Catecholamines in patients with 22q11.2 deletion syndrome and the low-activity COMT polymorphism.

OBJECTIVE: To investigate catecholamine phenotypes and the effects of a tyrosine hydroxylase inhibitor in individuals with the 22q11.2 deletion syndrome and low-activity catechol-O-methyltransferase (COMT). BACKGROUND: Many persons with the 22q11.2 deletion syndrome suffer severe disability from a characteristic ultrarapid-cycling bipolar disorder and associated "affective storms." One etiologic hypothesis for this condition is that deletion of the COMT gene from one chromosome 22 results in increased catecholamine neurotransmission, particularly if the undeleted chromosome 22 encodes a variant of COMT with low activity. METHODS: In a preliminary study, plasma, urine, and CSF catecholamines and catecholamine metabolites were measured in four teenage patients with a neuropsychiatric condition associated with 22q11.2 deletion and the low-activity COMT polymorphism on the nondeleted chromosome. In these four patients, and an additional institutionalized adult with the condition, an uncontrolled, open-label trial of metyrosine was administered in an attempt to lower catecholamine production and to alleviate symptoms. RESULTS: Mild elevations of baseline CSF homovanillic acid (HVA) were found in three of four patients and a moderate reduction in CSF HVA after metyrosine treatment in the patient with the highest pretreatment concentration. The course of the five patients during the clinical trial is described. CONCLUSIONS: In patients with the 22q11.2 deletion syndrome and low-activity COMT, controlled studies of pharmacologic agents that decrease catecholamine production, block presynaptic catecholamine storage, or enhance S-adenosylmethionine, the cosubstrate of COMT, are warranted.

Ontogeny of ionotropic glutamate receptor expression in human fetal brain.

Glutamate receptors have multiple roles in the central nervous system. Recent evidence suggests that the iontropic glutamate receptors are critical during brain development, particularly for corticogenesis, neuronal migration, and synaptogenesis. In this study, we examined subunit mRNA expression and binding sites of the NMDA, AMPA, and kainate receptors from gestational weeks 8-20 in human fetal brain. Expression of glutamate receptors was high during several periods in these brains. Different levels of expression of each NMDA, AMPA, and kainate receptor subunit transcripts were present during development, with a greater abundance of NR1, NR2B, NR2D, GluR7, and KA1 mRNA at most gestational ages. Binding sites for NMDA, AMPA, and kainate receptors were all detected, but each had a unique pattern of expression. These results demonstrate that glutamate receptors are expressed early in human brain development, and undergo complex changes over time consistent with their role in normal development.

A mortality index for postmarketing surveillance of new medications.

The rate of introduction of new pharmaceuticals is growing as a result of advances in molecular pharmacology and targeted drug development. The Fatal Toxicity Index (FTI) has been proposed as a means for monitoring drug toxicity through post-marketing surveillance. The FTI requires data regarding the general availability of a particular agent in the community which, in the US, is proprietary. The authors propose a Mortality Index as an alternative method for calculating relative lethality that does not rely on proprietary information for postmarketing surveillance. Using data from the Toxic Exposure Surveillance System (TESS) a Mortality Index was calculated from the proportion of deaths occurring among all patients who present to a health care facility with an overdose on the same agent or class of agents. The average Mortality Index for various drugs or drug classes for the years 1989 to 1997 is reported. Because the Mortality Index for desipramine appeared much greater than that for the other tricyclics, a chi-squared analysis was performed. The authors conclude, based on this analysis, that desipramine is significantly more likely to lead to death after overdosage than any other tricyclic antidepressant in the study. Also, the Mortality Index appeared to identify the impact of pediatric formulations on overdose lethality. We conclude that the Mortality Index may be a useful tool for determining the safety of agents during the postmarketing surveillance phase.

Mental illness in adults with fetal alcohol syndrome or fetal alcohol effects.

OBJECTIVE: The authors' goal was to use structured clinical interviews to characterize the type and frequency of mental illness in adults with fetal alcohol syndrome or fetal alcohol effects. METHOD: Twenty-five subjects who met criteria for fetal alcohol syndrome or fetal alcohol effects, who were older than 18 years old, and who had an IQ of greater than 70 were interviewed with the Structured Clinical Interview for DSM-IV Axis I Disorders and the Structured Clinical Interview for DSM-III-R Personality Disorders. RESULTS: Eighteen of the 25 subjects had received psychiatric treatment. The most common axis I disorders were alcohol or drug dependence (15 subjects), depression (11 subjects), and psychotic disorders (10 subjects). The most common axis II disorders were avoidant (six subjects), antisocial (four subjects), and dependent (three subjects) personality disorders. CONCLUSIONS: This study suggests that adults with fetal alcohol syndrome or fetal alcohol effects suffer from substantial mental illness.

