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Effect of chronic haloperidol and quinacrine coadministration on striatal HVA levels and stereotypic behaviors in response to apomorphine in the rat.

The effects of chronic administration of quinacrine, a phospholipase A2 inhibitor, on striatal homovanillic acid (HVA) levels and behavioral sensitivity to challenge with a dopamine agonist were examined in rats. Moreover, the ability of chronic phospholipase A2 inhibition to modulate the behavioral supersensitivity and striatal HVA reduction induced by chronic haloperidol administration was also examined. Daily intraperitoneal injection of quinacrine resulted in a significant reduction of striatal HVA levels. Coadministration of haloperidol with quinacrine in this paradigm caused a more profound reduction of striatal HVA levels than either drug administered alone. That this effect of combined administration is not simply due to postsynaptic effects of quinacrine on dopamine receptor sensitivity is suggested by the fact that behavioral supersensitivity was not induced by quinacrine alone nor was the behavioral supersensitivity induced by the quinacrine-haloperidol combination greater than that induced by chronic haloperidol administration alone. There were no effects of any treatment condition on striatal levels of serotonin (5-HT) or 5-hydroxyindoleacetic acid (5-HIAA). These data implicate phospholipase A2 activity in the regulation of dopaminergic transmission.

Animals↗

Structural requirements for cocaine congeners to interact with dopamine and serotonin uptake sites in mouse brain and to induce stereotyped behavior.

We report here saturation analysis of [3H]cocaine binding in various mouse brain regions, and the necessary structure-activity relationships for cocaine congeners to inhibit Na+-dependent [3H]cocaine binding and [3H]dopamine uptake in the mouse striatum, and to inhibit [3H]cocaine binding that cannot be stimulated by Na+ and [3H]serotonin uptake in the mouse cerebral cortex. Generally similar structure-activity relationships were noted for all these processes. The ester linkage between the tropane and phenyl rings was not required for activity, in contrast to the configuration of the groups on C2, and to a lesser extent C3, in the tropane ring. Stereospecificity was evident from the differences between cocaine and (+)-pseudococaine, and between WIN 35,065-2 and WIN 35,065-3. There were remarkable differences between the above structure-activity relationships and those for local anesthetic activity of cocaine congeners, indicating that sodium channels were not labeled to a measurable extent with [3H]cocaine under the present conditions. Preliminary data indicated a significant correlation between the potencies of cocaine congeners in inhibiting the Na+-dependent binding of [3H]cocaine and their potencies in inducing stereotyped sniffing upon intraventricular administration.

Animals↗

Naloxone prevents and blocks the emergence of neuroleptic-mediated oral stereotypic behaviors.

A commonly used animal model for tardive dyskinesia is the oral stereotypy that is expressed by a challenge dose of a dopamine agonist after daily administration of dopamine antagonists (neuroleptics). In the first of two experiments the expression of this dopamine agonist-induced oral stereotypy was prevented by the concomitant administration of the opiate antagonist naloxone. In a second experiment, if the stereotypy was allowed to be expressed, it could be blocked by the administration of naloxone. To the extent that the effects of chronic neuroleptic treatment in rats is a model for tardive dyskinesia, the results suggest that administration of naloxone can both prevent and block the dyskinetic syndrome associated with neuroleptic use.

Animals↗

Neonatal treatment with L-name (NG-nitro-L-arginine methyl ester) attenuates stereotyped behavior induced by acute methamphetamine but not development of behavioral sensitization to methamphetamine.

1. The neurodevelopmental hypothesis of schizophrenia postulates that disturbed nitric oxide (NO) function during neuronal development is one of premorbid factors for schizophrenia in later life. 2. The aim of present study is to investigate behaviorally whether neonatal inhibition of nitric oxide synthase (NOS) affects dopaminergic function, the abnormality of which may be ascribed to a major pathophysiology of schizophrenia. 3. Male rat pups were injected daily with NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), from postnatal day (PD) 1 to 14. 4. When methamphetamine (MAP) was challenged on PD42, MAP-induced stereotypy was significantly attenuated in the L-NAME treated rats. The development of sensitization to the stereotypy-inducing effect of MAP, however, was not prevented with neonatal L-NAME. 5. These results suggest that decreased NO production during neonatal period may disturb normal maturation of dopaminergic system and result in impaired dopaminergic function in adult period.

