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The effects of serotonergic stimulation on hippocampal and neocortical slow waves and behavior.

The effect of central serotonergic stimulation on hippocampal and neocortical electrical activity and behavior was studied in freely moving rats by administering: (a) tranylcypromine followed by tryptophan, (b) fluoxetine followed by 5-hydroxytryptophan, or (c) p-chloroamphetamine alone. In all rats, scopolamine-resistant hippocampal rhythmical slow activity (RSA), thought to be dependent on brain serotonin, maintained its normal relation to behavior, occurring in close correlation with Type 1 behaviors (postural changes, turning of the head, walking). This RSA was generally absent during stereotyped behavior (head weaving, forepaw treading, hindlimb splaying and tremor). Scopolamine-resistant neocortical low-voltage fast activity (LVFA), also though to be dependent on brain serotonin, was present during Type 1 behaviors and also during stereotyped behavior. Most rats that developed a full stereotyped behavior syndrome had behavioral and electrocortical seizures which were associated with a reduction in the amplitude of hippocampal activity. These seizures were suppressed by methysergide or benserazide. Metergoline (and methysergide to a lesser extent) suppressed the stereotypic behaviors of the serotonin syndrome, resulting in a striking increase in the locomotion caused by central serotonergic stimulation. Such locomotion was accompanied by RSA and LVFA. It was concluded that increased serotonergic activity in the CNS causes an increase in motor activity and a correlated increase in scopolamine-resistant hippocampal RSA and scopolamine-resistant neocortical LVFA and suggested that metergoline blocks serotonin receptors mediating stereotyped behaviors, thereby permitting the expression of serotonin-mediated locomotion.

5-Hydroxytryptophan↗

[Behavioral changes induced by repeated administration of mazindol, an anorexiant, in rats].

Behavioral changes in locomotor activity and stereotyped behaviors induced by daily administration (for 7 days) of mazindol (5 and 10 mg/kg, po) were compared with those induced by methamphetamine (10 mg/kg) in rats. On day 1, mazindol increased locomotor activity, which was enhanced by daily administrations. Stereotyped behaviors were also induced by mazindol, which became more marked following daily administrations. Methamphetamine markedly increased stereotyped behavior rather than locomotor activity on day 1, and the effects were not enhanced by daily administrations. The increased locomotor activity and stereotyped behaviors caused by mazindol and methamphetamine were markedly reduced by the dopamine receptor antagonist pimozide (0.1-0.4 mg/kg, ip) in a dose-dependent manner. These results suggest that repeated mazindol administration enhances locomotor-stimulant and stereotypy-producing effects, which are mediated by the central dopaminergic system.

Animals↗

The validity and reliability of the Wing Subgroups Questionnaire.

This study examined the validity and the internal and interrater reliability of the Wing Subgroups Questionnaire (WSQ), an assessment that classifies children with autism into one of three subtypes. Subjects were 42 students enrolled in multihandicapped special education classrooms. Results indicated that items pertaining to the active-but-odd and the aloof subtypes, and to typical development, demonstrated good consistency, whereas passive subtype items showed moderate consistency. Interrater reliability was good for all subtypes utilizing intraclass correlations, but it was moderate with regard to percentage agreement of subtype diagnosis. Interscale correlations were mostly low or negative, suggesting that the subtype scales are measuring distinct constructs. Significant differences among the subtypes were found on three measures of communication, three measures of social interaction, two measures of stereotypic behavior, and one measure of temper/aggression.

Adolescent↗

A proposed natural geometry of recovery from akinesia in the lateral hypothalamic rat.

