Attention deficit disorder with hyperactivity and the dopamine hypothesis: case presentations with theoretical background.
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Attention Deficit Disorder with Hyperactivity↗
Biomedical subjects
M Goldstein
Publications and source records attributed to M Goldstein.
Abundance in the embryonic brainstem of adrenaline during the absence of detectable tyrosine hydroxylase activity.
The activities of the catecholamine synthetic enzymes tyrosine hydroxylase and phenylethanolamine N-methyltransferase, and the concentrations of the catecholamines and their respective metabolites, have been measured in the dorsal and ventral halves of the brainstem at various ages in the embryonic and adult rat. The activity of phenylethanolamine N-methyltransferase in both parts of the brainstem at day 14 of gestation is at or greater than adult levels and thereafter displays relatively small variations during ontogeny. Tyrosine hydroxylase activity, in contrast, is undetectable at day 14 and increases slowly, achieving only 20-25% of adult values by day 18 of gestation. Adrenaline concentrations correlate well with the activity of phenylethanolamine N-methyltransferase, showing a precocious development, whereas noradrenaline and 3,4-dihydroxyphenylethylamine (dopamine) concentrations are more closely related to the enhancement of tyrosine hydroxylase activity; at day 18 of gestation, for example, they are only 5 and 10%, respectively, of the adult values. The concentrations of the metabolites of noradrenaline and dopamine are suggestive of a high rate of turnover. These results confirm previous immunocytochemical evidence of a tardy appearance of tyrosine hydroxylase-like immunoreactivity in the phenylethanolamine N-methyltransferase-positive perikarya of the embryonic medulla oblongata. In addition, the abundance of adrenaline in this area at early gestational stages strongly suggests that, despite the paucity of tyrosine hydroxylase, phenylethanolamine N-methyltransferase is active in vivo and is utilizing a substrate other than noradrenaline. It is likely, however, that at later stages of gestation, when tyrosine hydroxylase is present at sufficient activity to supply noradrenaline, the conventional synthetic pathway for adrenaline formation comes into being.
3,4-Dihydroxyphenylacetic Acid↗
Expressed emotion and relapse in first episodes of schizophrenia. A rejoinder to Macmillan et al (1986).
Re-analyses of data presented by Macmillan et al (1986b) challenge their conclusions that high expressed emotion is not prognostically significant for the course of schizophrenia or unrelated to the level of behavioural disturbance prior to admission. Several equally plausible models of causal relationships between EE and duration of untreated illness are presented. We conclude that our re-analyses of the Macmillan data do not warrant premature closure regarding the significance of the EE variable.
Antipsychotic Agents↗
Neurology residency training programs in the United States.
A survey of 127 neurology residency training programs (124 approved by the Accreditation Council for Graduate Medical Education; 3 by the American Osteopathic Association) in the United States indicated that 80% were sponsored by medical schools. Of the 2,700 MD neurology faculty in 1982, 3/5 were full-time. As of 1982, there were 1,300 neurology trainees, including 334 fourth-year postgraduates (PG4s); 21% were women, and 3% held DO degrees. From 1960 through 1983, about 5,000 PG4s were produced, and for 1984 through 1990 the program directors estimated that this number will be about 3,000; our own projection, however, was only 2,400.
Humans↗
Advanced Parkinson's disease: use of partial dopamine agonist, ciladopa.
Ciladopa is a partial dopamine agonist that is effective in patients with advanced Parkinson's disease who are no longer satisfactorily responding to levodopa. Thirty-one patients participated in a double-blind randomized study of ciladopa (added to levodopa) versus placebo. Among 21 patients randomized to treatment with ciladopa and levodopa, there was a 32% decrease in symptoms on the Modified Columbia University Disability Scale. This change was significant, p less than or equal to 0.05. Eight of the 21 patients (38%) improved by at least 50%. The mean number of hours "on" increased by 20%. This change was significant, p less than or equal to 0.05. Five of the 21 patients (24%) were on for at least 4 hours more than at baseline. Dyskinesias were not increased. The mean dose of ciladopa was 19.5 mg/d. The mean dose of levodopa in Sinemet was decreased by 10%. Studies with ciladopa in humans had to be discontinued because of the occurrence of microscopic testicular tumors in some rodents. Although improvement in patients taking ciladopa was modest, there were few adverse effects. These results are encouraging, because two other partial agonists are now available, and they may be as effective as ciladopa.