Animals↗

Alkylation of striatal dopamine receptors abolishes stereotyped behavior but has no effect on dopamine stimulated adenylate cyclase activity.

The role of dopamine stimulated adenylate cyclase (AC) activity in behaviours elicited by apomorphine stimulation of striatal dopamine receptors was investigated. Rats were treated with the irreversible dopamine receptor alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) alone or after pretreatment with either a D1 or D2 receptor antagonist and subsequently challenged with apomorphine. Animals that received no antagonist pretreatment showed significantly decreased striatal concentrations of D1 and D2 receptors and an abolition of apomorphine induced sniffing behaviour despite showing no change in striatal AC activity. In the groups which received antagonist pretreatment the reduction in the sniffing response paralleled the reduction in D2 receptor concentration whereas the incidence of vacuous oral movements was inversely related. In no case were the behavioural responses associated with changes in AC activity. We conclude that these behavioural effects observed in response to dopamine stimulation by apomorphine may be mediated through another second messenger system.

Adenylyl Cyclases↗

Chronic treatments with zotepine, thioridazine, and haloperidol affect apomorphine-elicited stereotypic behavior and striatal 3H-spiroperidol binding sites in the rat.

Apomorphine (AP)-elicited sterotypic behavior and striatal 3H-spiroperidol binding sites were studied in rats given 3 weeks of chronic treatment with one of the following neuroleptic drugs: zotepine (10 or 20 mg/kg/day IP); thioridazine (10 or 20 mg/kg/day IP); haloperidol (2 or 5 mg/kg/day IP). On days 10-12 after the chronic neuroleptic treatment, enhancement of AP-elicited stereotypy was seen in the high- and low-dose haloperidol-treated, as well as in the high-dose thioridazine and zotepine-treated rats when compared to that of saline-injected controls. No significant change in the response to AP was found in the low-dose thioridazine and zotepine-treated animals. Significant increases in the concentration of striatal 3H-spiroperidol binding sites were seen after treatment with all three neuroleptics, both high and low doses. A positive correlation was found between AP-elicited stereotypy and the concentration of striatal 3H-spiroperidol binding sites in the haloperidol-treated and control rats. However, no such correlation was seen after chronic thioridazine and zotepine treatments.

Animals↗

Properties of some 1-arylpiperazines as antagonists of stereotyped behaviors mediated by central serotonergic receptors in rodents.

This investigation evaluated the effects of the 1-arylpiperazines (1-(1-naphthyl)piperazine (1-NP), 1-(2-[4-aminophenylethyl]-4-[3-trifluoromethylphenyl]piperazine (PAPP), 1-(3-trifluoromethylphenyl)piperazine (TFMPP) and 1-(3-chlorophenyl)piperazine (mCPP) on head-twitching elicited by central 5-hydroxytryptamine2, (5-HT2) agonists and on the 5-HT motor syndrome associated with stimulating 5-HT1A receptors in rodents. 1-NP (0.25-16.0 mumol/kg i.p.) dose-dependently inhibited head twitching produced by carbidopa (100 mumol/kg i.p.) plus 5-hydroxy-L-tryptophan (1000 mumol/kg i.p.) in mice. Pretreatment with 4 mumol/kg of 1-NP shifted the entire dose-response curve for head-twitching induced by quipazine (0.33-46.7 mumol/kg i.p.) to the right without reducing locomotor stimulation produced by quipazine (8 mumol/kg) in mice placed in novel photocell cages. 1-NP, PAPP, TFMPP and mCPP (8 mumol/kg) antagonized twitching after 5-methoxy-N,N-dimethyltryptamine (100 mumol/kg i.p.) or 5-hydroxy-L-tryptophan. In rats, these arylpiperazines (1-32 mumol/kg) dose-dependently antagonized twitching elicited by quipazine (10 mumol/kg) without producing correlated alterations in locomotion. 1-NP, PAPP, and mCPP were equipotent and 6-fold more potent than TFMPP against twitching. None of these arylpiperazines caused twitching. 1-NP (4 mumol/kg) also antagonized twitching following the direct 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (6 mumol/kg i.p.) but not after the thyrotropin releasing hormone analog MK-771 (20 mumol/kg i.p.) in rats. Larger doses of 1-NP (4-32 mumol/kg) and PAPP (64 mumol/kg) but not TFMPP or mCPP (16-128 mumol/kg), also reduced the incidence of the 5-HT syndrome produced by 5-methoxy-N,N-dimethyltryptamine (30 mumol/kg) in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Association between stereotypic behavior and polydipsia in chronic schizophrenic patients.

