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Longitudinal examination of the behavioral, language, and social changes in a population of adolescents and young adults with autistic disorder.

This follow-up study evaluates the behavioral, language, and social outcomes in a population of autistic patients initially examined in childhood. We evaluated 102 (63%) of the 163 eligible subjects, including 54 adolescents (12-17 years of age) and 45 adults (> or = 18 years of age). Three patients had died in the interim. Behavior difficulties continued to be a problem in 69% of adolescents and adults. Thirty-five percent of adolescents and 49% of adults engaged in self-injurious behavior, and slightly more than 50% of adolescents and adults exhibited some stereotypic behaviors. Over 90% of both adolescents and adults had persisting social deficits. Language improved with age, although only 35% achieved normal or near-normal fluency. Comprehension also improved, although only 29% of subjects had achieved normal or near-normal comprehension of oral language. At the time of last follow-up, 28% of all patients and 53% of adults were living in residential placement. Only 11% of adults were employed on the open market, all in menial jobs; an additional 16% were employed in sheltered workshops. The social, behavioral, and language deficits identified in early life in autistic children tend to persist into adolescence and young adulthood.

Adolescent↗

A family of genes that codes for ELH, a neuropeptide eliciting a stereotyped pattern of behavior in Aplysia.

We describe a particularly advantageous experimental system for studying gene structure, expression and modulation in the nervous system. In the marine mollusc Aplysia, the bag cells, two discrete clusters of neurons, secrete a peptide of known behavioral function. This neuroactive peptide, egg-laying hormone (ELH), produces a characteristic and stereotypic behavioral repertoire, consisting first of a cessation of walking and inhibition of feeding, followed by head waving and egg laying. We have cloned the genes encoding ELH and characterized their organization and expression. At least five distinct genes for ELH exist within the chromosome. Sequence analysis of one recombinant clone unambiguously identifies a contiguous stretch of nucleotides that encodes the 36 amino acids of ELH. Transcription of this small multigene family results in the expression of at least five distinct RNA transcripts encoding ELH. The pattern of transcripts differs strikingly in different tissues: bag cells express three distinct mRNA species, whereas the atrial gland, a secretory reproductive gland, expresses two distinct mRNAs. Several other neuronal and nonneuronal tissues do not express ELH RNA. In vitro these mRNAs produce a series of long polypeptide precursors that must be processed to generate the active ELH peptide. This processing event is likely to generate several additional neuroactive peptides. Thus the same peptide, ELH, may be released in association with different combinations of other neuroactive peptides. The concept of combinatorial sets of neuropeptides, each bearing one overlapping peptide ELH, and each directing a differing pattern of behavior, greatly expands the information potential of a small set of genes.

Animals↗

Apparent tolerance to some aspects of amphetamine stereotypy with long-term treatment.

Previous reports have demonstrated that long-term amphetamine treatment results in a progressive augmentation of locomotion and focused stereotypy in the rat. A series of experiments were conducted to determine whether an increase in dopamine receptor sensitivity is the primary mechanism underlying the behavioral alterations associated with multiple amphetamine injections. Detailed observations of the focused stereotyped behaviors produced by amphetamine revealed that although some components were enhanced with long-term treatment, others were reduced. Thus, whereas repeated administration of 2.5 mg/kg d-amphetamine produced a progressive increase in repetitive head and limb movements, long-term treatment with 5.5 mg/kg d-amphetamine resulted in a reduction of licking and biting behaviors (oral stereotypies). These results, which suggest that different mechanisms mediate the various components of focused stereotypy, argue against the supersensitivity hypothesis. In fact, the apparent tolerance that develops to oral stereotypies may reflect a decrease in dopamine receptor sensitivity since repeated amphetamine administration also reduces the oral stereotypies produced by 0.5 or 2.0 mg/kg apomorphine, a direct acting dopamine agonist. Thus, the behavioral alterations produced by repeated amphetamine injections cannot be explained solely by an increase in receptor sensitivity.

Animals↗

NC-1900, an arginine-vasopressin analogue, ameliorates social behavior deficits and hyperlocomotion in MK-801-treated rats: therapeutic implications for schizophrenia.