Aged↗
Phenylethanolamine N-methyltransferase-like immunoreactivity in psoriasis. An immunohistochemical study on catecholamine synthesizing enzymes and neuropeptides of the skin.
Immunoreactivity for phenylethanolamine N-methyltransferase (PNMT), the enzyme involved in the conversion of norepinephrine to epinephrine, was present in the basal epidermis and upper dermis in 16 patients with psoriasis. The amount of immunoreactivity was increased tenfold in involved compared to uninvolved skin as characterized by computer-assisted image analysis. In skin from healthy volunteers no immunoreactivity could be found. In our subjects, no immunoreactivity was observed for the other catecholamine synthesizing enzymes (tyrosine hydroxylase; dopa-decarboxylase; dopamine-beta-hydroxylase), apart from single tyrosine hydroxylase positive adrenergic vascular nerves. Furthermore, in psoriasis, the immunoreactivity pattern of the peptides somatostatin, substance P, vasoactive intestinal polypeptide and bombesin was in agreement with skin from healthy volunteers.
Adult↗
The distribution of tyrosine hydroxylase-immunoreactive fibers in primate neocortex is widespread but regionally specific.
An antiserum directed against tyrosine hydroxylase (TH), an enzyme involved in dopamine and norepinephrine synthesis, was used to visualize axons immunohistochemically in monkey neocortex. Labeled fibers were distributed throughout the entire neocortex, but they had striking patterns of regional and laminar specialization. For example, primary motor cortex contained the greatest density of TH-labeled fibers, whereas primary sensory regions were sparsely innervated. Marked heterogeneity of fiber density was also present among the association regions of the frontal, parietal, and temporal lobes. In addition, the laminar pattern of innervation in a given region was correlated with its fiber density. Sparsely innervated regions had labeled fibers only in layer I and sometimes layer VI. In regions of intermediate density, labeled fibers tended to be located in layers I-superficial III and layers V-VI, whereas in densely innervated motor cortex TH-immunoreactive fibers were present in all cortical layers. Comparison of these distribution patterns with those produced by an antiserum directed against dopamine-beta-hydroxylase (DBH), a specific marker of neocortical noradrenergic axons, revealed marked differences. DBH-immunoreactive fibers were observed in some cortical locations where few or no TH-labeled fibers were present. In other regions, the density of TH-immunoreactive processes far exceeded that of DBH-labeled fibers. These findings indicate that nearly all of the immunoreactive fibers revealed by this anti-TH antiserum are dopaminergic. This interpretation was further supported by lesions of the ascending noradrenergic fibers in the brain stem, which reduced DBH immunoreactivity, but not TH immunoreactivity, in neocortex. The distinctive innervation patterns of TH-immunoreactive fibers suggest a functional specialization of the dopaminergic projections to primate neocortex.
Animals↗
Relationship between receptor occupancy and response at striatal dopamine autoreceptors.
