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PubMed1995

Dopamine receptor supersensitivity.

Dopamine (DA) receptor supersensitivity refers to the phenomenon of an enhanced physiological, behavioral or biochemical response to a DA agonist. Literature related to ontogenetic aspects of this process was reviewed. Neonatal 6-hydroxydopamine (6-OHDA) destruction of rat brain DA neurons produces overt sensitization to D1 agonist-induced oral activity, overt sensitization of some D2 agonist-induced stereotyped behaviors and latent sensitization of D1 agonist-induced locomotor and some stereotyped behaviors. This last process is unmasked by repeated treatments with D1 (homologous "priming") or D2 (heterologous "priming") agonists. A serotonin (5-HT) neurotoxin (5,7-dihydroxytryptamine) and 5-HT2C receptor antagonist (mianserin) attenuate some enhanced behavioral effects of D1 agonists, indicating that 5-HT neurochemical systems influence D1 receptor sensitization. Unlike the relative absence of change in brain D1 receptor number, DA D2 receptor proliferation accompanies D2 sensitization in neonatal 6-OHDA-lesioned rats. Robust D2 receptor supersensitization can also be induced in intact rats by repeated treatments in ontogeny with the D2 agonist quinpirole. In these rats quinpirole treatments produce vertical jumping at 3-5 wk after birth and subsequent enhanced quinpirole-induced antinociception and yawning. The latter is thought to represent D3 receptor sensitization. Except for enhanced D1 agonist-induced expression of c-fos, there are no changes in the receptor or receptor-mediated processes which account for receptor sensitization. Adaptive mechanisms by multiple "in series" neurons with different neurotransmitters may account for the phenomenon known as receptor supersensitivity.

Animals↗

PubMed1994

Role of oxytocin in the neuroadaptation to drugs of abuse.

Oxytocin (OXT), a neurohypophyseal hormone, has a wide range of behavioral effects outside its classic peripheral endocrine functions. OXT involvement in adaptive central nervous system processes has been demonstrated as an inhibitory, amnestic action on learning and memory in different paradigms. Because adaptation and learning are likely to be involved in the neural events leading to drug tolerance and dependence, the question logically arose whether OXT is able to influence the development of tolerance of and dependence on abused drugs. In this review, we summarize our results on the effects of OXT on opiate (including morphine, heroin, and the endogenous opiates beta-endorphin and enkephalin) tolerance and dependence, heroin self-administration, psychostimulant-induced behavioral changes, and behavioral tolerance and sensitization. The sites and mechanisms of action and the possible physiological role of OXT are also discussed. In the first part of this review the effects of exogenously administered OXT on both the acute and chronic behavioral effects of opiates and psychostimulants have been summarized. OXT inhibited the development of tolerance to morphine, heroin, beta-endorphin, and enkephalin, OXT also inhibited the development of cross-tolerance between the predominantly mu-agonist heroin and the predominantly delta-agonist enkephalin in mice. Naloxone-precipitated morphine withdrawal syndrome was also attenuated by OXT. Heroin self-administration was decreased by OXT administration in heroin-tolerant rats. OXT inhibited cocaine-induced exploratory activity, locomotor hyperactivity, and stereotyped behavior in rats and in mice. Behavioral tolerance to cocaine was also attenuated by OXT. On the contrary, OXT stimulated the development of behavioral sensitization to cocaine. OXT did not alter the stereotyped behavior induced by amphetamine. In the second series of experiments, the sites of action of OXT on drug-related behavior were investigated. Intracerebro-ventricular (ICV) and intracerebral (IC) administration of an OXT-receptor antagonist inhibited the effects of peripherally administered OXT on morphine tolerance, heroin self-administration, and cocaine-induced sniffing behavior. This suggests the central, intracerebral location of OXT target sites. Local IC microinjection of OXT in physiological doses into the posterior olfactory nucleus, tuberculum olfactorium, nucleus accumbens, central amygdaloid nucleus, and the hippocampus inhibited the development of tolerance to and dependence on morphine as well as cocaine-induced sniffing behavior and tolerance to cocaine. The physiological role of endogenous OXT in acute morphine tolerance has also been demonstrated, since OXT antiserum (ICV) and OXT-receptor antagonist (injected into the basal forebrain structures) potentiated the development of morphine tolerance. Finally, we investigated the possible mechanisms of action of OXT on drug related behavior. Both morphine tolerance and dependence, and cocaine administration, increased dopamine utilization in the mesencephalon and in the nucleus accumbens, respectively. OXT treatment decreased the alpha-methylparatyrosine-induced dopamine utilization in the mesencephalon and in the nucleus accumbens-septal complex. Chronic OXT treatment decreased the number of apparent binding sites of dopamine in the basal forebrain area. It also inhibited a cocaine-induced increase in dopamine utilization in the nucleus accumbens, but not in the striatum. In light of this information, it appears that OXT inhibits the development of opiate tolerance, dependence, and self-administration as well as the acute behavioral actions of and chronic tolerance to cocaine. This suggests the possible role of this neuropeptide in the regulation of drug abuse. Therefore, OXT may act as a neuromodulator on dopaminergic neurotransmission in limbic-basal forebrain structures to regulate adaptive CNS processes leading to drug addiction.