We previously reported that chronic administration of N-methyl-D-aspartate (NMDA) antagonists reduced the density of vasopressin V1a receptors in several brain regions in rats that demonstrated social interaction deficits and increased locomotor activity. These observations indicate the ability of arginine-vasopressin (AVP), or its analogues, to modulate behavioral abnormalities associated with blockade of NMDA receptors. The present study was performed to investigate the effect of NC-1900, an AVP analogue, on social behavior and locomotor activity in rats treated with MK-801, a non-competitive NMDA receptor antagonist. Male Wistar rats were administered MK-801 (0.13 mg/kg/day ip) or saline for 14 days. Social behavior and locomotor activity were measured 45 min after the injection of NC-1900 (10 ng/kg sc) or saline together with the last MK-801 or vehicle administration. Social interaction was quantified by an automated video-tracking system, and stereotyped behavior and ataxia were manually measured. Acute administration of NC-1900 partially reversed MK-801-induced hyperlocomotion and deficits in social interaction, while NC-1900 itself did not affect these behavioral measures in animals chronically treated with vehicle saline. These results suggest that the central AVP system may interact with glutamatergic and dopaminergic transmissions, and indicate potential therapeutic effects of AVP analogues on positive and negative symptoms of schizophrenia.

Analysis of Variance↗

Gender differences in the behavioral responses to cocaine and amphetamine. Implications for mechanisms mediating gender differences in drug abuse.

When ovariectomized female rats receive estrogen, the response to the psychomotor stimulants amphetamine or cocaine is enhanced. Estrous cycle-dependent differences in amphetamine-stimulated behaviors and striatal dopamine release are also noted. Intact female rats exhibit a greater behavioral response to amphetamine on estrus than they do on other days of the cycle. Ovariectomy results in attenuation of amphetamine-induced behavior and the striatal dopamine response to amphetamine. Physiological doses of estrogen given to ovariectomized rats reinstate both of these responses to a level comparable to that in estrous females. Furthermore, a sex difference is noted, in that females tend to exhibit a greater behavioral response to the psychomotor stimulants, and estrogen enhances this sex difference. Repeated treatment with amphetamine or cocaine produces a progressive increase in behavioral responsiveness with subsequent drug administration, a process known as sensitization. In rodents, behavioral sensitization results in increases in both frequency and duration of psychomotor behaviors such as rotational behavior, stereotyped grooming, headbobs, and forelimb movements. Interestingly, females display greater sensitization of behaviors in response to psychomotor stimulants than do males. Previous research results are summarized, and new results are presented, demonstrating that estrogen selectively enhances components of behavior that exhibit sensitization in female rats. Results also indicate gender differences in sensitization independent of gonadal hormones, suggesting that the neural systems that undergo sensitization are sexually dimorphic.

Amphetamine↗

The effect of (-) deprenyl (selegiline) on different behavioral changes induced by dopamine agonists in the rat.

The effect of (-) deprenyl was investigated both on the stereotyped behavior and on other types of activities induced by various dopamine (DA) agonists. (-) Deprenyl was given in a single dose, 1 h prior to the DA agonists. 1-2 mg/kg sc (-) deprenyl decreased the stereotypy induced by amphetamine (AMPH, 2.5 mg/kg sc), but 20 mg/kg was needed to reduce the stereotypy-inducing effect of apomorphine (APO, 0.3 mg/kg sc). The stereotypy-inducing effect of phenyl-ethyl-amine (PEA, 40 mg/kg sc) was significantly enhanced by 0.25 mg/kg sc (-) deprenyl pretreatment. The PEA or AMPH-induced increase in the horizontal activity (locomotion) and the vertical activity (rearing) remained unchanged after a single dose of (-) deprenyl, showing that this drug acts primarily on the nigro-striatal dopaminergic system.

Amphetamine↗

Haloperidol, but not apomorphine, differentially affects low response rates of male and female Wistar rats.

Amphetamine-induced behavioral differences between male and female rats have been observed in tests for stereotyped behavior, locomotor activity and rotational behavior. It has also been shown that amphetamine differentially affects schedule-controlled behavior of male and female rats. The present experiments were designed to further investigate sex differences in sensitivity to agents which act upon the dopaminergic system. In the first experiment, male and female rats responding on a schedule which maintained low response rates were challenged with different low (less than 0.5 mg/kg) doses of apomorphine. Low doses of apomorphine act on the dopamine receptors on the dopaminergic terminals themselves to inhibit the release of endogenous dopamine. In the second experiment, the same subjects were given different doses of haloperidol, which selectively blocks the post-synaptic dopamine receptors. The results of the present experiments showed that haloperidol, but not apomorphine, differentially affected the behavior of male and female subjects. A behavioral difference between the sexes was thus observed when post-synaptic dopamine receptors were blocked by a dopamine antagonist, but not when dopaminergic stimulation of post-synaptic dopamine receptors was reduced by pre-synaptic inhibition of dopamine release. These results suggest a role for post-synaptic receptor mechanisms in mediating sex differences in sensitivity to dopaminergic agents, although other possible mechanisms remain to be investigated.

