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Prefrontal cortical and hippocampal modulation of haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors in the rat.

Effects of prefrontal cortical or hippocampal excitotoxic lesions on behavioral parameters related to dopaminergic transmission in the basal ganglia were investigated in the rat. We examined haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors after ibotenic acid lesions of the medial prefrontal cortex (MPFC), dorsal (DH), or ventral hippocampus (VH) in adult rats. Haloperidol-induced (1 mg/kg) catalepsy was decreased in rats with either MPFC or VH but not DH lesions. While both DH and VH lesioned animals demonstrated a reduction in apomorphine-induced (0.75 mg/kg) stereotypic behaviors, the VH lesioned animals also showed an enhancement of locomotor activity. MPFC lesioned rats tended towards potentiation of stereotypic behaviors and reduced locomotion after apomorphine administration. These data indicate that loss of prefrontal cortical or hippocampal modulation leads to an enhancement of DA transmission within the basal ganglia, though the pattern of augmentation depends on the area lesioned.

Animals↗

Environmental enrichment: effects on stereotyped behavior and dendritic morphology.

We evaluated whether environmental enrichment-related effects on the development of stereotyped behavior in deer mice were associated with alterations in dendritic morphology. Deer mice were reared under enriched or standard housing conditions and then tested in automated photocell detectors and classified as stereotypic or nonstereotypic. Dendritic morphology was assessed in layer V pyramidal neurons of the motor cortex, medium spiny neurons of the dorsolateral striatum, and granule cells of the dentate gyrus using Golgi-Cox histochemistry. Enriched nonstereotypic mice exhibited significantly higher dendritic spine densities in the motor cortex and the striatum than enriched stereotypic or standard-cage mice. Significant increases in dendritic arborization following environmental enrichment also were observed. These results suggest that the enrichment-related prevention of stereotyped behavior is associated with increased dendritic spine density.

Animals↗

Sensitization of amphetamine-induced stereotyped behaviors during the acute response: role of D1 and D2 dopamine receptors.

During the response to an injection of amphetamine, rapid changes occur in the ability of the drug to induce stereotyped behaviors. This enhanced responsivity does not involve changes in the caudate-putamen or nucleus accumbens extracellular dopamine response, but appears to require activation of dopamine receptors. In the present studies we examined the role that D1 and D2 dopamine receptors might play in the development and expression of the enhanced stereotypy response. In one series of experiments we used the dopamine agonists, SKF 82958 and quinpirole as relatively selective probes at D1 and D2 dopamine receptors, respectively, to test for changes in dopamine receptor sensitivity following a pretreatment ('priming') with 4.0 mg/kg amphetamine. Doses of both SKF 82958 and quinpirole which were sub-threshold to induce perseverative behaviors in control animals, promoted stereotyped behaviors in amphetamine-primed animals, suggesting an enhanced sensitivity of both D1 and D2 receptors. In a second series of experiments, we sought to determine whether priming with these relatively selective dopamine receptor agonists, as well as the mixed D1/D2 agonist, apomorphine, would result in an enhanced stereotypy response to the subsequent administration of non-stereotypy producing doses of amphetamine (0.5-1.5 mg/kg). Priming with the dopamine receptor agonists each resulted in an enhanced amphetamine-induced stereotypy response. These results indicate that both D1 and D2 dopamine receptors contribute to both the development and the expression of the altered stereotypy responsivity, though several dose- and time-related observations suggest that other mechanisms likely contribute as well. Because these changes are apparent during the amphetamine response, they may have important implications for the evolving behavioral alterations which result when stimulants are administered in a binge pattern of drug abuse.

Amphetamine↗

Effects of alpha-adrenergic blocking agents on stereotyped behavior induced by apomorphine in rats.

1. The effects of alpha-adrenergic blocking agents on stereotyped behavior induced by apomorphine in rats were studied. 2. Pretreatment of rats with 5 and 10 mg/kg of phenoxybenzamine or phentolamine displaced the dose-response curves for apomorphine-induced stereotypy to the left in a dose dependent manner. The ED50 for apomorphine was reduced from 1.92 +/- 0.38 (mean +/- SEM) to 0.63 +/- 0.08 by 10 mg/kg phenoxybenzamine and from 1.92 +/- 0.38 to 0.61 +/- 0.10 by 10 mg/kg phentolamine. 3. These results support the view that the expression of dopaminergic-induced stereotyped behavior is dependent on noradrenergic activity in the central nervous system.

