in feeding motivation that at the end of the meal is directed toward available, alternative stimuli such as chains, the choice of stimuli reflecting the sensory feedback from the activity. Drinking behavior may also become an expression of feeding behavior after metabolic water requirements are met. In addition to these processes specific to feeding motivation, it seems likely that nonspecific processes, which operate more generally across motivational systems, contribute to the persistence of the behavior. Behavioral arousal may facilitate performance of active behaviors, and sensitization of the underlying neural elements may lead to the behavior being more easily elicited and maintained. A crucial factor in the sensitization process would seem to be the channeling of complex behavior by the environment into a few and very often repeated sequences of behavior. This approach suggests that stereotypies can be prevented by either reducing the level of motivation underlying the stereotypy, or by allowing for the expression of more complex behavior and thereby preventing the processes of channeling and sensitization from occurring.

Animal Welfare↗

The effects of novelty and behavioral stereotype on the development of amnesia in mice.

The aim of the present study was to analyze the significance of the interaction between the basic behavioral strategy, the extinction of the novelty of information, and the efficacy of amnesia-inducing influences. Using a combination of training to passive avoidance with holding the animal in the unsafe sector of the apparatus, comparative analysis was performed of the reproduction of a memory trace in aggressive and submissive mice of line C57BL/6J with and without six sessions of familiarization with the apparatus. These experiments showed that preliminary habituation prevented the development of amnesia in submissive but not aggressive individuals. The cause of these differences in the effects of preexposure on the development of amnesia involves the selectivity of the process of extinction of information novelty characteristic for the behavioral stereotype.

Aggression↗

Failure of increased brain gamma-aminobutyric acid levels to influence amphetamine-induced stereotyped behavior.

Increased brain gamma-aminobutyric acid (GABA) levels secondary to the administration of sodium valproate failed to inhibit amphetamine-induced stereotyped behavior. This observation raises some doubt as to whether GABA plays a role in the physiology of the striatum and suggests that GABA does not play a role in the pathophysiology of chorea. If this is true, pharmacologic attempts to increase brain GABA may not improve human choreatic disorders.

Aminobutyrates↗