Animals↗

Effects of D2-dopaminergic receptor stimulation on the lordotic response of female rats.

The effects of LY163502, a highly selective D2 dopaminergic agonist, on the lordotic response of ovariectomized, estrogen-treated rats were evaluated. LY163502, administered subcutaneously or orally, produced a significantly greater lordotic response than vehicle. LY175877 [the opposite (+) enantiomer] was found to be inactive. The effects of subcutaneous administered LY163502 were abolished by prior treatment with dopaminergic receptor antagonists such as haloperidol or cis-flupenthixol. These studies are supportive of the view that LY163502 can initiate and potentiate female sexual behavior by stimulating D2 type dopaminergic receptors. In contrast to the enhancement of lordotic response that was observed in nonreceptive female rats, LY163502 was found to have suppressive effects on lordotic response frequency of receptive (estrogen-progesterone-treated) female rats. Reductions in lordotic responding occurred in two dose ranges, above and below the dose range found to potentiate lordotic response. The maximal suppressive effect at the low dose range was observed at 250 pg/kg, SC. This reduction in lordotic responding was proposed to be associated with a selective dopaminergic autoreceptor activation, leading to a diminished dopamine release and expression of a dopamine-mediated behavior (i.e., lordotic response). The reduction of lordotic responding that was observed at higher doses (25 micrograms/kg-25 mg/kg) was associated with an induction of stereotypic behavior that may have disrupted the sexual response pattern.

Animals↗

Influence of imidazole on behavioral effects induced by dopaminergic agonists in rats.

Imidazole (IMI) (from 18.7 to 300 mg/Kg) i.p. injected in adult rats induced shaking, which was antagonized by both morphine (MOR) and haloperidol (HALO) but not by methysergide (MET). I.p. IMI pretreatment inhibited the penile erections (PE) and stretching and yawning (SY) typically elicited by N-n-propylnorapomorphine (NPA), a well-known CNS dopamine (DA) receptor stimulant, injected either i.p. or i.c.v., whereas it enhanced stereotyped behavior (SB). IMI had similar effects on the same parameters considered when injected before lisuride, an ergot derivative also active as a central DA receptor agonist. In this case not only SB but also and above all aggressiveness were markedly potentiated, both the signs appearing at doses of lisuride which were "per se" ineffective. Aggressiveness, like SB, was not sex linked and was antagonized by HALO and MOR, but not by MET. IMI alone potentiated the fighting induced by electrical shock, an effect which was abolished by HALO pretreatment. Considering the results obtained as a whole it is submitted that IMI antagonizes PE and SY through a selective blockade of a class of DA receptors, presumably DA presynaptic autoinhibitors, thus potentiating SB and aggressiveness, which involve stimulation of DA postsynaptic receptors.

Adrenergic Agonists↗

Antagonistic effects of isofloxythepin on dopamine D1 and D2 receptors and behaviors in rats.

1. In vitro, isofloxythepin competed for the binding of [3H]SCH 23390 to striatal D1 receptors and for the binding of [3H]spiperone to striatal D2 receptors with IC50 values of 6.1 (+/- 1.2) x 10(-10)M and 8.4 (+/- 2.6) x 10(-10)M, respectively. Isofloxythepin further inhibited the D1 receptor-mediated, dopamine-stimulated adenylate cyclase in the striatal tissue. 2. Fifteen hours after rats were injected with a single dose of isofloxythepin (1 mg/kg, SC), the ex vivo binding curve of [3H]spiperone to striatal D2 receptors was markedly inhibited, whereas the binding curve of [3H]SCH 23390 to striatal D1 receptors was unaffected. 3. Fifteen hours after isofloxythepin pretreatment, D1 agonist SKF 38393 (15 mg/kg, IP)-stimulated grooming behavior was not affected, whereas the D2 agonist quinpirole (3 mg/kg, IP)-stimulated stereotyped behavior was completely abolished. 4. On the basis of the findings from in vivo studies, we conclude that, although isofloxythepin is found to have high affinity for both D1 and D2 receptors in vitro, it lacks D1 antagonistic potency in vivo.

Adenylyl Cyclases↗

(+)-Amphetamine oral 'drug taking behavior' in naive and tolerant rats.