The Eshkol-Wachmann movement notation is used to analyze and describe neurological recovery from the akinesia caused by severe bilateral lateral hypothalamic (LH) damage in rats. Exploratory movement recovers along several relatively independent dimensions which appear successively. First, lateral head scanning movements recover. At about the same time or later, longitudinal (backward-forward) head scans appear. After movements along these two dimensions increase in amplitude and involve the whole body, vertical (dorsal-ventral) head scans with snout contact (along vertical surfaces) typically appear, and increase gradually in amplitude. Later, vertical rearing without snout contact emerges. Recovery proceeds cephalocaudally, as more caudal limb and body segments are recruited along each of the above dimensions separately. LH rats show delayed recruitment of caudal limb and body segments ('strait-jacket phenomenon'). Support of the body and management of limb and body segments' contact with the ground also recover relatively independently, in a proximodistal fashion. In recovery, arrests between bouts of activity become shorter. Movement first becomes organized in relation to the animals' own body, and only much later, in relation to the environment. In each sequence of movement after pronounced immobility, the rat recapitulates the process of recovery; and, any time it starts to move, it repeats the movements at a particular amplitude several times until there is an increase to the next larger size movement ('warm-up' phenomenon). These regularities explain the apparently bizarre stereotyped behavior in partial enclosures ('behavioral traps') seen in LH rats recovering from akinesia. They also explain some aspects of exploration in rats and normal social behavior of wild animals, particularly in situations involving fear and conflict.

Animals↗

Aggression and psychopathology in persons with severe or profound mental retardation.

We examined aggression and psychopathology in persons with severe or profound mental retardation. Most aggressive episodes were directed toward other clients, and ratings of aggression were positively correlated with self-injury, stereotypic behavior, and being ambulatory. In a linear regression analysis of psychopathological correlates, aggression was most consistently predicted by dependent personality and psychosis. To better describe the construct of aggression, we also developed an Aggression-psychopathology scale. Persons with mental retardation and aggression were more likely to be impulsive, attention-seeking, dependent, socially inadequate, and anxious. Intensive efforts to modify the psychopathological correlates of aggression may improve treatment planning and outcome.

Adolescent↗

[Applying a structured intervention to a high-functioning autistic adolescent].

The nurse-author describes her structured response to the aggressive and stereotypical behavior of a high-functioning autistic adolescent. Methods consisted of the therapeutic application of routines and scheduling, establishing clear expectations, using consequences in response to established rules, cooperating with a periodic autistic teacher, transferring the adolescent to a different junior high school, planning an individual curriculum, and providing emotional and active support to the client's mother. The intervention occurred between January and December, 2002. By the end of treatment, the client was no longer violent, his social interaction skills had improved, and he was attending his classes on a regular basis. Concurrently, his mother's anxiety levels had decreased. The nurse took on several functions normally associated with therapists during the nursing process in her attempt to effect change in the client's perceptions. The author discusses the effectiveness of creating a positive atmosphere and of extending her nursing roles and functions beyond the hospital to family and school settings.

Adolescent↗

Effects of a vestibular stimulation program on stereotypic rocking behavior.

This study measures the effect of a vestibular stimulation program on the stereotypic rocking behavior of three severely mentally retarded persons within both experimental and natural settings. A multiple baseline design was used. Frequency and duration of stereotypic rocking behavior were measured by a partial-interval time sample. Results indicated a statistically significant reduction of both frequency and duration of rocking behavior directly after receiving vestibular stimulation and 1 hour after stimulation. The rocking behavior remained reduced after 6 days without the vestibular stimulation program. It was concluded that vestibular stimulation resulted in a reduction of the stereotypic rocking behavior of these subjects.

Adolescent↗

Apomorphine: effects on the timing and sequencing of pecking behavior in chicks.

Stereotyped behavior induced by apomorphine is thought to be "autistic", that is, impervious to environmental influence. This assumption is tested by analyzing the patterning of pecks at two differently colored stimuli in three-day old chicks treated with either 0.3 mg-kg-1 or 0.4 mg-kg-1 apomorphine. While normal chicks strongly prefer one stimulus over the other, apomorphine appears to render the choice behavior of chicks insensitive to differences between the stimuli. This result might suggest that apomorphine-treated chicks no longer perceive differences between the stimuli, but an analysis of the timing of pecks reveals that differences are still perceived since the two stimuli elicit different rates of pecking.

Animals↗

Effects of lead on the behavioral complex stereotypes and regional brain dopamine levels in rats.