Ontogeny of human brain dopamine receptors. I. Differential expression of [3H]-SCH23390 and [3H]-YM09151-2 specific binding.

Dopamine receptor expression in human fetal forebrain (between 6 and 20 weeks of gestation) was measured using tissue-slice receptor autoradiography with the D1-like and D2-like antagonists [3H]-SCH23390 and [3H]-YM09151-2, respectively. Tissue sections were assayed in saturation studies and examined for age- and sex-related changes in Bmax. We made the following observations: (1) the ages at which D1- and D2-like receptors were first expressed in whole forebrain sections could be reliably identified but were not significantly different from one another (gestational age 65 days for D1- vs. 72 days for D2-like receptors); (2) age-related increases in both D1- and D2-like receptors were demonstrated in forebrain and, from the middle of the first to the middle of the second trimester, the Bmax for each ligand increased by an order of magnitude after the onset of the specific binding site's expression; (3) age-related increases in D1-like receptors, but not D2-like receptors, could be demonstrated in cortex; and, (4) in one case of trisomy 18, the Bmax for [3H]-SCH23390 was significantly elevated above the 95% confidence interval when compared to an age-regressed normal sample. Although D2-like receptor density significantly increased with age in forebrain, age-regressed changes in D2-like receptor expression in cortex and striatum did not reach statistical significance. Likewise, a comparison of the mean Bmax's by sex for both ligands in midgestational striatum failed to reach significance. These data corroborate the findings of other investigators who have delineated the ontogeny of dopaminergic systems in other animal species. The regional differences in the expression of dopamine receptor families may be relevant to the role which dopamine may play during normal gestational brain development. Moreover, significant deviations in dopamine receptor expression during gestation (as seen in this one case of trisomy 18) may signify underlying pathological processes that ultimately are manifested by abnormal psychological development and/or cognitive functioning.

The teratogenicity of N(omega)-nitro-L-ariginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, in rats.

Exposure of gravid rats to the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) in drinking water or by implanted osmotic minipumps significantly elevates maternal blood pressure, reducing uteroplacental perfusion. Administration by either route causes fetal growth retardation, but oral exposure also causes hind limb reduction malformations. The present study employed both oral and intraperitoneal routes to determine the period of sensitivity to developmental toxicity, dose-response, and possible fetotoxic mechanisms. Hind limb hemorrhage occurred only in litters from dams exposed to oral doses of 1 to 2 mg/mL from gestational days 15 through 17. In contrast to oral exposure, single intraperitoneal injections caused both fore and hind limb reductions at doses of 25 mg/kg and above administered on gestational day 16 and later. Many other exposures that reduce uteroplacental perfusion have been associated with vascular disruptive dysmorphogenesis. These exposures include phenytoin, calcium channel inhibitors, cocaine, and uterine vascular clamping. Limb hemorrhage induced by these exposures is usually limited to distal structures, typically phalanges, and the incidence of affected fetuses rarely exceeds 50%. By contrast, hemorrhage caused by L-NAME frequently involves entire limbs, extending into adjacent flank in severe instances, and 100% of fetuses from treated dams may be affected. The basis of this difference and the differing defect patterns associated with the various routes of exposure are unclear, but the generation of reactive oxygen species during resumption of normal perfusion may play a role in this vascular disruption.

Platelet serotonin measures in adolescents with conduct disorder.

Dysregulation of serotonergic function has been associated with aggression in several studies involving children, adolescents, and adults. This study investigated the relationship of platelet serotonergic measures to conduct disorder type, severity of aggression, and social skills impairment. Standardized assessments of diagnosis, aggression, impulsivity, and social skills were obtained from 43 male adolescents (ages 13-17) incarcerated at an involuntary residential treatment facility for juvenile offenders. Blood samples were collected and assayed for whole blood serotonin (5-HT) and platelet [3H]-paroxetine-labeled 5-HT-transporter binding. Whole blood 5-HT was higher in adolescents with conduct disorder, childhood type than in subjects with conduct disorder, adolescent type. Whole blood 5-HT was positively correlated with violence rating of the current offense and total offense points, and staff ratings of social skills impairment. Our findings are consistent with a relationship between 5-HT dysregulation and aggressive behavior in incarcerated adolescent boys with conduct disorder, particularly of childhood onset.

