Behavioural effect of intraventricular application of methoxy-indolealkylamines in the rat.
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Four macaques with lesions of dorsolateral frontal cortex and 4 normal monkeys were injected with 1 mg/kg d-amphetamine. Observations of social behaviors and motor activity were conducted over a 1-month period. The results of this experiment show a partial dissociation of effects of amphetamines on behavior of normal and frontally lesioned animals. The frontal monkeys showed a dramatic increase in hyperactivity while normal monkeys showed a variable motor response to the drug. Conspecific social interactions were disrupted by amphetamine in normal as well as lesioned animals. A functional system featuring the caudate nucleus and dorsolateral frontal cortex is presented. In addition, the possible influence of these areas on the balance of behavior modulated by limbic structures is explored. Changes in catecholamine levels are also hypothesized.
The animal amphetamine model of schizophrenia has been based primarily on stereotyped behavior. The present study sought to demonstrate an amphetamine-induced deficit in attentional processes. To this end, the effects of acute and chronic (14 days) 1.5 mg/kg dl-amphetamine administration on the ability of rats to ignore irrelevant stimuli were examined using the paradigm of latent inhibition (LI) in a conditioned emotional response (CER) procedure. The procedure consisted of three stages: pre-exposure, in which the to-be-conditioned stimulus, tone, was presented without being followed by reinforcement; acquisition, in which the pre-exposed tone was paired with shock; and test, in which LI was indexed by animals' suppression of licking during tone presentation. Experiment 1 showed that chronic but not acute treatment abolished LI. Experiment 2 showed that animals receiving chronic amphetamine pretreatment but pre-exposed and conditioned without the drug, exhibited normal LI. In Experiment 3, animals which received chronic amphetamine pretreatment and were pre-exposed under the drug but conditioned without it, also showed normal LI. The implications of these results for the animal amphetamine model of schizophrenia are discussed.
Rats were reinforced with water on a continuous reinforcement schedule and were also punished with electric shock for every fifth response applied to a silent, isometric, force-sensing manipulandum. Oral doses of chlordiazepoxide (3.0, 9.0, 27.0 mg/kg) increased both conventional rate and force of punished responding. In contrast, d-amphetamine (0.8, 1.6, 3.2 mg/kg, by gavage) further decreased conventional rate and force of response, but this latter drug increased the rate of recorded responses that were lower than the 15-g force criterion for response consequences. The results for chlordiazepoxide are viewed in terms of its anxiolytic properties, while the d-amphetamine data appear to support a theory of amphetamine effects based on the concept of stereotyped behaviors.
Rats in colonies were observed for 7 days after half of them were implanted with slow-release silicone pellets containing d-amphetamine base. The drug-implanted animals were initially hyperactive and exploratory, but this gradually evolved over the next 24 h into motor stereotypies of an increasingly more circumscribed nature. On the 4th day after amphetamine implantation they transiently withdrew to the burrows area; thereafter they were characterized by heightened startle responses and increased social behaviors such as fighting and fleeing. During the last phase some of the drug-implanted animals tended to focus their fighting behaviors on one other drug-implanted animal. This late phase of constant amphetamine intoxication in rats has a number of similarities to amphetamine psychosis in humans, and can serve as a useful animal model for the study of its biochemical correlates.
The effects of apomorphine (0.001--32.0 mg/kg) on elicited and operant pecking were studied in pigeons. Elicited pecking was measured in a 1-h observation test. Apomorphine caused dose-related increases in the pecking elicited by the drug in all the subjects, with maximal responding at 3.2 mg/kg. In contrast, operant responding on a multiple, 5 min fixed interval, 30 response fixed-ratio schedule revealed individual differences in sensitivity to the drug. A dose of 0.32 mg/kg eliminated key pecking in fixed-interval and fixed-ratio components in 4 (group 1) of the 15 subjects while 3.2 mg/kg eliminated responding in 9 other subjects (group 2), and 2 of the subjects (group 3) required 32.0 mg/kg to eliminate responding. The 13 birds in groups 1 and 2 showed decreases in operant responding with concomitant increases in elicited pecking. For the 2 remaining birds, increases in operant behavior were highly correlated with increased stereotypy. The effects of apomorphine on operant behavior appeared to depend on induced stereotypy, with rate-decreasing effects resulting from the disruption of ongoing behavior by stereotyped pecking aimed elsewhere in the chamber, and rate increases resulting from the redirection of elicited pecking towards the operant key.
d-Amphetamine is effective in controlling seizures in petit mal epilepsy. The flash-evoked afterdis-charge (FEAD) in rats has been proposed as a model of the peit mal seizure. The experiments reported here investigated the dose response relationship for the suppression of FEAD by d-amphetamine, and compared its effects with those of the dopamine-mimetic, apomorphine. Significant suppression of FEAD was observed at doses of d-amphetamine greater than 0.2 mg/kg. A maximum decrease of 60% occurred at 1.2 mg/kg. Higher doses did not result in any further suppression. In contrast, apomorphine and no effect on the FEAD even at doses that induced intense stereotypic behavior. In other experiments, administration of either the dopamine antagonist pimozide or the alpha-adrenergic antagonist phenoxybenzamine exacerbated FEAD and also prevented the suppression of FEAD by d-amphetamine. The results of these experiments support the hypothesis that the FEAD is a valid model of the petit mal seizure. Furthermore, they provide evidence that norepinephrine is necessary for the seizure-suppressant action of d-amphetamine.