The irreversible dopamine (DA) receptor antagonist N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was used to determine the extent of receptor reserve at DA autoreceptors regulating in vivo tyrosine hydroxylase activity. Rats were treated with vehicle or EEDQ (1 X 0.5-2 X 6 mg/kg, subcutaneously) and, 24 hr later, dose response curves were generated for DA agonist reversal of gamma-butyrolactone-induced striatal L-3,4-dihydroxyphenylalanine (L-DOPA) accumulation. Double reciprocal plots were obtained of equieffective doses of agonist required to elicit response at several levels of effect before and after partial irreversible receptor inactivation. A pseudo-dissociation constant (pseudo-KA, in units of dose) and the fraction of receptors remaining active (q) were determined; these values were then used to calculate the relationship between receptor occupancy and response. The ED50 (1 microgram/kg) for the full DA receptor agonist N-propylnorapomorphine (NPA) was shifted 2.8, 4.8-, and 11.3-fold to the right after partial irreversible receptor blockade which left the fraction of receptors remaining active (q) at 0.37, 0.17 and 0.058, respectively. Corresponding maximal reversal of L-DOPA accumulation was 100, 77, and 58%, indicating a nonlinear relationship between receptor occupancy and response for NPA and the presence of a large receptor reserve; maximal and half-maximal responses were calculated to require occupancy of 30 and 3.8% of the total receptor pool, respectively. Dose response curves were also obtained for the DA autoreceptor-selective agents EMD 23,448 and (+)- and (-)-3-PPP before and after EEDQ treatment. In controls, EMD 23,448 and (+)-3-PPP, like NPA, completely reversed striatal gamma-butyrolactone-induced L-DOPA accumulation, whereas the maximal effect of (-)-3-PPP was 52% reversal. After EEDQ treatment (6 mg/kg), EMD 23,448 and (+)-3-PPP showed relatively small shifts in ED50 values. Furchgott analysis demonstrated that all three atypical agents are partial agonists at the DA autoreceptor with efficacies of 0.19 (EMD 23,448), 0.12 [(+)-3-PPP], and 0.05 [(-)-3-PPP] relative to NPA. The presence of a larger receptor reserve at pre-versus postsynaptic D2 DA receptors and the partial agonist character of drugs such as EMD 23,448 and the enantiomers of 3-PPP may account for their autoreceptor selectivity.
4-Butyrolactone↗
Development of a dopamine- and cyclic adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP-32) in the prenatal rat central nervous system, and its relationship to the arrival of presumptive dopaminergic innervation.
The development of a dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein with an apparent Mr of 32,000 (DARPP-32) has been investigated in the central nervous system of the prenatal and newborn rat by immunocytochemical methods. DARPP-32 first appears in the rat brain at day 14 of gestation, in the anlage of the primary olfactory cortex and the caudate nucleus. Over the next few days, the number of immunoreactive cell bodies in these 2 areas, and in the olfactory tubercle and frontal cortex, increases rapidly. By the day of birth, most of the brain regions that will ultimately contain DARPP-32-positive somata already display a disposition toward DARPP-32-like immunoreactivity similar to that observed in the adult animal. In addition to the nuclei mentioned above, DARPP-32-containing cell bodies also appear over the intervening period in the olfactory nucleus, nucleus accumbens, central amygdaloid nucleus, lateral funiculus, and the choroid plexus and ependymal layers of the third, fourth, and lateral ventricles and the Sylvian aqueduct. Many of these immunoreactive cells disappear during subsequent postnatal maturation. DARPP-32-immunoreactive fibers were also observed in the prenatal and newborn rat CNS. As in the adult, the processes were observed in known target areas of the DARPP-32-containing neurons, namely, the globus pallidus, ventral pallidum, internal capsule, and substantia nigra. The ontogeny of tyrosine hydroxylase (TH)-like immunoreactivity was analyzed simultaneously. Of particular interest was the observation that the arrival within a given brain region of the presumed dopaminergic, TH-containing innervation, part of whose postsynaptic function is putatively mediated by DARPP-32, was preceded by at least 2 d by the appearance of the DARPP-32-containing cells. Moreover, the subsequent reorganization of the DARPP-32-positive somata within the caudate nucleus into distinct clumps also predated by 1 or 2 d the aggregation of the TH fibers into the same microzones. The development of DARPP-32-like immunoreactivity is mostly complete by the day of birth, and is consistent with its playing a role in mediating some of the postsynaptic actions of dopamine pathways. The appearance of this protein does not seem to be dependent on the presence of a dopaminergic innervation.
Animals↗
Receptor reserve at the alpha-2 adrenergic receptor in the rat cerebral cortex.