Animals↗

PubMed1998

Electrical but not chemical kindling increases sensitivity to some phencyclidine-like behavioral effects induced by the competitive NMDA receptor antagonist D-CPPene in rats.

We have previously reported that a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849), produces stereotyped behaviors and hyperlocomotion in amygdala kindled rats at doses which do not induce such phencyclidine (PCP)-like behaviors in nonkindled rats, indicating that kindling predisposes rats to such adverse effects of competitive NMDA receptor antagonists. From these data we predicted that epileptic patients may exhibit a hypersensitivity to PCP-like adverse effects of competitive NMDA receptor antagonists, which was subsequently confirmed in a clinical trial with D-CPPene (SDZ EAA-494; 3-(2-carboxypiperazine-4-yl)propenyl-1-phosphonate). For further exploration of the functional alterations in NMDA receptor responsiveness produced by kindling, we studied whether the enhanced susceptibility of amygdala-kindled rats to PCP-like adverse effects of CGP 37849 is also observed with D-CPPene. Furthermore, we determined whether the enhanced susceptibility of kindled rats to such adverse effects occurs only after relatively short intervals following the last seizure, as used in our previous study, or is a more permanent phenomenon. For this purpose, we compared adverse effects in kindled rats not only with naive (non-implanted) controls, as done in our previous study, but used electrode-implanted nonkindled rats as an additional control to assess the possible bias of mere electrode-implantation. In addition, we studied whether the enhanced susceptibility to NMDA receptor antagonists of electrically kindled rats is also present in chemically kindled animals. In some experiments, the PCP-like uncompetitive NMDA receptor antagonist MK-801 (dizocilpine) was included for comparison. In amygdala kindled rats, D-CPPene produced significantly more stereotyped behaviors than in electrode-implanted or naive nonkindled controls. The enhanced sensitivity of electrically kindled rats to PCP-like stereotypies induced by D-CPPene was observed both 7 and 180 days after the last kindled seizure, indicating a long-lasting if not permanent hypersensitivity to these adverse effects. In addition, more intense circling was observed in amygdala kindled rats, whereas hyperlocomotion only tended to be more intense after D-CPPene in kindled rats. These alterations in D-CPPene-induced behaviors were not observed after chemical kindling with pentylenetetrazole, but D-CPPene induced significantly less hypothermia in chemically kindled rats both 7 and 70 days after the last seizure. The data demonstrate that kindling produces long-lasting alterations in some adverse effects of D-CPPene, substantiating that epileptogenesis as initiated by kindling renders the brain more susceptible to PCP-like behavioral side effects of competitive NMDA receptor antagonists.

Animals↗

PubMedDate not supplied

Language and behavior in children with Sotos syndrome.

