Neuroendocrine responses to challenge with dl-fenfluramine and aggression in disruptive behavior disorders of children and adolescents.

Prolactin (PRL) and cortisol (CORT) responses to a single oral administration (1.0 mg/kg) of the indirect serotonin agonist dl-fenfluramine were assessed in unmedicated prepubertal and adolescent males with disruptive behavior disorders (DBD). Neuroendocrine responses were correlated with scores on aggression rating scales in prepubertal and adolescent DBD patients and compared with those of matched adolescent normal control subjects. Net dl-fenfluramine-induced PRL and CORT release was not correlated with aggression rating scores in prepubertal and adolescent DBD patients and did not differ significantly between adolescent DBD patients and normal control subjects. Although the present study does not demonstrate a serotonergic abnormality in aggression or DBD, this may be more a reflection of limitations of the neuroendocrine challenge test procedures or the methods used than evidence that serotonergic function in the central nervous system is normal in aggression.

Test-retest reliability of the prolactin and cortisol responses to D,L-fenfluramine challenge in disruptive behavior disorders.

We examined the intraindividual stability of plasma prolactin (PRL) and cortisol responses to D,L-fenfluramine challenges (1.0 mg/kg, p.o.), at a 1-week interval, in boys with disruptive behavior disorders. Two acute administrations of fenfluramine produced consistent and predictable effects on net prolactin responses (peak delta PRL, area under the curve delta PRL), but variable and unpredictable effects on net cortisol responses. The time course and magnitude of fenfluramine blood levels, not nor-fenfluramine, paralleled net PRL responses to fenfluramine. These data indicate that the PRL response to fenfluramine shows continuity within individuals over the course of 1 week, providing a reliable index to reflect the overall function of the serotonin system in the limbic-hypothalamus.

Spontaneous alternation behavior: an animal model for obsessive-compulsive disorder?

This study entailed the adoption of a well-established behavioral paradigm, spontaneous alternation, as a possible animal model for some of the symptoms observed in obsessive-compulsive disorder (OCD) in humans. Food-deprived rats were run in a T-maze in which both a black and a white goal box were equally baited with a small amount of chocolate milk. Each rat was given 7 trials every other day during which it was placed in the start box and allowed to make a choice. The mean number of choices until an alternation occurred was recorded. After a stable baseline of spontaneous alternation was achieved the effects of manipulating the serotonergic system were tested. Both the nonselective 5-HT agonist 5-MeODMT (1.25 mg/kg) and the more selective 5-HT1A agonist 8-OH-DPAT (2 mg/kg) disrupted spontaneous alternation. A course of chronic treatment (2 x 5 mg/kg for 21 days) with the selective 5-HT uptake blocking agent fluoxetine had a protective effect on the 5-MeODMT-induced disruption of spontaneous alternation behavior. Serotonergic manipulations of spontaneous alternation may be a simple animal model for the perseverative symptoms or indecisiveness seen in people diagnosed with OCD.

Platelet imipramine binding and serotonin uptake in obsessive-compulsive patients.

Platelet imipramine binding was measured in 16 drug-free nondepressed patients (aged 20-61 years, mean +/- SD 35 +/- 8) suffering from obsessive-compulsive disorder (OCD) and in 16 sex-, race- and age-matched healthy controls. Imipramine binding capacity and affinity were not different in the 2 groups. Platelet serotonin (5-HT) uptake capacity, Vmax, was also measured in 15 of these patients and their matched controls. Vmax was significantly higher in the patients (309 +/- 149 pmol/10(9) cells/min) than in the controls (181 +/- 110). An increase in platelet 5-HT uptake supports the involvement of 5-HT in OCD and may suggest that a hyperactive serotonergic system is present in this disorder.

Amino acid levels in elderly nursing home residents.