The behavioral complex stereotype responses such as rearing, preening, scratching and biting were observed in an open-field situation in rats ingesting 2% lead acetate in drinking water for a period of 30 days. Endogeneous levels of dopamine were measured spectrophoto-fluorometrically in three brain regions; namely, cerebral cortex, cerebellum, and brain stem. The behavioral rearing response was diminished on day 3 and between days 7 to 22 of lead ingestion as compared to the control. Subsequently, this response was progressively increased from day 26 to 30. The animals showed depressed response of preening on day 2 and 6. From day 9, the preening response exhibited a continuous increasing pattern until the last day of the experiment. However, the complex stereotypy of scratching behavior of rats showed a parabolic pattern against the normal scratching behavior. A similar pattern of biting response has been observed in lead-intoxicated animals. Both the scratching and biting responses were higher than the control at the end of the experiment. Dopamine levels increased in the cerebral cortex on days 13, 23, and 30. In the cerebellum, the dopamine level was reduced on day 13 and increased on day 23. The brain stem exhibited increased level of dopamine on days 3, 13, 23, and 30 as compared to the control. These evidences clearly show an association of dopamine with complex stereotypy behaviors of lead intoxication.

Animals↗

Pentadecapeptide BPC 157 attenuates chronic amphetamine-induced behavior disturbances.

AIM: To investigate the effect of pentadecapeptide BPC 157 on chronic exposure to amphetamine in rats, particularly the changes commonly referred in chronic amphetamine studies as tolerance (lesser grade of stereotyped behavior, without increased excitability) and reverse tolerance (ie, prominent stereotyped behavior and heightened startle response upon late amphetamine challenges). METHODS: After initial application (initial single dose-regimen), amphetamine (10 mg/kg,ip) was given once daily till d 5 (continuous administration-regimen), and thereafter on d 8, 16, and 46 (intermittent administration regimen). Fo r stereotyped behavior and heightened startle response the observation period was 120 min after amphetamine application, and each animal was observed for 10 s in 5 min intervals. Pentadecapeptide BPC 157 (10 microg/kg or 10 ng/k g, ip) or saline (5.0 mL/kg, ip) were given only at the beginning of the experiment, simultaneously with the initial dose of amphetamine. RESULTS: In relation to applied initial-single/continuous/intermittent amphetamine applications regimen, the control amphetamine rats throughout the experiment showed the changes in stereotyped behavior and heightened startle response, increment or decrement, commonly explained in chronic amphetamine studies as tolerance and reverse tolerance. After t he initial application of the amphetamine, the higher BPC 157 dosage apparently attenuated the stereotyped behavior, while the lower dosage of BPC 157 did not reach a statistical significance. Considering the forthcoming amphetamine challenges, in the rats initially treated with pentadecapeptide BPC 157, either 10 microg- or 10 ng-dose, at the time of the first application of amphetamine, the stereotyped behavior remains to be attenuated after all additional amphetamine challenges (on d 2-5, 8, 16, and 46). This attenuation was not limited to stereotyped behavior only. After the initial application of the amphetamine the heighten ed startle response was also apparently mitigated in rats receiving the BPC 157 dosage, either higher or lower. Later, confronted with the forthcoming amphetamine challenges, they showed apparently less abnormal excitability at all tested points. CONCLUSION: In summary, gastric pentadecapeptide BPC 157 (ie, both microg- and ng-BPC 157 regimens) attenuated chronic amphetamine disturbances. This effect was present throughout the observation period at a statistically significant level. Therefore, it seems that this gastric pentadecapeptide BPC 157 has a modulatory effect on dopamine system, and it could be used in chronic amphetamine disturbances.

Amphetamine↗

Stereotyped motor behaviors associated with autism in high-risk infants: a pilot videotape analysis of a sibling sample.