OBJECTIVE: To examine language and behavior in children with Sotos syndrome, an overgrowth syndrome involving advanced bone age, characteristic facies, and developmental disability. METHOD: Twenty-seven children with Sotos syndrome were compared with 20 children with overgrowth, intellectual disability, and facies not characteristic of Sotos syndrome. Ages ranged from 5 to 16 years. Direct assessment was undertaken with standardized measures of intelligence and language abilities. Behavior was examined by parent and teacher report. RESULTS: Children with Sotos syndrome had levels of intelligence in the severely disabled to average range, with the majority falling in the borderline range. Mean level of intelligence was significantly higher than that observed for children in the comparison group. Language abilities were developed to a level consistent with overall level of intelligence. Rates of parent- and teacher-reported behavior problems were significantly higher than normal, but, with the exception of temper tantrums, did not differ from those observed in children in the comparison group. Attention-deficit hyperactivity disorder was observed in 38% of children with Sotos syndrome. They were more irritable and had more stereotypic behavior and inappropriate speech than is expected in children with intellectual disabilities, and they were more withdrawn and had more stereotypic behavior than children in the comparison group. CONCLUSIONS: Assessment of language abilities revealed no specific language impairment. High rates of behavior problems were observed, but these were not higher than those observed for other large, delayed, dysmorphic children.

Abnormalities, Multiple↗

PubMed1997

Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine.

Methylphenidate promotes a dose-dependent behavioral profile that is very comparable to that of amphetamine. Amphetamine increases extracellular norepinephrine and serotonin, in addition to its effects on dopamine, and these latter effects may play a role in the behavioral effects of amphetamine-like stimulants. To examine further the relative roles of dopamine, norepinephrine, and serotonin in the behavioral response to amphetamine-like stimulants, we assessed extracellular dopamine and serotonin in caudate putamen and norepinephrine in hippocampus in response to various doses of methylphenidate (10, 20, and 30 mg/kg) that produce stereotyped behaviors, and compared the results with those of a dose of amphetamine (2.5 mg/kg) that produces a level of stereotypies comparable to the intermediate dose of methylphenidate. The methylphenidate-induced changes in dopamine and its metabolites were consistent with changes induced by other uptake blockers, and the magnitude of the dopamine response for a behaviorally comparable dose was considerably less than that with amphetamine. Likewise, the dose-dependent increase in norepinephrine in response to methylphenidate was also significantly less than that with amphetamine. However, in contrast to amphetamine, methylphenidate had no effect on extracellular serotonin. These results do not support the hypothesis that a stimulant-induced increase in serotonin is necessary for the appearance of stereotyped behaviors.

Amphetamine↗

PubMed1995

Comparison of a novel tropane analog of cocaine, 2 beta-propanoyl-3 beta-(4-tolyl) tropane with cocaine HCl in rats: nucleus accumbens extracellular dopamine concentration and motor activity.

2 beta-propanoyl-3 beta-(4-tolyl) tropane (PTT) is a novel tropane that has been shown to be approximately 20 times more potent than cocaine in binding to the 3 beta-[4'-iodophenyl] tropane-2 beta-carboxylic acid methyl ester (RTI-55) site on the dopamine transporter, an effect partially attributable to the methyl constituent at the para position on the phenyl ring. In addition, PTT lacks the ester linkage of cocaine, thus increasing its metabolic stability. This study was undertaken to compare the quantitative and temporal effects of PTT and cocaine on in vivo neurochemical measures and motor behavior. The effects of PTT (0.3, 1.0 and 3.0 mg/kg; i.p.) and cocaine HCl (3.0, 10.0, & 30.0 mg/kg; i.p.) on nucleus accumbens extracellular dopamine concentrations [DA]e were evaluated using in vivo microdialysis. Locomotor activity and stereotypic behaviors were also assessed. PTT and cocaine increased [DA]e and total locomotor activity in a dose-dependent manner with PTT approximately 30 times more potent than cocaine. The relationship between [DA]e and locomotor activity was linear over the test session for cocaine, but not for PTT. In a subsequent experiment, pronounced stereotypic behaviors were evident in rats administered cocaine (10.0 and 30.0 mg/kg) or PTT (3.0 mg/kg). The stereotypy elicited by PTT was longer in duration and greater in intensity than that elicited by the highest dose of cocaine. These results extend previously published data by demonstrating similar in vivo potencies for PTT on nucleus accumbens [DA]e and locomotor activity. However, these data do not support the hypothesis that the time course of increased nucleus accumbens [DA]e and stimulated locomotor activity are related.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2025

Capturing continuous, long timescale behavioral changes in Drosophila melanogaster postural data.