We have compared levels of albumin and serum amino acids in a group of 87 recent admissions to a nursing home, average age 83 years, with a group of healthy moderately old subjects, average age 69 years. We found that the nursing home group was characterized by decreased levels of albumin, by increased total levels of the measured amino acids, and by increased levels of the nonessential amino acids. In contrast, there were no significant group differences in the essential amino acids. Among the nursing home patients, there was a negative correlation between essential amino acids and disability, consistent with nutritional deficits in the more disabled patients, and a positive correlation between essential amino acids and subjective complaints of pain, suggesting that pain is associated with breakdown or mobilization of endogenous protein stores. Though the nursing home patients had decreased serum levels of tryptophan, there was no association between serum tryptophan or other variables that could be related to the availability of tryptophan for transport into brain, with ratings of either depression or pain. Glutamine levels were significantly increased in the nursing home residents, and among these patients they were positively correlated with measures of cognitive impairment.

Elevated platelet MAO is related to impulsivity in disruptive behavior disorders.

Platelet monoamine oxidase (MAO) activity was measured in 32 drug-free prepubertal boys with externalizing symptoms of disruptive behavior disorders and 47 boys with no DSM-III-R diagnoses, and correlated to questionnaire and laboratory performance measures of impulsivity. A subgroup of boys with high MAO activity exhibited significantly poorer performance (i.e., more impulsivity) than a subgroup of low MAO activity on laboratory tasks requiring response inhibition. High MAO patients were more impulsive than high MAO controls on some performance tasks and elevated platelet MAO was unrelated to personality questionnaire measures of impulsivity or to patient status. These data suggest that biological markers such as MAO activity may correlate better with performance than clinical questionnaire measures. Abnormally high platelet MAO activity may not be sufficient to produce externalizing symptoms in children, perhaps interacting with an underlying behavioral dimension of impulsivity.

Reduction of (3H)-imipramine binding sites on platelets of conduct-disordered children.

Binding characteristics of tritiated imipramine on blood platelets were determined in daytime hospitalized prepubertal children who had mixed diagnoses of conduct disorder (CD) plus attention deficit disorder hyperactivity (ADDH) and in inpatient adolescents who had a history of aggressive behavior. The number of (3H)-imipramine maximal binding sites (Bmax) was significantly lower in the prepubertal patient group of CD plus ADDH; the dissociation constant (Kd) was not significantly different. There were significant negative correlations between Bmax and the Externalizing or Aggressive factors of the Child Behavior Checklist when the CD plus ADDH prepubertal patients were combined with their matched controls and within the adolescent inpatient group. We propose that a decreased platelet imipramine binding Bmax value, as an index of disturbed presynaptic serotonergic activity, is not specific to depression and may be used as a biologic marker for the lack of behavioral constraint in heterogeneous. populations of psychiatric patients.

Electrodermal activity of undersocialized aggressive children: a pilot study.

Electrodermal activity of 11 children with conduct disorder (CD) and 11 normal children were compared during periods of rest, moderate tone and loud bell stimulation. The CD group was best differentiated from controls by lower reactivity to the first bell, while on tonic measures they showed normal values. The electrodermal profile of the CD children thus resembled that of adult sociopaths on phasic measures only. The possibility of using electrodermal measures for predicting outcome and for differential diagnosis is raised.

Biogenic amine alterations in limbic brain regions of muricidal rats.

Endogenous levels of serotonin, 5-hydroxyindoleacetic acid (5-HIAA), dopamine, 3-4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured in eight brain regions of muricidal (mouse killing) and non-muricidal rats. The regions studied were: the frontal cortex, caudate nucleus, septal area, hypothalamus, thalamus, amygdalae with pyriform cortex, anterior hippocampal formation, and brain stem. Serotonergic systems showed significant differences in discrete brain regions of muricidal rats as compared to those of non-muricidal rats. The differences were: significantly higher serotonin levels in the amygdalae and significantly higher 5-HIAA levels in the hippocampus of the muricidal rats. Serotonin levels were also higher in the hypothalamus of the muricidal rats, but the difference reached only borderline significance. Dopaminergic systems also showed significant differences in the septum of muricidal rats, where DOPAC levels were significantly lower than those of non-muricidal rats. The hippocampus of muricidal rats showed significantly higher dopamine levels. HVA levels in the hippocampus of muricidal rats were also higher but reached only borderline significance. These data suggest both central serotonergic and central dopaminergic involvements in rat muricidal behavior. The discrete brain regions which showed differences further suggest a limbic involvement.

Place conditioning with morphine and phencyclidine: dose dependent effects.

