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PubMed1993

Altered spontaneous behavior and sensitivity to apomorphine in rats following pretreatment with S(+)-aporphines or fluphenazine.

Rats were pretreated for 2 weeks with similarly effective doses of the typical neuroleptic fluphenazine (FPZ) or the experimental weak partial D2 agonists S(+)N-n-propylnorapomorphine (NPA) and S(+)11-hydroxy-N-n-propylnoraporphine (11-OH-NPa). Spontaneous and dopamine (DA) agonist (apomorphine; APO) stimulated stereotyped behaviors or locomotion, and interactions with APO were evaluated over the following 2 weeks. While FPZ induced marked supersensitivity in APO stereotype, (+)NPA showed no significant change, and (+)11-OH-NPa produced only a small, transient increase in response; NPA also lacked a supersensitizing effect on locomotor arousal induced by APO. The time-course of stereotyped responses to APO following pretreatment with FLZ included a marked increase following FPZ that became maximal at day 5 and normalized by day 9; there was a parallel reduction of acute antisteotypy efficacy of FPZ. (+)11-OH-NPa had similar, but much lesser and shorter-lived effects. Spontaneous locomotion was markedly depressed following FPZ, recovered in 1 week, exceeded controls at day 9, and returned to baseline by day 11; (+)11-OH-NPa, again, had similar but smaller effects. Acute effects of FPZ to reduce spontaneous or APO-induced locomotion were greater after FPZ pretreatment and normalized within a week; (+)11-OH-NPa had a similar but smaller effect. Locomotor arousal by APO was altered inconsistently in the week after pretreatment with FPZ or (+)11-OH-NPa. Thus, FPZ appeared to induce tolerance and supersensitivity in central DA systems, most clearly seen following a several-day period to eliminate the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

The effects of a selective cAMP phosphodiesterase inhibitor, rolipram, on methamphetamine-induced behavior.

The effects of rolipram, a selective cAMP phosphodiesterase inhibitor, on locomotor activity, rearing, and stereotyped behavior (sniffing, repetitive head movements) induced by methamphetamine (MAP) over 1 hour were investigated in rats. Coadministration of rolipram (4 mg/kg IP) significantly attenuated the responses of locomotor activity, rearing and repetitive head movements to MAP (2,4 or 8 mg/kg IP). Rolipram (0.5, 1, 2, or 4 mg/kg IP) dose-dependently inhibited locomotor hyperactivity and rearing induced by 4 mg/kg of MAP. The rearing was completely inhibited by 4 mg/kg of rolipram, whereas the maximal inhibition of the locomotor hyperactivity was about 50%. However, rolipram did not alter MAP-induced sniffing and repetitive head movements. These results indicate that there is heterogeneity in the response of MAP-induced behavior to rolipram, suggesting that MAP-induced behavioral alteration may be partly regulated by cAMP levels in the brain.

Animals↗
PubMed2004

Specifying PDD-NOS: a comparison of PDD-NOS, Asperger syndrome, and autism.

OBJECTIVE: To describe the clinical characteristics of children given a diagnosis of pervasive developmental disorder-not otherwise specified (PDD-NOS) by expert clinicians and to compare these to the clinical characteristics of children given a diagnosis of autism and Asperger syndrome (AS). METHOD: Two hundred sixteen children with autism, 33 with AS, and 21 with PDD-NOS were compared on measures of level of functioning (communication, daily living and social skills, IQ, and age of acquisition of language) and on various symptoms of autism (impaired communication and reciprocal social interaction and a preference for repetitive and stereotyped activities). RESULTS: In terms of level of functioning measures, the PDD-NOS children had scores that were between those of the children with autism and those of the children with AS. In contrast, the PDD-NOS group had fewer autistic symptoms, especially repetitive stereotyped behaviors, than both the autism and AS groups (chi2 = 11.06, p =.004). Children with PDD-NOS could be placed into one of three subgroups: a high-functioning group (24%) who resembled AS but had transient language delay or mild cognitive impairment; a subgroup resembling autism (24%) but who had late age of onset or too severe cognitive delays or were too young to potentially meet the full diagnostic criteria for autism; and a group (52%) not fulfilling the criteria for autism because of fewer stereotyped and repetitive behaviors. CONCLUSIONS: With some revision to current diagnostic criteria, a more homogenous atypical group with significant impairments in social-communication but fewer repetitive behaviors can be differentiated from the more nonspecific PDD-NOS group. This differentiation may lead to better reliability in diagnosis and to further progress in studies of etiology.