Animal behavior spans many timescales, from short, seconds-scale actions to daily rhythms over many hours to life-long changes during aging. To access longer timescales of behavior, we continuously recorded individual Drosophila melanogaster at 100 frames per second for up to 7 days at a time in featureless arenas on sucrose-agarose media. We use the deep learning framework SLEAP to produce a full-body postural dataset for 47 individuals resulting in nearly 2 billion pose instances. We identify stereotyped behaviors such as grooming, proboscis extension, and locomotion and use the resulting ethograms to explore how the flies' behavior varies across time of day and days in the experiment. We find distinct daily patterns in all stereotyped behaviors, adding specific information about trends in different grooming modalities, proboscis extension duration, and locomotion speed to what is known about the D. melanogaster circadian cycle. Using our holistic measurements of behavior, we find that the hour after dawn is a unique time point in the flies' daily pattern of behavior, and that the behavioral composition of this hour tracks well with other indicators of health such as locomotion speed and the fraction of time spend moving vs. resting. The method, data, and analysis presented here give us a new and clearer picture of D. melanogaster behavior across timescales, revealing novel features that hint at unexplored underlying biological mechanisms.

Animals↗

PubMed1995

Involvement of nitric oxide in phencyclidine-induced hyperlocomotion in mice.

The present study was undertaken to investigate the involvement of nitric oxide (NO) in the behaviors induced by 1-(1-phenylcyclohexyl) piperidine (phencyclidine; PCP) in mice, using N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase. PCP (1, 3, and 10 mg/kg s.c.) dose dependently induced hyperlocomotion and stereotyped behaviors, including sniffing, head movement, and ataxia, in mice. PCP also caused a marked deficit of motor coordination in mice, the effect being exerted in a dose-dependent manner. Although pretreatment with L-NAME (50 mg/kg i.p.) slightly enhanced the ataxia induced by PCP (3 mg/kg), it failed to modify other stereotyped behaviors and the lack of motor coordination induced by PCP (2 mg/kg). The hyperlocomotion induced by PCP (3 mg/kg) was significantly enhanced by L-NAME (5 and 50 mg/kg) and 7-nitro indazole (25 mg/kg), but not by D-NAME (50 mg/kg), a less active enantiomer of L-NAME. However, the behavioral changes induced by PCP, at the high dose, 10 mg/kg, were not enhanced by L-NAME and D-NAME. The enhancing effects of L-NAME on the PCP (3 mg/kg)-induced hyperlocomotion were significantly prevented by L-arginine (1 g/kg i.p.). However, D-arginine (1 g/kg i.p.) and L-lysine (1 g/kg i.p.) had no effect in this regard. These results suggested the involvement of central NO production in the mediation of PCP-induced behaviors, hyperlocomotion in particular, in mice.

Animals↗

PubMed1991

Behavioral aspects of stress.

Many researchers view stress theory as having evolved from a specific response for each specific stimulus, through a standardized general adaptation syndrome for a wide variety of stressors, to a newly hypothesized model that suggests a standardized physiological response for psychological stressors and specific homeostatic responses for physical stressors. Stressors can originate from within an individual (endogenous) or from the environment (exogenous). A sense of control over one's environment (exogenous stimuli) and predictability of stimuli are extremely important in determining the potency of psychological stressors. The performance of highly repetitive, stereotyped behaviors has been shown to help animals cope with environments containing little or unvaried stimulation. Chronic psychological stressors are the most problematic area of stress research and animal care. Animals may respond behaviorally to chronic stressors by either achieving adaptation or by showing such conditions as learned helplessness, intensification of drives, stereotyped behavior, and absence of normal behaviors. A chronic endogenous buildup of motivation to perform specific behaviors that an animal has been prevented from performing can be quantified and result in animals displaying signs of chronic stress, i.e., altered metabolism (hormones), suppressed immune system, and learned helplessness. It is of paramount importance that the behavioral and physiological variables utilized in stress research be relevant to the particular species and questions under study.

Acute Disease↗

PubMed1992

Nonpharmacologic management of stereotypic self-mutilative behavior in a stallion.