We assessed temporal associations between polydipsia and motor stereotypies in chronic schizophrenia. Subjects included: (a) a polydipsic patient with marked stereotypies; (b) a polydipsic patient with no history of stereotypy; (c) a nonpolydipsic patient. Stereotyped grooming and pacing were significantly associated with drinking for polydipsic patients only (polydipsic patients evidenced a 87% and 66% concordance between excessive grooming and drinking versus 12% in the control). Our findings provide the first empirical demonstration that polydipsia is temporally associated with other repetitive behaviors. The use of behavioral assessment to examine etiological theories suggesting that polydipsia stems from interacting environmental, biological, and pharmacological variables is discussed.

Adult↗

Reducing stereotyped behavior: a component analysis of the DRI schedule.

Three people with mental handicaps took part in a study which investigated the effects of various components of the DRI schedule on their levels of stereotyped behaviour. Three single-case experiments were carried out each investigating a separate component. Results suggested that the reductive effects of DRI could not be attributed to either the density of reinforcement available or to the prompting component. The success of the schedule was primarily attributable to the non-contingent interaction between the subject and the experimenter.

Adolescent↗

[Effect on the immobilization-induced stress on the immune response in mice with various behavioral stereotypes].

CBA and C57BL/6J mice with aggressive and submissive types of zoo-social behavior fixed during 10-day confrontation testing demonstrated different immune response to immobilization stress. In aggressive mice with confrontation experience stress resulted in a decrease in the immune response in comparison with aggressive inexperienced mice. Therewith, the immune response of CBA mice did not differ from the control level (the immunized mice without experience of victories and defeats), and in C57BL/6 mice the immune response was two times lower than in the control. In contrast to the control and aggressive mice, stress did not suppress the immune response in submissive animals. It is suggested that stress-induced changes in the immune response depend on zoo-social rank of an individual underlain by a particular neurochemical pattern of the brain.

Aggression↗

Development of spontaneous stereotyped behavior in deer mice: effects of early and late exposure to a more complex environment.

Abnormal repetitive behaviors such as stereotypies are associated with neurodevelopmental disorders and are often observed under conditions of environmental restriction, particularly early in development. Few studies, however, have systematically assessed the effects of environmental enrichment and almost no information is available as to whether a sensitive period exists for such enrichment effects. We hypothesized that spontaneous stereotypies exhibited by deer mice housed under standard laboratory conditions were the result of environmental restriction and that a sensitive period exists for the development/prevention of stereotypies. Exposure to a more complex environment early in the post-weaning period resulted in substantially less stereotypy in the complex environment. Importantly, this outcome was maintained even after mice were housed in standard cages for an identical period of time. Later exposure to the more complex environment also resulted in significantly lower levels of stereotypy compared to controls. These effects were observed in the experimental housing condition as well as in a standard test context. The effects of early and late enrichment support the importance of environmental restriction in the genesis of stereotype and provide support for the efficacy of early and late enrichment in the prevention of stereotypies.

Age Factors↗

Methylphenidate: diurnal effects on locomotor and stereotypic behavior in the rat.

The dose-response relationship and time course of effect on motor activity after a single dose of methylphenidate given at different times of the light/dark cycle was investigated using a computerized infrared activity analysis system. After 5 to 7 days of acclimation and 2 days of baseline activity recording, rats received a single subcutaneous injection of vehicle (saline) or of 0.6, 2.5, 10 or 40 mg/kg methylphenidate at 08:00, 14:00, 20:00, or 02:00. Recording was then resumed for an additional 36 to 48 hours. The locomotor indices analyzed were horizontal activity, total distance, vertical activity, stereotypic activity, and number of stereotypic movements. Saline and 0.6 mg/kg did not alter motor activity, but 2.5, 10 and 40 mg/kg significantly increased (P < 0.01) motor activity. The time to the maximum effect and the duration of effect increased with dose. Ten mg/kg had the most robust effect on locomotor activity, while the largest dose, 40 mg/kg, elicited a more focused stereotyped activity that limited the amount of forward ambulation. A single injection of methylphenidate had only transient effects. The locomotor stimulating effects of the lower doses were similar whether given during the light or dark phase, despite the large diurnal variations in baseline activity between the activity phases. The stereotypic effects of the highest dose of methylphenidate, however, varied between the light and dark phase, with a smaller stereotypic effect during the dark phase when compared to administration during the light phase.