Asperger Syndrome↗
PubMed2004

Nonstereotyped responding in positive schizotypy after a single dose of levodopa.

Stereotyped behavior and left-sided orientation biases, associated with the dopamine (DA) system, were observed in populations of the schizophrenia spectrum disorders. We investigated whether heightened DA concentrations influence both side biases and stereotyped responding in a visuo-motor computer task, in which 90, 180, and 270 degrees rotated objects had to be brought into a target position. To account for the role of the schizophrenia spectrum, task performance was also analyzed as a function of healthy participants' high or low magical ideation (MI), a positive schizotypal feature. The first 36 participants (20 women) remained substance free. In a second sample, 20 men received levodopa and 20 men a placebo in a double-blind procedure. Results showed that high MI scorers responded more stereotyped than low MI scorers, without being specifically biased towards the left side. Rotation preferences toward one or the other side made high MI scorers less flexible for objects efficiently to be rotated into the opposite direction. This inflexibility may reflect impaired left hemisphere functioning. Unexpectedly, in the levodopa group, high MI scorers performed superior to low MI scorers. Since DA actions appear to follow an inverted U-shape function, the 'low' performing high MI scorers profited from the enhanced DA availability. Our observation in the levodopa group points to a dissociation between schizotypy and schizophrenia: while cognitive improvement in schizophrenia can occur after treatment with atypical neuroleptic agents, in our positive schizotypal participants a DA agonist resulted in improved task performance. This dissociation may point to protective neurochemical mechanisms preventing healthy schizotypes from developing full-blown psychotic symptoms.

Adult↗
PubMed1977

Effects of a verbal warning and overcorrection on stereotyped and appropriate behaviors.

In Experiment I, the effects of a verbal warning, such as is used in Overcorrection, delivered contingently on the stereotyped mouthing behavior of two autistic/retarded children were examined. A multiple baseline design across subjects was used. The results indicated that the mouthing of one child was reduced to a near-zero level and mouthing of the second child was moderately reduced. Appropriate toy play and inappropriate object manipulation failed to show systematic changes in occurrence when mouthing was decelerated. In Experiment II, the same subjects and experimental design were used to assess the effects of a positive practice Overcorrection procedure delivered contingent on mouthing behavior. Overcorrection reduced the mouthing of both subjects. There were no systematic changes in inappropriate object manipulation but one subject did demonstrate an increased occurrence of appropriate toy play. In addition, this subject often engaged in aggressive/escape behaviors during Overcorrection, suggesting that the procedure was aversive to him.

Aggression↗
PubMed2002

Estrogen and opioids interact to modulate the locomotor response to cocaine in the female rat.

Estrogen is known to modulate the behavioral response to cocaine; however the mechanisms by which this is accomplished is unknown. In this study we examine one possible candidate, the endogenous opioid system. Adult Sprague-Dawley rats were ovariectomized (OVX), half received Silastic implants with estradiol benzoate (OVX-EB), the other half received empty implants (OVX). After 1 week, spontaneous locomotor and stereotyped activity was measured for 60 min using an automated system. On day 2, locomotor activity was recorded for 30 min. Rats were injected with saline (SAL) or naloxone (NAL) (2 mg/kg, i.p.) and activity measured for the next 20 min. Each of these groups were further subdivided, one that received a saline injection (SAL) and another that received a cocaine injection (COC) (15 mg/kg, i.p.). Locomotor and stereotyped activities were recorded for 60 min. This resulted in the following injection groups: SAL-SAL, NAL-SAL, SAL-COC and NAL-COC. During habituation, OVX rats displayed an overall higher level of activity than OVX-EB rats. Similar to what is observed in males, naloxone significantly reduced locomotion and stereotyped behavior but only in OVX rats. Estrogen administration to OVX rats abolished the effect of naloxone. Surprisingly, when naloxone was administered prior to cocaine, an increase in cocaine-induced locomotor and stereotyped activity was observed, but only in OVX-EB rats. These results indicate that opioid modulation of cocaine-induced locomotor and stereotype activity in the female differs from that reported in the male. In addition in the female, the effect of opioids on cocaine-induced locomotor behavior is dependent on plasma levels of estrogen.