Self-mutilative behavior, a form of stereotypic behavior, can be a serious problem in stallion management. An 11-year-old Quarter Horse stallion was referred for evaluation of repeated episodes of self-mutilation and aggressive behavior. Historically, this behavior worsened when the horse was isolated from other animals and confined to a stall for long periods. Observations of the stallion revealed episodes of self-mutilation and other forms of stereotypic behavior precipitated by stressful situations. Modification of this behavior was achieved by environmental and nutritional management and provision of adequate exercise. Nonpharmacologic intervention can be a simple and inexpensive way to correct self-mutilative behavior.

Aggression↗

PubMed1987

6-hydroxydopamine treatments enhance behavioral responses to intracerebral microinjection of D1- and D2-dopamine agonists into nucleus accumbens and striatum without changing dopamine antagonist binding.

Behavioral responses to D1 and D2-dopamine agonists are enhanced when these agonists are administered systemically to 6-hydroxydopamine (6-OHDA)-lesioned rats. In the present investigation, microinjection of SKF-38393, a D1-dopamine agonist, into the nucleus accumbens of adult rats lesioned as neonates with 6-OHDA produced a dose-related increase in locomotor activity that was enhanced markedly compared to control. LY-171555, a D2-agonist, elicited less locomotor activity than did SKF-38393 after microinjection into this site. Administration of SKF-38393 or LY-171555 into the nucleus accumbens did not increase locomotion in unlesioned rats at the doses administered to lesioned animals. In adult-6-OHDA-lesioned rats, microinjection of SKF-38393 into the nucleus accumbens also increased locomotion more than did LY-171555. As described previously, systemic administration of SKF-38393 produced little locomotion in adult-6-OHDA-lesioned rats, whereas LY-171555 produced a markedly enhanced response. Administration of SKF-38393 or LY-171555 into the caudate nucleus of neonatally and adult-6-OHDA-lesioned rats produced negligible locomotor activity, but did induce stereotypic behaviors similar to those observed after systemic treatment with these drugs. Stereotypic behaviors occurred to a greater degree in the 6-OHDA-lesioned rats than in unlesioned controls. A regional specificity for certain behaviors induced by dopamine agonist administration was observed. In spite of the enhanced behavioral responses of D1 and D2-dopamine agonists after microinjection into the brain of 6-OHDA-lesioned rats, binding of [3H]spiperone (D2-receptor antagonist ligand) and [3H]SCH 23390 (D1-receptor antagonist ligand) to tissue from striatum and nucleus accumbens was not altered significantly. In contrast to this lack of change in binding characteristics in 6-OHDA-lesioned rats, blockade of dopaminergic transmission with haloperidol treatment caused an elevation of [3H]spiperone binding sites in striatum without affecting affinity for the site. However, chronic haloperidol treatment did not alter significantly [3H]SCH 23390 binding to striatal membranes. These latter findings suggest that chronic dopamine receptor blockade need not produce the same adaptive mechanisms as destruction of dopamine-containing neurons. Thus, a change in receptor characteristics as measured by dopamine antagonist binding does not account for the behavioral supersensitivity observed after D1- and D2-dopamine agonist administration to neonatally or adult-6-OHDA-treated rats.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2006

Introducing a semi-naturalistic exhibit as structural enrichment for two brown bears (Ursus arctos). Does this ensure their captive well-being?

In this study we used the daily activity pattern and use of space as indicators of change in the program of structural enrichment, implemented with 2 subjects of the species Ursus arctos in the Barcelona Zoo. We collected 930 sampling points in each study phase for each of the individuals: The samples were taken in a balanced way at different times of day. We observed a wider range of behavior in the male than the female. With respect to the indicators, we observed statistically significant differences in behavior in both individuals in the 2 study phases. Both individuals showed an increase in vigilance, maintenance, and inactivity when their enclosure was changed. In terms of the subjects' well-being, we considered the percentage of stereotyped behavior within acceptable limits. The percentage of activity observed in the male was very similar to that of individuals of this species in the wild. In terms of the use of space, we observed homogeneity only in the male during the enrichment program. The 2 individuals responded in different ways to the structural enrichment.

Animal Welfare↗

PubMed2002

Brain-derived neurotrophic factor expression is increased in the rat amygdala, piriform cortex and hypothalamus following repeated amphetamine administration.