Attention deficit hyperactivity disorder and whole-blood serotonin levels: effects of comorbidity.

Whole-blood serotonin (5-hydroxytryptamine, 5-HT) levels were measured in children with attention deficit hyperactivity disorder (ADHD) with and without comorbid conduct disorder (CD) or oppositional-defiant disorder (ODD). It was hypothesized that the whole-blood 5-HT levels of ADHD probands would be significantly correlated with the whole-blood 5-HT levels of their mothers. Fifty-two children who met DSM-III-R criteria for ADHD were selected consecutively from an ADHD clinic (47 males--35 Caucasians, 10 African-Americans, and 2 Hispanics; 10 females--all Caucasians). Whole-blood 5-HT was assayed by high performance liquid chromatography and compared between ADHD children with and without comorbid CD or ODD. The familiality of whole-blood 5-HT levels was studied by Spearman's rank-order correlation. There were no significant age, race, or sex effects. There was no significant difference in whole-blood 5-HT levels between children with ADHD only (n = 22; 190 +/- 45 ng/ml) and ADHD with CD or ODD (n = 30; 212 +/- 67). However, 7 out of 30 (23%) children with ADHD+CD/ODD had whole-blood 5-HT levels > 270 ng/ml, while none of the ADHD-only children had whole-blood 5-HT levels > 270 ng/ml, a statistically significant difference. Whole-blood 5-HT levels showed significant positive correlations between 36 children with disruptive behavior disorders and their biological mothers (rs = 0.47). There was no difference in mean levels of whole-blood 5-HT between subgroups of children with ADHD with or without comorbid CD or ODD.(ABSTRACT TRUNCATED AT 250 WORDS)

Ontogeny of [3H]-SCH23390 and [3H]-YM09151-2 binding sites in human fetal forebrain.

In order to determine the gestational age at which binding sites for the dopamine "D1-like" and "D2-like" receptor antagonists, [3H]-SCH23390 and [3H]-YM09151-2, respectively, can be reliably detected in the human and to identify any discrete anatomic distribution of these binding sites, fetal forebrain tissue sections from mid-first (n = 4) and mid-second (n = 4) trimester gestations were used for receptor autoradiography. Specific binding for both ligands was detectable at the earliest fetal age examined (gestational week 6). Age-related increases in maximum saturation binding were demonstrated for both ligands using tissue sections from basal forebrain. The Bmax for both [3H]-SCH23390 and [3H]-YM09151-2 binding increased ten-fold comparing gestational week 6 and gestational week 18 values. In the cortex at gestational day 120, [3H]-YM09151-2 specific binding could be seen at the gray-white matter boundary, which was more prominent by gestational day 140. In contrast, [3H]-SCH23390 specific binding to the cortex at gestational day 120 did not appear to differentiate specific areas and did not increase between gestational days 120 and 140. These preliminary observations in human fetal brain provide evidence that dopamine "D2-like" binding sites can be localized in a discrete cortical area in the course of normal human brain development. Characterizing these binding sites and the population of cells that demonstrates these binding sites may be relevant to neurodevelopmental hypotheses of psychiatric disorders.

Concentration and distribution of [3H]-SCH23390 and [3H]-YM09151-2 binding sites in midgestational human fetal cortex.

Binding sites for the dopamine receptor antagonists [3H]-SCH23390 and [3H]-YM09151-2 have been demonstrated in human fetal forebrain at the sixth gestational week and appear to increase in concentration in an age-related fashion throughout the first trimester. Using the techniques of receptor autoradiography with midsecond trimester human fetal cortex (gestational weeks 17 and 20), the distribution and concentration of binding sites for these radiolabeled ligands were compared. Saturable [3H]-SCH23390 specific binding was demonstrated in the cortical plate of the tissue obtained at gestational week 17 (KD = 0.16 nM, BMAX = 0.005 fmol/mm2). Although saturable binding for [3H]-SCH23390 could be demonstrated in the cortical plate at gestational week 20 (KD = 2.35 nM, BMAX = 0.008 fmol/mm2), image subtraction revealed specific binding in the intermediate zone as well. Saturable [3H]-YM09151-2 specific binding was likewise demonstrated in the cortical plate at gestational week 17 (KD = 0.36 nM, BMAX = 0.044 fmol/mm2). At gestational week 20, specific and saturable [3H]-YM09151-2 binding appeared to be stratified in the subplate zone, between the cortical plate and the intermediate zone (KD = 2.02 nM, BMAX = 0.076 fmol/mm2). These data suggest that specific, saturable binding for dopamine receptor antagonists can be demonstrated in human cortex by the completion of corticogenesis and at the earliest stages of cortical differentiation. The cells that express these binding sites may play a role in developing forebrain dopaminergic neuronal systems, the disturbance of which may be relevant to adult psychopathology.