Animals↗
PubMed1983

The effects of intrahippocampal ibotenic acid and their blockade by (-) 2-amino-7-phosphonoheptanoic acid: morphological and electroencephalographical analysis.

Intrahippocampal injections of the excitotoxin ibotenic acid caused a biphasic behavioral pattern in rats. Both the immediate induction of hyperactivity and stereotypical behaviors and a secondary phase of progressively decreasing behavioral activities beginning 15-20 min after ibotenate administration, were accompanied by characteristic seizures measured by bilateral recordings in hippocampus and cortex. Typically, EEG changes consisted of high voltage spiking in all leads. The phase of behavioral depression was accompanied by episodic, short (5-30 s) seizures. In addition, cortical slow waves very similar to those elicited by intrahippocampal muscimol were observed during this period. Attempts were made to correlate occurrence and severity of seizures with the extent of neuronal degeneration. While a trend in favor of such a correlation existed, a firm causal relationship could not be established; some animals could display seizure activity with only marginal concomitant nerve cell loss and vice versa. Intrahippocampal co- and post-administration of ibotenate with (-) 2-amino-7-phosphonoheptanoic acid entirely prevented or stopped the occurrence of both EEG changes and neuronal degeneration. Ibotenate-induced seizures and lesions and their specific blockade by a selective antagonist may constitute valuable experimental paradigms for the investigation of seizure disorders.

2-Amino-5-phosphonovalerate↗
PubMed1997

Mapping of locomotor behavioral arousal induced by microinjections of dopamine within nucleus accumbens septi of rat forebrain.

Dopamine (DA) at ca. ED50 (16 microg) or saline was stereotaxically microinjected unilaterally 2 h after pretreatment with an MAO inhibitor into left or right nucleus accumbens septi of 697 freely moving rats (1394 injections) to define subregions involved in DA-induced behavioral arousal throughout the anatomical extent of the accumbens. Locomotion was quantified electronically and behavioral responses were assigned to histologically verified injection sites; postural or stereotyped behaviors characteristic of DA injections in caudate-putamen did not occur. Screening with 60 injections across mid-accumbens (2.2-3.2 mm rostral to bregma) indicated that locomotion was elicited non-homogeneously, and was particularly intense dorsomedially. Sites yielding intense arousal and their inactive surround were mapped along the rostrocaudal axis (1.4-4.2 mm anterior to bregma) in coronal sections. Responses to DA showed lateral symmetry and were similar across rostrocaudal levels, with intense responses in dorsomedial accumbens along its border with the caudate-putamen. This functional localization does not coincide closely with reported distributions of DA or its receptors, nor with histologically or histochemically defined core-shell regions of this limbic structure. Nucleus accumbens in rat brain thus appears to be organized functionally into distinct subregions differing markedly in ability to produce locomotor hyperactivity in response to exogenous DA.

Animals↗
PubMed2003

Behavioral approaches to promoting play.

A variety of techniques grounded in behavioral psychology, and more specifically in applied behavior analysis, have been established to increase and improve play skills in children with autistic spectrum disorders. This article introduces a set of efficacious methods, which range from highly structured techniques to more naturalistic strategies. It focuses on object play as other authors in the issue discuss social play in greater depth. Behavioral techniques that are reviewed include: discrete trial training, use of stereotyped behaviors to increase play skills, pivotal response training, reciprocal imitation training, differential reinforcement of appropriate behavior, in vivo modeling and play scripts, and video modeling. A discussion of expanding behavior techniques to teach more complex play as well as training in varied environments is also presented. References are provided to allow the reader to obtain more in-depth information about each technique.

Autistic Disorder↗
PubMed1986

Hand-rearing baboons for laboratory investigations.