The startle response to an auditory stimulus was potentiated by treatment with d-amphetamine sulfate. Administration of L-dopa after pretreatment with the extracerebral decarboxylase inhibitor MK-486 also increased startle activity. After long-term exposure to amphetamine the startle response to L-dopa and d-amphetamine was enhanced. These findings are consistent with the consequences of long-term amphetamine administration on other amphetamine-induced behaviors (e.g. stereotype), and are discussed in terms of the effects of long-term amphetamine treatment on pre- and postsynaptic dopamine receptors and serotonin.
The use of (-)DP-5,6-ADTN as a non-radioactively labeled ligand for an in vivo DA receptor assay is described and compared with racemic DP-5,6-ADTN, previously used for that purpose. The effects of four DA agonists (NPA, bromocriptine, DP-7-OH-ATN and 3-PPP) on the specific (-)DP-5,6-ADTN binding are related to their potencies to decrease striatal HVA concentrations and to induce stereotypy in rats. NPA and DP-7-OH-ATN caused a maximal decrease in HVA levels, when only a fraction of the receptors were occupied, while the occurrence of stereotypy was associated with a high receptor occupation, reflecting the higher affinity of these agonists for presynaptic than for postsynaptic receptors. Bromocriptine did not show this effect, as the dose-response relationships for HVA decrease, for induction of stereotypy and for the decrease in specific (-)DP-5,6-ADTN binding were all virtually equal to each other. While NPA and bromocriptine behaved as full postsynaptic agonists, in that maximal stereotyped behavior was observed after high doses, DP-7-OH-ATN was found to be a partial postsynaptic agonist, as it did not induce maximal stereotypy at a maximal receptor occupation. Racemic 3-PPP only caused a state of hypoactivity, but did neither affect specific (-)DP-5,6-ADTN binding nor striatal HVA levels. Our results are discussed in view of theories on the relation between receptor occupation and pharmacological effects and it is concluded that the in vivo receptor binding method using (-)DP-5,6-ADTN is a very useful tool for such investigations.
We compared the predictability of the behaviour of hyperactive children with that of aggressive children, combined hyperactive/aggressive children and normal children. Detailed behaviour measurements relating to each child and an experimenter were recorded during playroom session. Predictability was expressed in information-theoretical measures and data were tested by means of a Multivariate Analysis of Variance (MANOVA) with between-subject factors "hyperactivity" and "aggression". Hyperactivity was characterised by chaotic social and communicative interaction between child and experimenter and by rigidity in the intra-child transitions of activity states. Aggression on the other hand, was associated with lower predictability of activity behaviours of the child in the context of interaction with the experimenter, which may be due to oppositional features in the child.
Metamorphosis in the moth Manduca sexta culminates with the secretion of the peptide eclosion hormone (EH), which triggers the stereotyped behavior of adult emergence (eclosion) from the pupal cuticle. In restrained but spontaneously behaving animals, the release of EH occurred shortly before the onset of subjective night (Fig. 3) and coincided with a depletion of EH from the neurohemal organs of the brain, the corpora cardiaca-corpora allata complex (CC-CA; Fig. 4). EH is produced by neurons within a bilaterally paired group of brain neurosecretory cells (Group Ia) which project to the CC-CA via the nervi corporis cardiaci- 1 + 2 (NCC-1 + 2; Fig. 1). Electrical stimulation of the NCC-1 + 2 caused a marked increase in the levels of EH secreted from isolated CC-CA (Fig. 2), while stimulation of the other nerves innervating the neurohemal organs did not. Electrical activity in the NCC-1 + 2 paralleled that of the cerebral neurosecretory cells (Fig. 1). Chronic extracellular recordings revealed a sudden increase in the tonic firing of several units within this nerve approximately 2 to 3 h before normal eclosion (Fig. 5), coincident with the release of EH bioactivity from the CC-CA (Fig. 6). The Group Ia neurons were electrically inactive on the day before eclosion (Day-1), but on the day of eclosion (Day 0) a subgroup of these cells exhibited both enhanced synaptic input and elevated rates of tonic firing during the normal time of EH release (Fig. 7). No significant differences in resting membrane potential or spike waveform characteristics were detected among the various subsets of Group Ia cells on either Day-1 or Day 0, while a significant increase in the resting input resistance was seen in the active subgroup on Day 0 (Fig. 8). This increase may be due to the regulatory effects of the steroid 20-hydroxyecdysone, which inhibits the release of EH and may act by preventing the synaptic activation of the EH neurons until the final day of adult development.