Animals↗

The effect of darkness on amphetamine induced stereotyped behavior in cats.

Transient elimination of visual stimuli (20 min darkness in the experimental chamber) did not affect the amphetamine induced stereotyped behavior and accompanied arousal in cats. It is concluded that anqhetamine stereotyped behavior in cats represents centrally initiated event of animal response to drug which is, under some conditions, independent of environmental visual input.

Amphetamine↗

Neuropeptide-dopamine interactions. II. Cyclo (His-Pro) augmentation of amphetamine- but not apomorphine-induced stereotypic behavior.

Histidyl-proline diketopiperazine (cyclo [His-Pro]) not only exists in the basal ganglia of rodents, monkeys, and humans, but also exhibits a variety of biologic activities, some of which appear to be mediated via dopaminergic mechanisms. We investigated the potential modulation by cyclo (His-Pro) of amphetamine- and apomorphine-induced stereotypic behavior, a behavior that is associated with the activation of postsynaptic dopamine receptor. Administration of amphetamine to rats resulted in a dose-dependent increase in stereotypic behavior that was further augmented if animals were pretreated with cyclo (His-Pro). Although apomorphine also led to a dose-related progression in the stereotypic behavior, the apomorphine effects were not modified by cyclo (His-Pro) pretreatment. We conclude that cyclo (His-Pro) either acts indirectly at the presynaptic dopamine site or modulates other neurotransmitters to potentiate actions of amphetamine.

Amphetamine↗

Effects of outdoor housing on self-injurious and stereotypic behavior in adult male rhesus macaques (Macaca mulatta).

We examined the effects of outdoor housing on self-injurious and stereotypic behavior in adult male rhesus macaques with a history of self-wounding that were previously singly housed indoors for at least 4 y prior to the study. Baseline behavioral observations were collected over 2.5 mo. In phase 1, animals were relocated outdoors in 1 of 2 experimental conditions, group-housed (n = 8) or single-housed (n = 5), for 6 wk. In phase 2, group-housed animals were observed outdoors for an additional 6 wk. Behavioral observations were done using focal sampling techniques. In phase 1, rates of self-biting and self-directed stereotypies and time spent displaying idiosyncratic self-directed stereotypies decreased significantly when group- and single-housed animals were housed outdoors. Rates of yawning and scratching were significantly decreased for group- and single-housed animals and, for group-housed animals, self-grooming decreased with outdoor housing. In phase 2, rates of self-biting, time engaging in idiosyncratic self-directed stereotypies, and yawning remained significantly lower during weeks 7 through 12 (outdoor housing) compared with those under indoor housing. Rates of scratching and time spent self-grooming decreased significantly during the first 6 wk but then returned to baseline levels. Our findings suggest that self-biting and self-directed stereotypic behavior in rhesus macaques with a history of self-injurious behavior is significantly reduced by outdoor housing regardless of whether animals are socially or individually housed.

Animals↗

Persistence of stereotypic behavior: examining the effects of external reinforcers.

Basic research has shown that behavioral persistence is often positively related to rate of reinforcement. This relation, expressed in the metaphor of behavioral momentum, has potentially important implications for clinical application. The current study examined one prediction of the momentum metaphor for automatically reinforced behavior. Participants were 3 children who had been diagnosed with an autism spectrum disorder and who engaged in stereotypic behavior maintained by automatic reinforcement. Results suggested that stereotypic behavior was more resistant to disruption following periods of access to preferred stimuli delivered on a variable-time schedule than following periods without access to preferred stimuli. The implications of these findings for the treatment of automatically reinforced behavior are discussed.

Attention↗

Antagonistic activity of ascorbic acid (vitamin C) on dopaminergic modulation: apomorphine-induced stereotypic behavior in mice.