The drinking behavior of naive rats changes predictably in a free choice experiment involving water vs. 0.02%, 0.01% and 0.003% (+)-amphetamine solutions: The higher the concentration of the amphetamine solution, the sooner a number of rats quit drinking it, and the less is ingested by those still drinking it. Physically dependent rats having undergone three withdrawals immediately reject (+)-amphetamine solution in a free choice test with water available. The avoidance of withdrawal symptoms does not motivate further self-administration. Therefore, (+)-amphetamine self-administered in drinking water is neither a reinforcer for naive nor for physically dependent rats in sustaining drug taking behavior. In acute and chronic experiments, the transition from increased motor activity to stereotypical behavior could be demonstrated and evidence was produced that tolerance develops to the (+)-amphetamine-induced increase in motor activity.

Administration, Oral↗

Antagonism of caffeine-facilitated conflict-induced behavior by depressants in cats.

Cats trained in 4-6 weeks to obtain a reward (food pellet) were made 'neurotic' by a randomly occurring air blast at the reward box. Previous studies have shown that d-amphetamine facilitates development of 'neurotic' (conflict-induced) behavior. Caffeine, another stimulant, was examined to determine how it affects positive reinforcement behavior, induction of 'neurosis' and its interaction with depressants. Caffeine, given orally, induced stereotyped behavior, facilitated development of the 'neurotic' behavior and disrupted the feeding cycle. Chlorpromazine, pentobarbital, diazepam, prazepam and fluazepam delayed the onset of the caffeine-facilitated conflict behavior. Phenobarbital antagonized the caffeine effect. Studies of conflict-induced behavior in the cat appear to be useful for the investigation of drug interactions and for the detection of side effects of drugs that are not ordinarily considered to have effects on the central nervous system.

Animals↗

Effects of hand-rearing on the behavioral development of infant and juvenile gorillas (Gorilla g. gorilla).

Nineteen hand-reared and seven mother-reared infant and juvenile gorillas were observed for a period of 3 years. Almost all hand-reared individuals developed stereotyped behaviors during the first months. In most cases these behaviors disappeared in the first or second year. Social behaviors, solitary play, nest building and grooming developed at about the same age in hand-reared and mother-reared infants. Hand-reared immatures showed significantly more solitary play, more aggression and less social play than mother-reared ones, especially when raised in pairs. When young gorillas were kept in groups, the frequencies of these behaviors came nearer to those of mother-reared immatures. No significant differences were noted in social play. When introduced to conspecifics, hand-reared infants sometimes reacted with indiscriminant aggression. Gorillas should thus preferably be reared in peer groups and be introduced to adults not later than one year of age.

Animals↗

Is stimulation of both D1 and D2 receptors necessary for the expression of dopamine-mediated behaviors?

Recent electrophysiological findings have indicated that D1 dopamine (DA) receptor stimulation by SKF 38393 enables the inhibitory effects of the D2 receptor agonist quinpirole on nucleus accumbens neurons. In the present study, a similar interaction was shown for quinpirole-induced stereotyped behaviors. In control rats, SKF 38393 enhanced the stereotyped responses induced by quinpirole, converting lower-level stereotypies (sniffing and rearing) to more intense oral behaviors (licking and gnawing). In rats depleted of DA (79% reduction) by the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT), the behavioral effects of quinpirole were abolished. However, quinpirole-induced stereotyped responses were reinstated by SKF 38393 suggesting that D1 receptor stimulation by endogenous DA is necessary for D2 receptor-mediated stereotyped responses (sniffing, rearing). In support of this suggestion, stereotyped behaviors produced by the non-selective D1/D2 agonist apomorphine were not affected by AMPT pretreatment. In contrast to the effects of quinpirole, the ability of SKF 38393 to induce grooming responses was not abolished by AMPT pretreatment or by combined pretreatment with AMPT and reserpine (greater than 99% DA depletion). These results indicate that D1 receptor stimulation enables D2 receptor-mediated stereotyped responses, but that this relationship is not reciprocal since D2 receptor stimulation is not necessary for the grooming response elicited by SKF 38393.

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

Peripheral and intracerebroventricular administration of human chorionic gonadotropin alters several hippocampus-associated behaviors in cycling female rats.