In a place conditioning paradigm, rats were exposed to one of two distinctive environments following injection of drug or vehicle. Preference was measured under drug free conditions by allowing subjects free access to both settings and measuring where they spent more time. Comparisons were made between morphine and saline; PCP and saline; and one of several doses of morphine and a standard dose. Morphine was preferred over saline and, when compared to the reference dose, lower doses of morphine were less preferred and higher doses more preferred. PCP was never preferred over saline and under some conditions produced a conditioned place aversion. The ability to generate dose dependent effects with morphine should allow more sophisticated studies in which shifts in dose response curves are required.

The orienting response in schizophrenia: proposed resolution of a controversy.

The habituation of the skin conductance orienting response ( SCOR ) was studied in 36 schizophrenic and 11 normal male subjects. Scoring criteria significantly influenced results: more inclusive criteria (used in most SCOR studies) scored 56% of patients as nonresponders and 19% as slow habituators . More restrictive criteria scored 75% of patients as nonresponders, and the remainder as faster habituators than normals. The faster habituation of patient responders could be explained by the effects of low response amplitude. Evidence is given for the greater validity of the restrictive scoring criteria; on this basis the schizophrenic patients in this study were SCOR nonresponders or fast habituators . The data suggest that the more inclusive scoring criteria can confuse spontaneous and orienting activity. Clinical and theoretical implications are discussed.

Classical conditioning, decay and extinction of cocaine-induced hyperactivity and stereotypy.

Following 10 daily pairings of multiple conditioned stimuli with injection of cocaine (15 mg/kg), the presentation of the stimuli alone elicited behaviors in rats similar to those induced by cocaine. The behaviors included increased duration or frequency of rearing, sniffing, head bobbing, and horizontal locomotor activity (crossing). The level of the conditioned response for several of these behaviors approximated that induced by the drug itself. The conditioned drug effect showed decay over 15 days but little extinction during 4 daily trials. Brain concentrations of the dopamine metabolites, homovanillic acid and dihydroxyphenylacetic acid, were similar in the conditioned and pseudoconditioned control groups in both the caudate and mesolimbic areas. The behavioral results demonstrate that, in a classical conditioning paradigm, previously neutral stimuli can elicit behaviors similar to those induced by cocaine and that certain conditioned responses show time related decline. This agrees with the reported conditioning of amphetamine's behavioral effects but differs in terms of the action on brain dopamine turnover.

Infants' cross-modal transfer from solid objects to their graphic representations.

12-month-old infants were familiarized either tactually or visually with objects and then tested for visual recognition memory using either (1) the familiar and a novel object, (2) colored pictures of the objects, or (3) outline drawings of them. In Study 1, infants showed recognition memory on all 3 visual intramodal problems but showed cross-modal transfer only when objects were used as test stimuli. With increased familiarization times in Study 2, transfer from tactually presented samples to both pictorial displays was achieved, indicating that after feeling an object the infants were able to recognize it visually solely on the basis of its contour. With reduced familiarization times in Study 3, there was no evidence for transfer from visually presented samples to the 2 pictorial displays, replicating the pattern of results observed cross-modally in Study 1 and suggesting that, at least in certain respects, cross-modal and intramodal perception follow similar principles.

Hormonal influences on seizure kindling: the effects of post-stimulation ACTH or cortisone injections.

Repeated application of brain stimulation can lead to a progressively augmenting electrical and behavioral response-- a phenomenon termed seizure kindling. In this experiment, stimulation was delivered once per day, and was followed by peripheral (intraperitoneal) administration of ACTH or cortisone. An intermediate or a high dose of either hormone (0.3 IU or 3.0 IU of ACTH/animal, 10 mg or 25 mg cortisone/animal) delayed the completion of kindling if administered shortly after each kindling stimulation. Lower doses (0.03 IU of ACTH or 2 mg of cortisone) had no significant effects. The high dose of ACTH or cortisone was no longer effective if administration was delayed more than 4 h after stimulation. Peripherally administered ACTH and cortisone can influence processes initiated by the brain stimulation which presumably underlie the augmentation of response to successive stimulations. This time-limited action is analogous to the effects of these hormones on memory consolidation.