The in vivo release of endogenous dopamine (DA) has been measured from the rat caudate nucleus. A push-pull cannula was implanted into the brain and the tissue was perfused with artificial cerebrospinal fluid (CSF) containing amphetamine in concentrations ranging from 5 X 10(-3) to 5 X 10(-7) M. The DA released into the perfusate was determined by a radioenzymatic procedure. DA release was increased to levels significantly above its resting rate by amphetamine concentrations of 5 X 10(-6) M or greater. Release stimulated by 5 X 10(-5) M amphetamine was significantly reduced by removing calcium from the perfusing fluid; the unstimulated release rate was not significantly affected. The concentrations of amphetamine required to increase DA release in vivo would appear to be similar to those found in the brain following intraperitoneal doses which produce increases in locomotor activity and stereotyped behavior.
This study evaluated the psychometric properties of the Parent Interview for Autism (PIA), a structured interview for gathering diagnostic information from parents of young children with autism. Internal consistency was evaluated in a sample of 165 children under 6 years old, and test-retest reliability and construct validity were evaluated in subsamples of the original group. Results revealed internal consistency and test-retest reliability above .60 for 9 of the 11 dimensions constituting the PIA, as well as significant correlations between the PIA and other measures of autism. Six of the PIA dimensions differentiated a group of young children with autism from a developmentally comparable group with mental retardation. Implications of these findings and suggestions for future research are discussed.
The effect of chronic apomorphine treatment on behavioural activity as well as brain dopamine metabolism was studied in normal and neonatally L-triiodothyronine-treated rats. Neonatal hyperthyroidism was accompanied by an increase in spontaneous locomotor activity as well as by enhanced synthesis and release of dopamine as evidenced by increased catecholamine synthesis in crude synaptosomal preparation (P2 pellet), elevated tyrosine hydroxylase activity and higher concentrations of homovanillic acid and 3, 4-dihydroxyphenylacetic acid in striatum of rats. Repeated apomorphine treatment (1 mg/kg/day s.c) for 15 days, beginning from the 15th day of age, produced hypermobility and stereotyped behavior (consisting of sniffing, gnawing, rearing) which appeared to be more pronounced in neonatally hyperthyroid rats than in normal controls. In addition, apomorphine-treated hyperthyroid animals marched in a row with straub tail, and displayed increased aggressiveness and bizarre social behavior consisting of "mock fighting" when left in pairs. In contrast to normal rats, apomorphine-treated hyperthyroid animals displayed marked hyperactivity which was evident even at 24 hours after the last injection of apomorphine. Administration of apomorphine resulted in significant decreases in striatal tyrosine hydroxylase, catecholamine synthesis in crude synaptosomal preparation (P2 pellet) as well as dopamine metabolite levels in brains of both normal and hyperthyroid animals. Our present data showing that apomorphine potentiates behavioural activity in hyperthyroid rats suggest that L-triiodothyronine and apomorphine probably share certain features common to activating dopaminergic neurons in the brain.
Reports of ephedrine-induced psychoses resembling amphetamine psychosis prompted studies of this classic sympathomimetic agent in systems that indicate central dopaminergic actions. Ephedrine induced dose-related stereotyped behavior in rats. This behavior was antagonized by haloperidol, but not by alpha- or beta-adrenergic blockers. Pretreatment with AMPT, but not reserpine, attenuated the stereotypy induced by ephedrine under one of two sets of conditions. Consistent prolactin suppression in humans was not seen. These findings are discussed in the context of clinical and pharmacologic data regarding other dopamine agonist drugs (the central nervous system stimulants, apomorphine, ET 495). These data suggest the possibility that synergistic noradrenergic and dopaminergic facilitation may be important in the induction of the stimulant psychoses.
The narcotic antagonist naloxone does not antagonize antinociception elicited in the rabbit by 100 microgram/kg of mescaline centrally administered, whereas pretreatment with 6-hydroxydopamine (6-OHDA) inhibits this mescaline effect. Stereotyped behavior of rabbits following central mescaline administration is also prevented by 6-hda pretreatment. Since 6-OHDA in known to produce a degeneration of catecholamine containing nerve terminals, a crucial role of catecholamines is suggested in the complex of effects seen in the rabbit after central administration of the hallucinogen.
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There is increasing recognition that autism is a syndrome, not a disease entity. But it is not yet clear why some children develop autistic behavior more easily than others. It has been noted that autistic symptoms occur more frequently in children with mental retardation, blindness, congenital rubella, phenylketonuria, etc., and that there are very few cases of classical infantile autism in the general population. Very rarely has autism been associated with Down's syndrome. This is a report of a case of Down's syndrome and infantile autism.