Among the various neurotransmitter systems implicated in the mechanism of action of ascorbic acid (vitamin C), the relationship between the dopaminergic system and ascorbic acid is not particularly clear. Ascorbic acid is speculated to have an antagonistic effect on dopaminergic modulation. With this background in mind, in the present study we have seen the effect of ascorbic acid per se and in combination with typical and atypical antipsychotic agents against apomorphine-induced stereotypic behavior in mice. Male Laka mice weighing 20-25 g were used in the present study. Apomorphine-induced stereotypic behavior was used as an animal model. Various dopaminergic modulators were used. Ascorbic acid dose-dependently inhibited stereotypic behavior produced by apomorphine in mice. It potentiated the antipsychotic activity of haloperidol (0.1 mg/kg i.p.), a typical antipsychotic agent. When administered along with atypical antipsychotics, clozapine (1-2 mg/kg i.p.), sulpiride (10-20 mg/kg i.p.) and risperidone (0.0025 mg/kg i.p.), ascorbic acid also potentiated their activity. Also when given along with SCH-23390, a selective D(1) antagonist, an additive effect was observed. Ascorbic acid also inhibited the supersensitization response of apomorphine on reserpinization (2 mg/kg i.p.). Interestingly, at a lower dose (100 mg/kg i.p.), ascorbic acid potentiated the dopaminergic activity of apomorphine (0.5 mg/kg) and BHT-920 (0.25 mg/kg i.p.). However, when given concomitantly with SKF-38393, it failed to alter the response of SKF-38393. The data substantiate the hypothesis that ascorbic acid potentiated the activity of typical as well as atypical antipsychotics and that the effect of ascorbic acid on the dopaminergic system is markedly dose dependent; a low dose (100 mg/kg i.p.) potentiated the dopaminergic action while higher doses (400-1,600 mg/kg i.p.) blocked it.

Animals↗

Stereotyped behavior elicited by amphetamine in the rat: influences of the testes.

Castrating male rats in adulthood increased the duration of stereotyped behavior in responses of 5 mg/kg injections of d-amphetamine sulfate; exogenous treatment with testosterone propionate (TP) reversed this effect. Ovariectomy in adulthood had no effect on stereotypy, but TP injections reduced stereotyped responding by ovariectomized females. Thus testosterone exerts comparable effects on stereotypy elicited by amphetamine in both sexes. Males castrated at 1, 6 or 10 days of age but not males castrated in adulthood displayed levels of stereotyped behavior comparable to those of ovariectomized females when all animals were given TP in adulthood. Control experiments indicated that age of castration rather than time since castration was the critical factor, implying that secretions of the testes early in life exert effects on systems that regulate the responses of adults to amphetamine.

Animals↗

Visual screening: an alternative method for reducing stereotypic behaviors.

Visual screening, a mildly aversive response suppression procedure, was evaluated across two studies for its effectiveness in reducing topographically similar and dissimilar stereotypic behaviors of four developmentally disabled children. In the first study, a multiple baseline design across subjects and behaviors was used to assess the effectiveness of the procedure as a treatment for reducing the visual and auditory self-stimulatory responses of two 9-yr-old mentally retarded and behaviorally disturbed children. A multiple baseline design across subjects was used in the second study to evaluate the effectiveness of visual screening as a treatment for reducing stereotypic fabric pulling and self-mutilative ear bending, respectively, of two 13-yr-old mentally retarded, autisticlike adolescents. Long-term follow-up data for both studies were reported. The results suggested that visual screening was an easily administered, effective, and exceptionally durable treatment procedure for controlling a variety of stereotypic behaviors commonly associated with the developmentally disabled.

Adolescent↗

Use of nonexclusionary timeout for the elimination of a stereotyped behavior.

The purpose of the present study was to investigate the effectiveness of a nonexclusionary timeout procedure in reducing a high-frequency stereotyped behavior in a 28-year-old profoundly mentally retarded and autistic male. The experimental design consisted of baseline (A), treatment (B), and 1- and 6-month follow-up studies. After 2 weeks of treatment, the target behavior was reduced to a virtually zero rate of occurrence and the low rate of response was maintained throughout follow-up. Findings suggest that nonexclusionary timeout may prove to be a cost-effective intervention for reducing or eliminating disruptive stereotyped behaviors. The need for further research is indicated.