To conduct laboratory studies in unsedated animals that were similar anatomically and physiologically to man, five full term baboons (four Papio cynocephalus anubis, one Papio cynocephalus cynocephalus) were hand-reared. These infants were used as unsedated animal models in short-term lung clearance studies conducted from birth to 2 years of age. The hand-rearing techniques described here encouraged the formation of an infant-human rearer bond that permitted us to control the level of expressed aggressive behavior as the infant matured. These techniques resulted in baboons which displayed subordinate behavior, showed positive reception to human contact (without evidence of negative stereotypic behavioral anomalies) and remained cooperative subjects for our investigations of short-term pulmonary clearance. The baboons generally were above average in weight in comparison to conspecifically-reared baboons of similar age, sex and species. Representative lung retention curves presented on one baboon demonstrate the feasibility of lung clearance studies in these hand-reared animals. Due to its suitability for unsedated studies, this baboon model may be considered for other types of laboratory investigations.

Aging↗
PubMed1995

Altered behavioral responses in 2,4-dichlorophenoxyacetic acid treated and amphetamine challenged rats.

Although the mechanism of 2,4-D neurotoxicity remains unknown the serotonergic system appears to mediate some of the effects of 2,4-D in rats as reported in our previous studies. In the present study we examine the concept that a challenge to a system may overcome compensatory mechanisms and thereby reveal otherwise hidden neurotoxicant-induced damage. We report the behavioral results of 50 or 100 mg/kg 2,4-Dichlorophenoxyacetic acid (2,4-D) acute exposure plus amphetamine challenge of rats. The "Serotonin Syndrome" (SS) involving prominently head movement, piloerection, moist fur, backing, hunching, Straub tail, fore paw tapping of the nose and pivoting, was exhibited by these rats, being females more affected than males. Immobility, social apathy and asymmetry were also observed. All behaviors were not seen in the 2,4-D treated rats. Stereotyped behaviors were observed earlier and were more prolonged in 2,4-D treated and amphetamine challenged rats than in rats treated only with 5 or 10 mg/kg amphetamine. Spiperone blocked all the SS behaviors. In addition, in these rats, rearing and rotation behaviors were showed and were also sex dependent. We also demonstrate that haloperidol, in a non cataleptic dose, induced catelepsy in 2,4-D treated rats. 2,4-D appears to act through serotonergic and dopaminergic mechanisms. The intensity of the response is sex dependent. Our study demonstrates that 2,4-D plus amphetamine induces a Serotonergic Syndrome plus additional Dopaminergic modulation.

2,4-Dichlorophenoxyacetic Acid↗
PubMedDate not supplied

Differential behavioral responses to chronic amphetamine in adult male and female rats exposed to postnatal cocaine treatment.

The impact of cocaine exposure during development on behavioral sensitization as measured by locomotor activity and stereotypy following repeated intermittent administration of amphetamine is examined. Male and female Sprague-Dawley rats were exposed to cocaine at 50 mg/kg/day during postnatal days (PND) 11-20 and, as adults (PND193-212), were administered seven daily injections of 2.0 mg/kg amphetamine. Both locomotor activity and stereotypic behavior were assessed following the first and seventh injections. Control males and females showed sensitized behavior following repeated amphetamine injections with females showing greater locomotion while males showed increased stereotypy. Male rats pretreated with cocaine failed to develop sensitized locomotor or stereotypic responses following repeated amphetamine injections consistent with dampened D(1) receptor activity. Females pretreated with cocaine did not show a sensitized locomotor response but did display sensitization of stereotypy following repeated amphetamine administration. Thus, it appears that postnatal cocaine treatment produces differential effects on the circuits mediating sensitization behavior in male and female rats.

Amphetamine↗
PubMed1982

Behavioral effects of (-)10,11-methylenedioxy-N-n-propylnoraporphine, an orally effective long-acting agent active at central dopamine receptors, and analogous aporphines.

Substituted and unsubstituted 10,11-methylenedioxy derivatives of apomorphine (APO) or its N-propyl congener (NPA) were synthesized and evaluated for their ability to alter motor activity or to induce stereotyped behavior in the rat. Of these, (-)10,11-methylenedioxy-N-n-propylnoraporphine hydrochloride (MDO-NPA) was the most active, and the only compound which was found to be active after oral administration. Also, MDO-NPA was more potent than NPA or APO in producing stereotypy, but large doses of these three aporphines were equipotent in stimulating motor activity. The duration of action of MDO-NPA exceeded that of NPA and APO, and increased with increasing doses. The effects of MDO-NPA on general activity were biphasic: larger doses stimulated activity: smaller doses markedly inhibited it and induced catalepsy. Catalepsy did not occur with NPA or APO and their motor-inhibitory effects were apparent only in aroused rats. The stereotypic effects of MDO-NPA were blocked by small doses of haloperidol, but not by large doses of reserpine. The effects due to large or small doses of MDO-NPA were also blocked by a microsomal enzyme inhibitor which did not interfere with the actions of NPA. These results suggest that MDO-NPA is a long-acting, orally effective prodrug of NPA with depot properties and dose-dependent agonistic and antagonistic interactions with central dopamine-mediated systems.