Somatic and behavioral ontogeny in three rat strains: preliminary observations of dopamine-mediated behaviors and brain D-1 receptors.

1. The acquisition of developmental milestones and maturational motor reflexes were compared in three rat strains (culled to 8 pups/litter), F344, Buff and SD. 2. Open field behavior on postnatal day 21 was scored for locomotor activity, rears and center entries. 3. F344 rats, which model ADHD, were the slowest of the three strains in acquiring a number of developmental milestones and in gaining weight; but they were intermediate in their scores for locomotor activity and rearing during open field testing at postnatal day 21. 4. Preliminary autoradiographic data using the D-1 specific ligand [3H]SCH 23390 are included which suggest that D-1 receptors, which display age-dependent changes in concentration and distribution, are relevant to day 21 open field behavior. 5. F344 rats demonstrate developmental "dysmaturation" which is consistent with that observed in children with ADHD in that somatic growth is disproportionately delayed in comparison to neurological and motor maturation.

Brain receptor autoradiography with [3H]-YM 09151-2: a ligand for labeling dopamine D-2 receptors.

Using the technique of in vitro receptor autoradiography to slide-mounted tissue sections, we studied the suitability of [3H]-YM-09151-2 as a ligand for labeling D-2 receptors in adult F344 rat brains. Specific [3H]-YM-09151-2 binding accounted for 70-80% of the total bound ligand and reached equilibrium after a 60-90 minute incubation. Scatchard analysis revealed a Kd of 626 pM. The apparent Bmax was 23.2 fmol/tissue section. Autoradiographs demonstrated high grain densities in the striatum and olfactory tubercle. Diffuse specific binding was also observed in the cortex.

Comparison of the density and distribution of brain D-1 and D-2 dopamine receptors in Buffalo vs. Fischer 344 rats.

In vitro autoradiography was used to compare the D-1 and D-2 receptor densities in brains from Buffalo (BUFF) and Fischer 344 (F344) rats. The latter strain has been proposed as a model for human attention deficit disorder with hyperactivity (ADDH). The radioligands [3H]-SCH 23390 and [3H]-sulpiride were used to selectively identify dopamine D-1 and D-2 receptors, respectively. Certain forebrain structures from F344 rats have a higher density of D-2 receptors, but similar numbers of D-1 receptors compared to BUFF rats. Scatchard analysis of D-2 binding (in caudate-putamen) revealed a Bmax of 10.52 +/- 1.62 fmol/mg tissue and Kd of 12.72 +/- 0.93 nM in F344 rats and 3.00 +/- 0.57 and 3.87 +/- 0.58, respectively in BUFF rats (n = 3). These results support the hypothesis that high D-2 levels are correlated with certain behavioral traits, e.g., high levels of spontaneous activity. A similar increase in D-2 receptors may be responsible for some of the behavioral manifestations of ADDH in children.

Poor peer interactions and social isolation: a case report of successful in vivo social skills training on a child psychiatric inpatient unit.

The effects of social skills training comprising didactic instructions, coaching, modeling, feedback and reinforcement were examined in a child diagnosed Conduct Disorder and Attention Deficit Disorder in whom social isolation and poor peer interactions were prominent features. Treatment was implemented in the specific settings in which deficient social performance was noted using a multiple baseline design. Application of social skills training led to increased rates of appropriate interactions with peers and decreased rates of playing alone. In addition, pre- and posttreatment scores on the Child Behavior Checklist and School Behavior Checklist showed significantly decreased dysfunctional behaviors after training. Follow-up contact 1 and 12 months following discharge indicated that the child continued to socialize more with peers and to show improved adjustment.