Adult↗

Modulation of apomorphine-induced stereotyped behavior by cholecystokinin.

1. The goal was to verify if central or peripheral sulphated cholecystokinin octapeptide (CCK8) injections can modulate apomorphine (APO)-induced stereotyped behavior. Experiments were designed to determine the involvement of cholecystokinin receptor subtypes as well. 2. Animals which received CCK8 (0.0725, 0.145 and 14.5 nmol, icv) showed a significant (p < 0.05) decrease in APO (0.6 mg/kg, sc)-induced stereotyped behavior. 3. No other statistically significant difference was observed among groups. Since ip CCK8 (1.16 or 2.32 nmol/kg) injections did not interfere with APO-induced stereotypy, the results suggest that the CCK8 modulatory effects have a central action. 4. The results also suggest that the effects of icv CCK8 were not due to the stimulation of CCK8 receptors alone since central CCK4 (14.5 or 29.0 nmol) injections did not interfere with the expression of stereotypy.

Animals↗

Phencyclidine-induced stereotyped behaviors after injection of ethylketocyclazocine, Mr 2266 and naltrexone in rats.

The effects of ethylketocyclazocine (EKC), Mr 2266 and naltrexone on the stereotyped behaviors induced by an intraperitoneal injection of phencyclidine (PCP) were examined. PCP-induced turning, backpedalling, head weaving and sniffing were antagonized by pretreatment with EKC (0.25-4.0 mg/kg). While pretreatment with Mr 2266 (2.5 mg/kg), a kappa selective antagonist, and naltrexone (10 mg/kg), a mu selective antagonist, failed to affect the PCP-induced stereotypy, Mr 2266 antagonized the suppressing effect of EKC on PCP-induced stereotypy. Taken into consideration, this suggests that kappa opioid agonists such as EKC antagonize PCP-induced stereotyped behaviors through a kappa opioid mechanism, and that the mu opioid receptor may not play an important role in the PCP-induced stereotypy in rats.

Animals↗

Effects of single and long-term droperidol administration on open-field and stereotyped behavior of rats.

The effects of single and long-term droperidol administration on rat open-field and apomorphine-induced stereotyped behavior were studied. A single dose of droperidol decreased dose dependently not only locomotion and rearing frequencies in the open-field but also the apomorphine effects. Long-term droperidol administration induced significant tolerance to all parameters of activity recorded in the open-field. Unlike other dopamine blockers, droperidol withdrawn from long-term droperidol administration wasn't able to increase rats' open-field parameters significantly. However, like other dopamine blockers, droperidol withdrawn produced an augmented responsiveness to apomorphine-induced stereotyped behavior. These results suggest that the supersensitivity of central dopamine receptors developed after droperidol treatment may have peculiar characteristics.

Animals↗

Environmental enrichment: effects on stereotyped behavior and neurotrophin levels.

The present study evaluated whether environmental enrichment-related effects on the development of stereotyped behavior in deer mice were associated with alterations in neurotrophin levels. Deer mice were reared in enriched or standard cage conditions for 60 days. The mice were then tested in automated photocell detectors and classified as either stereotypic or nonstereotypic. This testing paradigm yielded four behaviorally distinct groups: enriched stereotypic, enriched nonstereotypic, standard cage stereotypic, and standard cage nonstereotypic. The motor cortex, striatum, and hippocampus were dissected, and the levels of brain-derived neurotrophin factor (BDNF) and nerve growth factor (NGF) in each brain region were analyzed using Promega ELISA kits. There were no differences in either NGF or BDNF in either the motor cortex or the hippocampus. In the striatum, the enriched nonstereotypic mice exhibited significantly more BDNF than the enriched stereotypic, the standard cage nonstereotypic, or the standard cage stereotypic mice. There were no differences in NGF in the striatum. These results provide evidence that the enrichment-related prevention of stereotyped behavior in deer mice is associated with increased BDNF in the striatum.

Animals↗