Administration, Oral↗
PubMed1978

Interaction between d-amphetamine and ethanol with respect to locomotion, stereotypies, ethanol sleeping time, and the kinetics of drug elimination.

The interaction between d-amphetamine and ethanol with respect to locomotor activity, stereotyped behavior, and sleeping time was investigated in rats. Ethanol 0.8 g/kg i.p. enhanced and prolonged locomotor activity produced by d-amphetamine 1 mg/kg s.c. The increased motility after 5 mg/kg d-amphetamine was not influenced by alcohol 0.8 g/kg i.p. or 3.2 g/kg orally, but slightly protracted. Stereotyped head and paw movements, as well as stereotyped licking, were distinctly strengthened and protracted by 3.2 g/kg ethanol orally. The modified d-amphetamine motility and stereotypies can be explained by alcohol-induced proloneation of the life of d-amphetomine. The effect is produced by alcohol's inhibition d-amphetamine p-hydroxylation in rat liver. After 3.2 g/kg ethanol i.p., the sleeping time of male rats amounted to 153 min. Simultaneous administration of 5 mg/kg d-amphetamine s.c. reduced the sleeping time to 84 min. This is obviously based on a central antagonism.

Animals↗
PubMed2002

Endogenous gonadal hormones modulate behavioral and neurochemical responses to acute and chronic cocaine administration.

Recent evidence demonstrates that there are sex differences in behavioral responses to cocaine. Further, reproductive gonadal hormones (estrogen, progesterone and testosterone) have been further implicated in mediating some of the cocaine-induced alterations. To better understand sex differences and the role of gonadal hormones in cocaine-induced locomotor and stereotypic behavior, intact and gonadectomized male and female Fischer rats were randomly assigned to either chronic cocaine (15 mg/kg) or saline treatments for 14 days followed by a challenge administration (7 days after the last cocaine/saline administration). Locomotor (ambulatory and rearing) and stereotypic activities were measured on days 1, 7 and 14 as well as after withdrawal/challenge with cocaine. Overall, intact female rats consistently showed a rapid (acquired by day 7) and longer lasting (persistent through the challenge dose) sensitization for all locomotor behaviors than any of the other groups. In contrast, intact males developed sensitization of these locomotor activities only in response to chronic cocaine administration, and after withdrawal and drug challenge the sensitization to cocaine-induced locomotor activity was no longer present. In female rats, gonadectomy affected ambulatory activity but not total and rearing responses after acute, sub-acute, chronic and challenge response to cocaine. On the other hand, castrated male rats were affected in cocaine-induced ambulatory activity but not rearing activity. In intact male rats, cocaine-induced stereotypic activity was rapidly and persistently sensitized after 7 days of cocaine administration, where gonadectomized male rats developed sensitization to cocaine-induced stereotypic activity only after a challenge cocaine administration. Although cocaine induced stereotypic activity, no statistically significant differences were observed between intact and ovariectomized female rats or throughout the different lengths of cocaine administration. After a challenge of cocaine, corticosterone levels were induced in all experimental groups. Moreover, no differences in levels of benzoylecgonine, a cocaine metabolite, were observed. Similar to our previous observations after acute cocaine administration, after challenge of cocaine, an increase in progesterone and a decrease in testosterone levels were observed in intact females and males, respectively. In summary, endogenous hormones seem to be involved in the behavioral activation and development of sensitization to cocaine.

Animals↗
PubMed2003

5-HT(1A) receptor subsensitivity in infancy and supersensitivity in adulthood in an animal model of depression.