Our recent demonstration of receptors for luteinizing hormone (LH)/human chorionic gonadotropin (hCG) in rat brain with the highest density within the hippocampus and dentate gyrus suggests novel functional roles for gonadotropic hormones within the brain. The present study investigated whether 125I-hCG can cross the blood-brain barrier and reach hippocampus and the possible role of hCG in the regulation of several behavioral activities associated with the hippocampal formation in the rat. About 1/100th of peripherally injected 125I-hCG crossed the blood-brain barrier in an intact form and was found in cerebrospinal fluid and in hippocampus. Intraperitoneal (IP) or intracerebroventricular (ICV) injections of highly purified hCG on the morning of proestrus of cycling female rats resulted in changes in several hippocampus-associated behaviors. hCG-treated animals were generally less active and showed less exploratory behavior as compared to saline-injected control animals. There was no difference, however, in latency to enter the open field between hCG-treated and control animals. Taste neophobia was dramatically decreased following IP as well as ICV injection of hCG. No differences were found in the memory component of T-maze performance; however, the hCG-treated rats exhibited decreased stereotypic behavior. In summary, hCG can cross the blood-brain barrier, and peripheral or central administration of hCG affects several hippocampus-associated behaviors suggesting that hippocampal LH/hCG receptors are most likely involved in mediating these effects. Some of the observed behavioral changes have parallels in pregnant women.

Animals↗

The effects of D1 or D2 dopamine receptor blockade on zif/268 and preprodynorphin gene expression in rat forebrain following a short-term cocaine binge.

Selective D1 or D2 dopamine receptor antagonists were used to investigate the transynaptic regulation of mRNAs coding for the opioid peptide, preprodynorphin, and the nuclear transcription factor, zif/268 after an acute cocaine binge. Rats were injected intraperitoneally with the D1 receptor antagonist, SCH 23390, or the D2 receptor antagonist, sulpiride, 30 min prior to 3 hourly injections of saline or 20 mg/kg cocaine and killed 1 h after the final injection. Behavioral ratings indicated that SCH 23390 blocked, whereas sulpiride augmented, cocaine-induced stereotypical behaviors. Striatal sections were hybridized with oligonucleotides coding for zif/268 and preprodynorphin. Quantitative image analysis of autoradiograms revealed that (1) SCH 23390 completely suppressed basal and cocaine binge-induced zif/268 mRNA in the striatal and cerebral cortical areas examined; (2) sulpiride enhanced basal levels of zif/268 mRNA in the medial caudate and dorsomedial shell of the nucleus accumbens; (3) sulpiride partially blocked cocaine binge-induced levels of zif/268 mRNA in the dorsal striatum but had no effect in sensory cortex; (4) SCH 23390, but not sulpiride, significantly reduced the constitutive expression of preprodynorphin mRNA; and (5) SCH 23390 and sulpiride blocked cocaine binge-induced expression of preprodynorphin mRNA in the dorsal striatum.

Animals↗

Behavioral response of altricial and precocial rodent fetuses to acute umbilical cord compression.

Norway rat fetuses (Rattus norvegicus) exhibit a stereotypic behavioral response when the umbilical cord is experimentally compressed with a vascular clamp. In this study, the development of the fetal behavioral response to cord compression was compared in altricial and precocial rodents, which differ markedly in neural and motor maturity at the time of birth. Both altricial and precocial species showed some form of behavioral response to umbilical cord compression. Fetuses of two altricial species, Norway rats and Mongolian gerbils (Meriones unguiculatus), expressed hyperactivity in response to cord compression throughout the last third of gestation. In contrast, precocial cotton rats (Sigmodon hispidus) and spiny mice (Acomys cahirinus) did not respond to cord compression until relatively late in gestation. Thus, altricial and precocial species do not express the cord compression response during comparable periods of neural development: precocial species are much more mature at the earliest expression of this behavior than altricial species. These findings are consistent with the interpretation that the cord compression response is a behavioral adaptation that can promote survival of the fetus in utero.

Animals↗

Dopamine-mediated behavior produced by the enkephalin analogue FK 33-824.

Intraperitoneal injection of FK 33-824 produced apomorphine-like stereotyped behavior in rats. Antagonism of this stereotypy by naloxone and neuroleptics suggests that FK 33-824 can activate opiate and dopamine receptors in the brain. Because increased dopaminergic neuronal activity is thought to be involved in schizophrenia and dopamine-mediated stereotypy has been used as an animal model for this illness, these results are consistent with an involvement of endogenous opiate-like peptides in schizophrenia. This involvement provides a possible mechanism for the reported improvement in schizophrenic psychosis produced by naloxone.

Animals↗