Animals↗

Opioid influence on some aspects of stereotyped behavior induced by repeated amphetamine treatment.

Rats were administered repeated IP injections of dl-amphetamine (AMPH) according to a chronic escalating dose schedule (three doses per 24 hr, for four days, two days or one day). Animals treated for four days exhibited a diminished oral stereotypy in response to a challenge of 12 mg/kg AMPH or 2 mg/kg SC apomorphine (APO), 72 hr after withdrawal. Pretreatment with 2 mg/kg IP naloxone (NAL) during the period of chronic AMPH administration prevented the reduction in oral stereotypy induced by AMPH or APO. No differences were detected among the mean of stereotypy scores from the different treatments in response to a challenge dose of 6 mg/kg AMPH. Neurochemical data showed that NAL pretreatment reversed the depletion of striatal dopamine content induced by chronic AMPH. When repeated injections of AMPH were given only one day, the diminished stereotypy response to AMPH or APO was not observed. Animals treated simultaneously with 1 mg/kg IP morphine or 5 micrograms/kg IP beta-endorphin and repeated AMPH injections for one day, showed a reduced stereotyped response to AMPH or APO. These results suggest that opioid peptides are involved in the mechanisms underlying the decrease in oral behaviors following AMPH treatment.

3,4-Dihydroxyphenylacetic Acid↗

Development of complex, stereotyped behavior in pigeons.

A pigeon's peck on one key moved a light down one position in a 5x5 matrix of lights, while a peck on another key moved the light across one position. Reinforcement depended upon the occurrence of four pecks on each key (moving the matrix light from the top left to the bottom right), and a fifth peck on either key ended a trial without food. Though there were 70 different sequences that led to reinforcement, each of 12 pigeons developed a particular, stereotyped sequence which dominated its behavior (Experiment 1). Extinction produced substantial increases in sequence variability (Experiment 2). Removal of the matrix cues disrupted performance, though it partially recovered with extended training (Experiment 3). The pigeons did not master a contingency which required a different sequence on the current trial than on the previous one (Experiment 4), though they were able to learn to emit sequences which began with either left-left or left-right response patterns (Experiment 5). The experiments suggest that contingencies of reinforcement may contribute to the creation of complex units of behavior, and that stereotypy may be a likely consequence of contingent reinforcement.

Journal Article↗

Stereotyped behavior in developmentally delayed or autistic populations. Rhythmic or nonrhythmic?

Stereotypies are high-frequency, highly repetitive, nonfunctional behaviors that are also often characterized as rhythmic. Rhythmicity suggests that the behavior is periodic, occurring at fixed intervals. Few studies, however, have rigorously demonstrated periodicity in stereotypy. This study examined various topographies of stereotypy in 9 participants and used spectral methods to detect existence of periodicties. Two general patterns emerged in the spectral analysis. Participants who engaged in stereotypic rocking showed peaks in their power spectra; participants who engaged in other topographies of stereotypy did not show peaks. Thus, it appears that although some stereotypies--notably, rocking--have a periodic component, rhythmicity does not appear to be a characteristic of stereotypy in general.

Adolescent↗

Observations of parent reactions to sex-stereotyped behaviors: age and sex effects.

To examine differential socialization of boys and girls by mothers and fathers, home observations were completed for families of 92 12-month-old children, 82 18-month-old children, and 172 5-year-old children. Mothers gave more instructions and directions than did fathers, while fathers spent more time in positive play interaction. Differences in parents' reactions to 12- and 18-month boys and girls were as expected, with the exception that boys received more negative comment for communication attempts than did girls. The suggestion in the literature that fathers would be more involved in sex typing than mothers was not confirmed in this study. The only 2 significant sex-of-parent x sex-of-child effects occurred at 18 months; fathers gave fewer positive reactions to boys engaging in female-typical toy play, and mothers gave more instruction to girls when they attempted to communicate. We argue that the second year of life is the time when children are learning many new skills and when parents are still experimenting with parenting styles and may well use stereotypical responses when unsure of themselves.

Child, Preschool↗