Flinders Sensitive Line (FSL) rats, a genetic animal model of depression, exhibit 5-HT abnormalities including an increased sensitivity to serotonergic agonists. Studies of 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT)-induced hypothermia have shown 5-HT(1A) receptor supersensitivity in adult FSL rats. The aims of the present study were to: (a) further characterize the 5-HT(1A) system in adult FSL rats by assessing their behavioral responses to 8-OH-DPAT (the 'serotonergic syndrome'-a pattern of stereotypic behavior on a number of parameters). (b) Examine behavioral and hypothermic responses of neonatal FSL pups to 8-OH-DPAT. In adult FSL rats the 'serotonergic syndrome' was measured (Exp. 1) and in 1-day-old pups body temperature and ultrasonic vocalizations (USV) were also examined (Exp. 2) following administration (s.c. and i.p., respectively) of 8-OH-DPAT (1 mg/kg). Overall, adult FSL rats exhibited a significant supersensitive behavioral response to 8-OH-DPAT compared to Sprague-Dawley controls. Under baseline conditions, body weight, USV and rectal temperature were significantly lower in FSL pups compared to controls. In contrast to the adults, 1-day-old FSL pups exhibited an overall pattern of subsensitive stereotypic response to the agonist. In conclusion, an abnormal pattern of response to 8-OH-DPAT was observable in FSL rats, as early as postnatal day 1. This may contribute to a better understanding of the involvement of the serotonergic system in depression, and lead to pharmacological interventions aiming to modulate 5-HT regulation.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

Autism and Clostridium tetani.

Autism is a severe developmental disability believed to have multiple etiologies. This paper outlines the possibility of a subacute, chronic tetanus infection of the intestinal tract as the underlying cause for symptoms of autism observed in some individuals. A significant percentage of individuals with autism have a history of extensive antibiotic use. Oral antibiotics significantly disrupt protective intestinal microbiota, creating a favorable environment for colonization by opportunistic pathogens. Clostridium tetani is an ubiquitous anaerobic bacillus that produces a potent neurotoxin. Intestinal colonization by C. tetani, and subsequent neurotoxin release, have been demonstrated in laboratory animals which were fed vegetative cells. The vagus nerve is capable of transporting tetanus neurotoxin (TeNT) and provides a route of ascent from the intestinal tract to the CNS. This route bypasses TeNT's normal preferential binding sites in the spinal cord, and therefore the symptoms of a typical tetanus infection are not evident. Once in the brain, TeNT disrupts the release of neurotransmitters by the proteolytic cleavage of synaptobrevin, a synaptic vesicle membrane protein. This inhibition of neurotransmitter release would explain a wide variety of behavioral deficits apparent in autism. Lab animals injected in the brain with TeNT have exhibited many of these behaviors. Some children with autism have also shown a significant reduction in stereotyped behaviors when treated with antimicrobials effective against intestinal clostridia. When viewed as sequelae to a subacute, chronic tetanus infection, many of the puzzling abnormalities of autism have a logical basis. A review of atypical tetanus cases, and strategies to test the validity of this paper's hypothesis, are included.

Autistic Disorder↗
PubMed2003

The PDD Behavior Inventory: a rating scale for assessing response to intervention in children with pervasive developmental disorder.

The PDD Behavior Inventory (PDDBI) is a rating scale filled out by caregivers or teachers that was designed to assess children having a Pervasive Developmental Disorder (PDD; autism, Asperger disorder, PDD-NOS, or childhood disintegrative disorder). Both adaptive and maladaptive behaviors are assessed in the scale, making it useful for treatment studies in which decreases in maladaptive behaviors and improvements in adaptive social and language skills relevant to PDD are expected. The adaptive behaviors assessed include core features of the disorder such as joint attention skills, pretend play, and referential gesture. The maladaptive behaviors sample a wide variety of behaviors observed in both lower- and higher-functioning individuals and include stereotyped behaviors, fears, aggression, social interaction deficits, and aberrant language. The inventory was found to have a high degree of internal consistency. Inter-rater reliability was better for adaptive behaviors than for maladaptive behaviors. Factor analyses confirmed the structure of the PDDBI and indicated good construct validity. In a subsample of children between 3 and 6 years of age, raw scores for adaptive behaviors increased with age in the parent and teacher versions, as did measures of social pragmatic problems. It was concluded that the PDDBI is both reliable and valid and is useful in providing information not typically available in most instruments used to assess children with PDD.

Adolescent↗