This study examined motor behaviors in a longitudinal cohort of infant siblings of children with autism. Stereotypic movements and postures occurring during standardized observational assessments at 12 and 18 months were coded from videotapes. Participants included eight infant siblings later diagnosed with autism spectrum disorder (ASD), a random sample of nine non-diagnosed siblings, and 15 controls. Videos were coded blind to diagnostic group. At 12 and 18 months the ASD group "arm waved" more frequently and at 18 months, one posture ("hands to ears") was more frequently observed in the ASD and non-diagnosed group compared to the controls. Overall, the siblings subsequently diagnosed with ASD and the comparison groups had considerable overlap in their repertoires of stereotyped behaviors.

Autistic Disorder↗

Metaphit, an acylating ligand for phencyclidine receptors: characterization of in vivo actions in the rat.

Metaphit, which acylates phencyclidine (PCP) receptors in vitro, was shown to acylate PCP receptors and antagonize the behavioral and electrophysiological effects of PCP in vivo. Metaphit (2 mumol/rat) administered i.c.v. produced PCP-like stereotyped behavior and ataxia in 10 to 20% of rats. At a lower dose, Metaphit (1 mumol/rat) antagonized the ability of PCP to induce stereotyped behavior and ataxia for 3 and 4 days, respectively. The Metaphit-induced antagonism of PCP induction of stereotyped behavior and ataxia was dose-dependent and specific as Metaphit did not antagonize induction of stereotyped behavior by amphetamine. Further evidence for a specific PCP receptor mechanism was the finding that PCP pretreatment blocked the effects of subsequent Metaphit administration. Metaphit also antagonized PCP-induction of stereotyped behavior, but not ataxia, after i.v. administration. Doses of Metaphit that produced long-term antagonism of the behavioral effects of PCP also produced a significant decrease in the maximum binding, but not Kd, of the binding of the PCP analog, [3H]-1-(2-thienyl)cyclohexyl]piperidine, in Metaphit-pretreated rats. The binding of [3H]etorphine and [3H]spiroperidol was not altered significantly by pretreating rats with Metaphit. (-)-Cyclazocine and (+)-SKF 10,047 induced stereotyped behavior and ataxia that was not antagonized by Metaphit-pretreatment. In electrophysiological experiments, Metaphit, like PCP, initially depressed the firing of caudate neurons as does PCP, but then irreversibly inhibited PCP-induced depression of caudate neurons. These results suggest that metaphit antagonized the effects of PCP by selectively acylating PCP receptors and that (-)-cyclazocine- and (+)-SKF 10,047-induced behavioral effects are not mediated primarily by PCP receptors.

Acylation↗

Effects of phencyclidine and methylphenidate on d-amphetamine-induced behaviors in reserpine pretreated rats.

The effects and interactions of phencyclidine (PCP), methylphenidate and d-amphetamine on locomotor activity, stereotyped behavior and ataxia in reserpine- and vehicle-pretreated rats were examined. The behaviors of rats receiving PCP alone or in combination with other drugs were quantified along three dimensions (locomotor activity, stereotyped behavior, and ataxia) on scales developed in this laboratory. The behaviors of groups receiving methylphenidate and/or d-amphetamine in treatment combinations other than those including PCP were quantified using a well known d-amphetamine behavioral rating scale. PCP, methylphenidate and d-amphetamine each induced significant increases in locomotor activity and stereotyped behavior when administered alone. Reserpine was found to antagonize PCP-induced locomotor activity and stereotyped behavior, and methylphenidate-induced stereotyped behavior at a dose which either potentiated or had no significant effect upon d-amphetamine-induced behavior (depending upon the scale used). Reserpine also potentiated PCP-induced ataxia. Whereas PCP potentiated the locomotor activity induced by d-amphetamine in both reserpine- and vehicle-pretreated subjects, methylphenidate marginally antagonized d-amphetamine-induced stereotypy in reserpine-pretreated subjects. PCP-induced ataxia in reserpine pretreated subjects appeared moderately reduced in subjects also receiving d-amphetamine. In general, the behavioral effects of PCP appear to be more similar to those of methylphenidate than to those of d-amphetamine, but differences are also found between PCP and methylphenidate. The results are discussed in relation to a behavioral model recently proposed as a method for differentiating indirect dopamine agonists on the basis of their neurochemical mechanisms of action.