N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an irreversible alpha-2 antagonist, was used to establish and quantitate the receptor reserve at the alpha-2 adrenergic autoreceptor mediating inhibition of [3H]norepinephrine ([3H]NE) release in rat cerebral cortical slices. EEDQ treatment had no effect on [3H]NE uptake or base-line release. Four hours after EEDQ treatment (0.8 mg/kg i.p.), the EC50 was shifted 7-fold to the right and there was a 21.5% decrease in the maximal response to the full alpha-2 agonist UK-14304. Using the double-reciprocal plot analysis, the equilibrium activation constant (KA) was calculated to be 1.41 +/- 0.8 microM. Similar analysis of alpha-2 autoreceptor response at various times after 1.6 mg/kg of EEDQ gave similar values for the KA. Therefore, evaluation of either the response of the remaining native receptors after partial irreversible inactivation or the response of newly synthesized receptors after nearly complete irreversible inactivation can be used to determine the KA of the receptor. Comparison of repopulation kinetics analyses for alpha-2 receptor response and estimated receptor number revealed that recovery of maximal response was much faster than actual receptor recovery. By examining the relationship between alpha-2 autoreceptor occupancy and response it was possible to determine that there is approximately a 60 to 70% receptor reserve; only 1.5% of the receptors need to be occupied by UK-14304 in order to obtain 50% of the maximal inhibition of [3H]NE release. The presence of a large receptor reserve must be taken into account when evaluating alpha-2 adrenergic autoreceptor regulation in the rat cerebral cortex.
Animals↗
New areas of research in male infertility.
Recent research in male reproduction holds much promise for future clinical application. Research on the relationship between sperm, semen, and the immune system may provide novel approaches to treating immune-related infertility. Investigations of sperm motility have shed new light on these complex mechanisms and may lead to rational approaches to the improvement of sperm function. New assays for secretory products unique to the testis show potential as markers for specific testicular cellular functions. In-vitro fertilization promises to become a viable treatment option for couples with male-factor infertility. Research on male contraception may lead to the development of safe and reversible male contraceptives.
Adrenal Cortex Hormones↗
[High-dose short time fibrinolytic treatment with streptokinase of massive lung embolism in the early postoperative period].
The treatment of a massive or fulminant pulmonary embolism (PE) occurring in the early postoperative phase by embolectomy or fibrinolysis with streptokinase (SK) or urokinase (UK) differs with regard to success and mortality. Embolectomy has a higher mortality and is not practicable in every hospital. Fibrinolysis differs according to substance (SK or UK), dosage, and duration. Five days after extirpation of a leiomyosarcoma--located retroperitoneally in the pelvis--a 72-year-old woman had a massive PE (scintigraphy diagnosis) (Fig. 1). On PEEP-breathing, nitroglycerin (66 micrograms/min), and dobutamin (416 micrograms/min), paO2 and SaO2 showed an increasing tendency, but 4 days after the diagnosis of PE--on the 8th postoperative day--paO2 and SaO2 dropped again (Fig. 3). Fibrinolysis was undertaken with 1.5 million units of SK over a period of 40 min through a Swan-Ganz catheter located in the pulmonary artery. A few hours after the fibrinolytic treatment, paO2 increased at a significant rate and FIO2 could be markedly reduced from 0.7 to 0.4. Twenty-four hours after SK lysis the pulmonary artery pressure (PAP) had still not decreased, but the cardiac output (CO) showed an increasing tendency. The scintigraphic control 17 days after the diagnosis of PE (Fig. 2) correlated with the clinical parameters. The patient was discharged. High-dose ultra-short fibrinolysis with SK in the early postoperative period is discussed in connection with efficiency and bleeding complications ("plasmin-lysis" versus "activator-lysis").
Aged↗
A clinical evaluation of an oxygen insufflation/suction catheter.
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Adolescent↗
An outbreak of fume fever in an electronics instrument testing laboratory.