The amygdala plays an important role in the regulation of motivational states, especially those associated with addiction. The amygdala also expresses high levels of brain-derived neurotrophic factor (BDNF), an activity-dependent neurotrophin that can influence the reinforcing and locomotor activating properties of psychostimulants. In the present study, we examined the effects of acute and repeated amphetamine administration on the expression and production of this factor in the forebrain of rats. Animals given a single, acute injection (5 mg/kg, i.p.) of D-amphetamine developed hyperactivity followed by stereotypical behavior but showed no change in the basal expression of BDNF mRNA or its immunocytochemical profile in any region except the piriform cortex. Repeated injections (5 days) of 5 mg/kg amphetamine were accompanied by an enhanced onset of stereotypical behavior and elevated BDNF mRNA in the basolateral amygdala, rostral piriform cortex and paraventricular nucleus of the hypothalamus. Repeated treatment also increased BDNF immunoreactivity in perikarya of these same regions. In addition, increased BDNF immunoreactivity was found in fibers of many projection targets of the basolateral amygdala--the central extended amygdala, olfactory tubercle, medial nucleus accumbens, and in small zones resembling striosomes in the dorsal medial striatum. These results suggest that the upregulation of BDNF expression and protein in the basolateral nucleus of the amygdala and its targets could be an important part of the neuroadaptive response to psychostimulants.

Amygdala↗

PubMed1986

Obligatory D-1/D-2 receptor interaction in the generation of dopamine agonist related behaviors.

Administered independently, the selective D-1 and D-2 agonists SKF 38393 and LY 171555 elicited dose dependent increases in complex motor behaviors such as locomotion or grooming. Typical stereotypic behaviors were observed only when these agents were combined and only at the higher doses of the D-1 agonist. AMPT pretreatment blocked the effects of the agonists administered independently, but all classes of behavior could be induced when they were administered in combination. Thus, expression of dopamine agonist induced behaviors requires concurrent activation of D-1 and D-2 receptors; the nature of the behavior appears to depend upon the ratio of D-1 to D-2 receptor activation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1991

Cultural, ethnic, racial, and religious factors: implications for ophthalmic nursing practice and research.

In her book, 9226 Kercheval: The storefront that did not burn, Milio (1970) states ... the one who would change others must himself be changed (p.xi). Thus if ophthalmic nursing practice is to have a positive impact upon patient outcomes in the twenty-first century, our nursing interventions and the empirical research that validates and legitimizes these interventions must be predicated upon factors that view the patient holistically. In particular, the integration of orthodox or traditional ophthalmic procedures with the patient's perceptions of health, cultural norms, values, religious doctrines, etc. If compromises between the nurse and the patient are not negotiated, nursing services will be avoided and nursing interventions such as patient education will be ignored (Reinhardt & Quinn, 1977). Sensitivity to cultural, ethnic, racial and religious factors will enhance ophthalmic nursing practice by helping to unravel such issues as patient compliance, differential responses to pain (Davitz, Sameshima, & Davitz, 1976; 1972; Zborowski, 1969; 1952), the relevance for utilizing a variety of teaching strategies for patient education, and family and community influence in the prescribed care of the patient. Having had our philosophy of health care shaped by a middle-class white, and traditionally patriarchal, value and belief paradigm (Donnelly & Sutterly, 1985), we tend to unconsciously gravitate toward ethnocentric attitudes and stereotypic behaviors when caring for patients who hold health beliefs and values different from our own. However, as we become acquainted with and learn to appreciate the norms and values of differing populations, there will be a diminution in ethnocentric attitudes and stereotypic behavior.

Clinical Nursing Research↗

PubMed2001

Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families.