Animals↗

Dissociation between spontaneously emitted and apomorphine-induced stereotypy in Peromyscus maniculatus bairdii.

Stereotyped behavior is repetitive, topographically invariant motor activity that lacks an obvious function. We have previously characterized the spontaneous and persistent stereotypies that occur in deer mice housed in standard laboratory cages. Providing these animals with enriched environments markedly reduces their vulnerability to develop stereotypic behavioral repertoires, thus enabling us to generate behaviorally distinct (stereotypic and nonstereotypic) mice of the same species. As stereotypic behaviors are readily induced by systemic administration of a dopamine (DA) agonist, the present study tested whether apomorphine would induce stereotypies in environmentally enriched (nonstereotypic) deer mice that were topographically similar to the stereotypies that are spontaneously emitted by standard-caged (stereotypic) deer mice. The effects of apomorphine were also evaluated in the standard-caged (stereotypic) deer mice. DA agonist-induced behaviors in nonstereotypic mice included stereotypies that were largely topographically distinct from spontaneously emitted stereotypies; apomorphine failed to produce statistically significant elevations in two of the three stereotypic behaviors typical of standard-caged deer mice. Furthermore, there was no evidence of increased DA receptor sensitivity in stereotypic mice. Thus, environmentally related stereotypy is distinct from systemically administered DA agonist-induced stereotypy, and is not exacerbated by such drug treatment. The results obtained do provide support, however, for a limited involvement of the DA system in the mediation of these behaviors.

Animals↗

Pharmacologic control of pemoline induced self-injurious behavior in rats.

Administration of oral Pemoline produces long lasting amphetamine-type stereotyped behavior and persistent self-biting behavior in rats. The effects of haloperidol, pimozide, diazepam, and serotonin depletion by pretreatment with p-chlorophenylalanine (PCPA) or chronic pretreatment with p-chloroamphetamine (PCA) on abnormal behavior produced by pemoline were studied. Diazepam consistently increased the duration of stereotyped behavior. It also reduced licking/biting and self-biting but the latter effects were not consistent. Pretreatment with PCA had negligible effects on stereotyped behavior. Pretreatment with PCPA dramatically increased locomotion and rearing without affecting the other components of stereotypy--stereotyped head movements, licking/biting, and self-biting. Haloperidol (0.2 and 0.3 mg/kg) produced a dose related normalization of pemoline induced behaviors, including elimination of self-biting. Pimozide (0.5, 0.8 and 1.3 mg/kg) had little or no effect on behaviors such as locomotions, rears, licking/biting, or stereotyped head movements but eliminated self-biting at 1.3 mg/kg. These data suggest that pemoline, like amphetamine, produces stereotyped behavior through central dopaminergic mechanisms. Dopaminergic mechanisms also appear to be involved in pemoline induced self-biting. pemoline is apparently pharmacologically and behaviorally very similar to amphetamine. Pemoline may provide a useful animal model for syndromes characterized by self-injurious behavior and other repetitive behaviors.

Amphetamines↗

Behavioral demonstration of a reciprocal interaction between dopamine receptor subtypes in the mouse striatum: possible involvement of the striato-nigral pathway.

It is well known that stimulation of the D-2 dopamine receptor in vitro inhibits the increased efflux of cyclic adenosine monophosphate caused by D-1 receptor agonists. Furthermore, behavioral data suggest that the striato-nigral pathway is more involved with the dopamine agonist-induced expression of oral behaviors, which are, in turn, mediated by stimulation of the D-1 receptor. We examined an in vivo model to determine whether this D-1/D-2 reciprocal interaction is detectable at a behavioral level. First, mice were pretreated with wide range of doses of the D-2 antagonist, spiperone, and then injected with a behaviorally active dose of apomorphine (a nonspecific direct dopamine agonist) and were observed for incidence of oral behavior and rated for stereotypic behavior. A biphasic effect of spiperone pretreatment was observed, at some low doses both stereotypy and oral behavior were enhanced, while at high doses, both agonist-induced behaviors were progressively inhibited. To test the specificity of this effect for the striato-nigral pathway, mice were administered discrete electrolytic lesions in the ventral portion of the internal capsule in one hemisphere. The animals that responded to apomorphine by rotating ipsilaterally to the lesion were used in two, five-point apomorphine dose-response curves, one with, and one without, pretreatment with the dose of spiperone which most enhanced stereotypic behavior and incidence of oral behavior. The spiperone pretreatment caused a clear increase in the maximum rotational response to apomorphine without affecting the ED50. These data suggest that behavior associated with the striato-nigral efferent from striatum is marked by the opposition of D-1 and D-2 receptors.