An apparent outbreak of fume fever was identified among six workers in an electronics instrument testing laboratory during a routine thermal evaluation of conductivity on electrical cable. The employees experienced characteristic symptoms of fume fever. Three employees required hospitalization; they demonstrated fever, leukocytosis with a left shift, and significant arterial-alveolar oxygen gradients, all of which resolved over several hours. To prevent future occurrences, an attempt was made to delineate the etiologic agent by exactly reproducing the circumstances of the event and analyzing for the evolution of metal fumes or pyrolysis products of polymers. The pertinent findings included overall poor ventilation in the laboratory and the development of significant chloride air contamination during the test. This latter finding raises the possibility that a chloropolymer contaminant was the etiologic agent.
Electronics↗
1-Methyl-4-phenylpyridinium (MPP+) but not 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively destroys dopaminergic neurons in cultures of dissociated rat mesencephalic neurons.
Dopaminergic neurons were studied in cultures of dissociated cells from the ventral mesencephalon of fetal rat embryos (gestational day E15-16). After a week of growth, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) was added to the growth medium for 24 h. Dopaminergic neurons were then visualized with tyrosine hydroxylase (TH) immunocytochemistry or catecholamine (CA) cytofluorescence. Concentrations of MPTP in the range of 10 to 100 microM obliterated CA fluorescence without affecting the number of TH-positive neurons. At concentrations greater than 100 microM, MPTP decreased the number of TH-positive neurons as well as the number of all other cell types. MPP+ (0.1-10.0 microM) produced a decrease in the number of TH-positive neurons without decreasing the total number of all cell types. The findings indicate that MPP+ but not MPTP is able to selectively destroy rat dopaminergic neurons in our cultures. The selective toxicity of MPP+ for dopaminergic neurons was partially prevented by pretreatment and co-incubation with mazindol (a selective inhibitor of dopamine uptake) but not by desipramine or deprenil, in confirmation of the notion that MPP+ enters dopaminergic neurons by the specific uptake mechanism for dopamine.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
The ascending projections of the dopaminergic neurons of the substantia nigra, zona reticulata: a combined retrograde tracer-immunohistochemical study.
The efferent projections of the dopaminergic neurons in the zona reticulata of the substantia nigra were examined using a combined retrograde tracer-immunohistochemical method. These dopamine (DA) neurons were found to project exclusively to striatal targets in a topographically defined fashion. The zona reticulata DA neurons do not innervate mesolimbic or mesocortical dopaminergic terminal fields, nor do they project to the superior colliculus or the ventromedial thalamic nucleus. These data suggest that the dopaminergic neurons of the zona reticulata represent a ventrally placed subset of the nigrostriatal DA cells of the pars compacta.
Animals↗
Human fetal substantia nigra grafted to the dopamine-denervated striatum of immunosuppressed rats: evidence for functional reinnervation.
Human fetal substantia nigra tissue, obtained following therapeutic termination of first trimester pregnancies, was grafted to cavities overlying the striatum in ciclosporin-treated rats whose nigrostriatal dopamine system had been removed unilaterally by 6-hydroxydopamine. Tyrosine hydroxylase (TH) immunocytochemistry revealed large numbers of surviving human substantia nigra neurons that matured and formed TH-positive nerve fibers reinnervating the host rat striatum. Apomorphine-induced rotational behavior in grafted animals was reduced by 70-80% in optimal cases 3-5 months after grafting. Thus human fetal dopamine neurons can correct functional deficits in dopamine-denervated rat hosts.
Animals↗
Uptake inhibition protects nigro-striatal dopamine neurons from the neurotoxicity of 1-methyl-4-phenylpyridine (MPP+) in mice.
Intracerebroventricular administration of MPP+ to C57 BL/6 mice caused a pronounced depletion of striatal levels of dopamine and 3,4-dihydroxyphenyl-acetic acid ipsilaterally, and a less marked depletion contralaterally. The MPP+-induced reductions were clearly diminished by pretreatment with the dopamine uptake inhibitors mazindol and nomifensine. Similar results were obtained from determinations using tyrosine hydroxylase immunohistochemistry. These results are consistent with the hypothesis that MPTP neurotoxicity is related to the formation of MPP+ from MPTP outside the dopamine neurons and that subsequent uptake of MPP+ into these neurons initiates degeneration.
1-Methyl-4-phenylpyridinium↗