Autism is a syndrome characterized by deficits in language and social skills and by repetitive behaviors. We hypothesized that potential quantitative trait loci (QTLs) related to component autism endophenotypes might underlie putative or significant regions of autism linkage. We performed nonparametric multipoint linkage analyses, in 152 families from the Autism Genetic Resource Exchange, focusing on three traits derived from the Autism Diagnostic Interview: "age at first word," "age at first phrase," and a composite measure of "repetitive and stereotyped behavior." Families were genotyped for 335 markers, and multipoint sib pair linkage analyses were conducted. Using nonparametric multipoint linkage analysis, we found the strongest QTL evidence for age at first word on chromosome 7q (nonparametric test statistic [Z] 2.98; P=.001), and subsequent linkage analyses of additional markers and association analyses in the same region supported the initial result (Z=2.85, P=.002; chi(2)=18.84, df 8, P=.016). Moreover, the peak fine-mapping result for repetitive behavior (Z=2.48; P=.007) localized to a region overlapping this language QTL. The putative autism-susceptibility locus on chromosome 7 may be the result of separate QTLs for the language and repetitive or stereotyped behavior deficits that are associated with the disorder.

Autistic Disorder↗

PubMed1996

Annetocin, an annelid oxytocin-related peptide, induces egg-laying behavior in the earthworm, Eisenia foetida.

Annetocin, an oxytocin-related peptide which we isolated from the earthworm Eisenia foetida, induced a series of egg-laying-related behaviors in the earthworms. These stereotyped behaviors consisted of well-defined rotatory movements, characteristic body-shape changes, and mucous secretion from the clitellum. Each of these behaviors is known to be associated with formation of the cocoon in which eggs are deposited. In fact, some of the earthworms injected with annetocin (> 5 nmol) laid eggs. Such egg-laying-related behaviors except for oviposition were also induced by oxytocin, but not by Arg-vasopressin and some other bioactive peptides isolated from E. foetida. Furthermore, annetocin also induced these egg-laying-like behaviors in the leech Whitmania pigra, but not in the polychaete Perinereis vancaurica. These results suggest that annetocin plays some key role in triggering stereotyped egg-laying behaviors in terrestrial or fresh-water annelids that have the clitella.

Amino Acid Sequence↗

PubMed1994

The behavioral effects of the stereoisomers of 4-methylaminorex, a psychostimulant, in the rat.

In this study, we examined the effect of the isomers of the psychostimulant 2-amino-4-methyl-5-phenyl-delta 2-oxazoline (4-methylaminorex or 4-MAX) on behavior in rats. The s.c. administration of the stereoisomers of 4-MAX, trans-4S,5S, cis-4R,5S, cis-4S,5R and trans-4R,5R (0.3-3 mg/kg), produced a dose-dependent increase in locomotor activity. However, at a dose of 10 mg/kg, the isomers of 4-MAX produced an initial increase in locomotor activity followed by the appearance of stereotyped behaviors (continuous sniffing, chewing, head bobbing, etc.) then a subsequent phase of rebound-enhanced locomotor activity all over a time course of 4 hr. The rank order of potency for the stereoisomers of 4-MAX was: 4S,5S > 4R,5S =4S,5R < 4R,5R. To determine what neurotransmitter systems may mediate the action of 4-MAX, the ability of various receptor antagonists to block or attenuate the effect of trans-4S,5S-4-MAX (3 mg/kg s.c.) on locomotor activity was examined. The selective dopamine (DA) D1 antagonist (-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H- benzo- [d]naph-thio[2,1b]azepine (SCH 39166) and the D2 receptor antagonist (-)-eticlopride significantly, attenuated the behavioral action of trans-4S,5S-4-MAX, whereas antagonists to serotonergic and adrenergic receptors were ineffective. These results suggest that the ability of 4S,5S-4-MAX to induce locomotor hyperactivity and stereotypical behaviors and to increase rearing durations is primarily mediated by DA receptors. To determine whether the action of 4-MAX is dependent upon 5-hydroxytryptamine or DA concentrations in nerve terminals, rats were pretreated with either reserpine, alpha-methyl-p-tyrosine or d,l-p-chlorophenylalanine. Both reserpine and alpha-methyl-p-tyrosine pretreatment markedly attenuated the locomotor activity produced by trans-4S,5S-4-MAX. Moreover, L-dopa partially reversed the inhibitory action of alpha-methyl-p-tyrosine on 4S,5S-4-MAX-induced behavioral activation. In contrast, the administration of d,l-p-chlorophenylalanine did not alter the behavioral responses produced by trans-4S,5S-4-MAX. Taken together, our results suggest that 4-MAX may increase several locomotor behaviors by inducing neuronal DA release, which subsequently interacts with dopaminergic receptors.

Animals↗