Animals↗

Estradiol application to one striatum produces postural deviation to systemic apomorphine.

In order to test whether estrogen acts directly in the dorsal striatum to affect dopamine-mediated behavior, ovariectomized female Long-Evans rats were given a unilateral striatal application of estradiol, injected systemically with apomorphine (APO), and tested for lateralization of stereotypic behaviors. In the first experiment, estradiol, cholesterol, or an empty cannula was inserted and the rat given 0.7 mg/kg APO 1-4 hours later. Rats directed their stereotypic behaviors to the side ipsilateral to the insert of estradiol with dorsal striatal inserts, but not with inserts in ventral striatum or neocortex. Neither cholesterol nor the empty cannula inserts were effective in producing lateralization of the stereotypic behaviors. In the second experiment, intrastriatal inserts of 17 alpha-estradiol were ineffective in producing a lateralization of APO-induced stereotyped behavior. In the third experiment, several doses of APO (0.07, 0.75 and 3.0 mg/kg) were tested. At the highest dose no lateralization of APO-induced stereotypic behavior was observed. These results strongly suggest that estradiol acts directly in the dorsal striatum to antagonize APO and thus produce a lateralization of stereotypic behaviors (postural deviation).

Animals↗

Apomorphine and piribedil in rats: biochemical and pharmacologic studies.

We studied the biochemical and pharmacologic modes of action of piribedil and apomorphine in the rat. Although both drugs have many points in common, they are also different in many of their manifestations. Apomorphine causes high-intensity, short-duration stereotyped behavior; it is distributed within the brain in uneven fashion, the striatum being the area of lowest concentration as measured by fluorometry. Direct stereotactic injection within the dopaminergic mesolimbic system, and particularly the tuberculum olfactorium, produced constant intense responses. All effects of apomorphine can be blocked by pimozide, but propanolol, a beta blocker, only reduces aggression and ferocity, leaving stereotyped behaviors intact. Finally, L-5-HTP tends to reduce aggression, ferocity, and to a lesser extent stereotypy; MIF or piribedil, as well as reserpine, potentiates the stereotyped behaviors induced by apomorphine, whereas L-DOPA usually decreases them. Piribedil, on the other hand, causes low-intensity, long-duration stereotyped behavior. It is distributed within the brain almost uniformly. Most effects of piribedil can be blocked by pimozide, but propanolol blocks only aggression and ferocity, leaving stereotyped behaviors intact. On the other hand, clonidine, an alpha-receptor agonist, blocks stereotyped behaviors induced by piribedil but markedly increases aggression, ferocity, and motor activity. L-5-HTP and L-DOPA have little effect on piribedil-induced manifestations. Reserpine decreases piribedil stereotypy. The main metabolite of piribedil, S 584, had no clear-cut pharmacologic action in our hands at the dosage used. It is concluded that both apomorphine and piribedil produce stereotyped behavior by modifying the physiologic balance between mesolimbic and nigrostriatal dopaminergic systems. The other actions of apomorphine and piribedil upon aggression, ferocity, and motor activity are not always in parallel and depend probably on the fact that piribedil is less specific, affecting also noradrenergic, serotonergic, histaminergic, and/or cholinergic circuits. The usefulness of piribedil against some forms of human tremor and its low-intensity antiakinetic action probably result from this pattern of pharmacologic activity.

Amygdala↗