Cytochrome P450 20A1 in zebrafish: Cloning, regulation and potential involvement in hyperactivity disorders.

Cytochrome P450 (CYP) enzymes for which there is no functional information are considered "orphan" CYPs. Previous studies showed that CYP20A1, an orphan, is expressed in human hippocampus and substantia nigra, and in zebrafish (Danio rerio) CYP20A1 maternal transcript occurs in eggs, suggesting involvement in brain and in early development. Moreover, hyperactivity is reported in humans with chromosome 2 microdeletions including CYP20A1. We examined CYP20A1 in zebrafish, including impacts of chemical exposure on expression. Zebrafish CYP20A1 cDNA was cloned, sequenced, and aligned with cloned human CYP20A1 and predicted vertebrate orthologs. CYP20A1s share a highly conserved N-terminal region and unusual sequences in the I-helix and the heme-binding CYP signature motifs. CYP20A1 mRNA expression was observed in adult zebrafish organs including the liver, heart, gonads, spleen and brain, as well as the eye and optic nerve. Putative binding sites in proximal promoter regions of CYP20A1s, and response of zebrafish CYP20A1 to selected nuclear and xenobiotic receptor agonists, point to up-regulation by agents involved in steroid hormone response, cholesterol and lipid metabolism. There also was a dose-dependent reduction of CYP20A1 expression in embryos exposed to environmentally relevant levels of methylmercury. Morpholino knockdown of CYP20A1 in developing zebrafish resulted in behavioral effects, including hyperactivity and a slowing of the optomotor response in larvae. The results suggest that altered expression of CYP20A1 might be part of a mechanism linking methylmercury exposure to neurobehavioral deficits. The expanded information on CYP20A1 brings us closer to "deorphanization", that is, identifying CYP20A1 functions and its roles in health and disease.

Exposure to enriched environments during adolescence prevents abnormal behaviours associated with histone deacetylation in phencyclidine-treated mice.

Enriched environments (EEs) during development have been shown to influence adult behaviour. Environmental conditions during childhood may contribute to the onset and/or pathology of schizophrenia; however, it remains unclear whether EE might prevent the development of schizophrenia. Herein, we investigated the effects of EE during adolescence on phencyclidine (PCP)-induced abnormal behaviour, a proposed schizophrenic endophenotype. Male ICR mice (3 wk old) were exposed to an EE for 4 wk and then treated with PCP for 2 wk. The EE potentiated the acute PCP treatment-induced hyperlocomotion in the locomotor test and prevented chronic PCP treatment-induced impairments of social behaviour and recognition memory in the social interaction and novel object recognition tests. It also prevented the PCP-induced decrease of acetylated Lys9 in histone H3-positive cells and increase of the histone deacetylase (HDAC)5 level in the prefrontal cortex. To investigate whether the histone modification during adolescence might be critical for the effect of EE, 3-wk-old mice were first treated with sodium butyrate (SB; an HDAC inhibitor) for 4 wk and then treated with PCP for 2 wk. Chronic SB treatment during adolescence mimicked the effects of EE, including potentiation of hyperlocomotion induced by acute PCP treatment and prevention of social and cognitive impairments, decrease of acetylated Lys9 in histone H3-positive cells and increase of the HDAC5 level in the prefrontal cortex associated with chronic PCP treatment. Our results suggest that EEs prevent PCP-induced abnormal behaviour associated with histone deacetylation. EEs during childhood might prove to be a novel strategy for prophylaxis against schizophrenia.

Learning deficits and agenesis of synapses and myelinated axons in phosphoinositide-3 kinase-deficient mice.

Although previous studies have reported a role for phosphoinositide-3 kinase (PI3K) in axonal definition and growth in vitro, it is not clear whether PI3K regulates axonal formation and synaptogenesis in vivo. The goal of the present study was to clarify the role of PI3K in behavioral functions and some underlying neuroanatomical structures. Immunohistochemistry, an electron-microscopic analysis and behavioral tests were carried out. Knockout mice lacking the p85alpha regulatory subunit of PI3K (p85alpha-/- mice) significantly showed learning deficits, restlessness and motivation deficit. Expression of phosphorylated Akt, which indirectly shows the activity of PI3K, was high in myelinated axons, especially in axonal bundles in the striatum of wild-type mice, but was significantly low in the striatum, cerebral cortex and the hippocampal CA3 of p85alpha-/- mice. The axonal marker protein level decreased mainly in the striatum and cerebral cortex of p85alpha-/- mice. In these two regions, myelinated axons are rich in the wild-type mice. However, the density of myelinated axons and myelin thickness were significantly low in the striatum and cerebral cortex of p85alpha-/- mice. Synaptic protein level was clearly decreased in the striatum, cerebral cortex, and hippocampus of p85alpha-/- mice when compared with wild mice. The present results suggest that PI3K plays a role in the generation and/or maintenance of synapses and myelinated axons in the brain and that deficiencies in PI3K activity result in abnormalities in several neuronal functions, including learning, restlessness and motivation.

Serum pseudocholinesterase in psychiatric patients.

Serum pseudocholinesterase activity was measured in 123 subjects: 16 agitated depressives, 12 retarded depressives, 7 acute schizophrenics, 14 residual schizophrenics, 16 healthy individuals, 45 surgical patients, and 13 first-degree relatives of 4 agitated depressive patients. The agitated depressive and acute schizophrenic patients had significantly higher pseudocholinesterase serum activity than their retarded inmates. As first-degree relatives of agitated depressive patients showed high levels similar to their ill relatives, a genetic component might play a crucial role. The level of pseudocholinesterase activity in serum of the surgical patients was significantly lower than that of all the psychiatric patients and the controls. The implications of this observation are still obscure.

Platelet tritiated imipramine binding and MAO activity in Alzheimer's disease patients with agitation and delusions.

Decreased platelet 3H-imipramine binding density and decreased monoamine oxidase (MAO) activity have been considered as biological characteristics of several neuropsychiatric disorders, and may be related to central serotonin defects. Since serotonin system defects occur in Alzheimer's disease (AD), and decreased brain 3H-imipramine binding density, and increased brain and platelet MAO activity are reported also, we studied platelet 3H-imipramine binding density (Bmax) and platelet MAO activity in AD outpatients without antecedent psychiatric disorder. AD subjects with significant symptomatic behavioral disorder, predominantly agitation and delusions, and AD subjects without symptomatic behaviors were compared with controls. Age, sex, mini-mental state examination score, and illness duration did not distinguish the two AD groups. The agitated/delusional group showed significantly lower Bmax values than uncomplicated AD subjects or controls. MAO activity was significantly increased among female AD subjects without symptomatic behaviors compared to those who were agitated or to controls. These results indicate that 3H-imipramine binding and MAO activity may distinguish AD subjects with agitation or delusions from those without symptomatic behaviors, and suggest the existence of a biologically based Alzheimer's behavioral subtype.

[Effect of L-DOPA on the function of the brain neuromediator systems]. / O vliianii L-DOFA na sostoianie neiromediatornykh sistem mozga.

L-DOPA effects on the activities of enzymes controlling the neurotransmitters utilization: monoamine oxidases (MAO) A and B and acetylcholinesterase (AChE) were demonstrated in synaptosomes and mitochondria of the cells in sensorimotor cortex and caudate nucleus. Sixty minutes after a single dose of L-DOPA the MAO and AChE activities were virtually unchanged in subfractions of both brain regions. After a prolonged (30 days) treatment (1000 mg/kg total dose) MAO B activity increased whereas the MAO B and AChE activities decreased only in cortical synaptosomes and mitochondria. The data suggest that under effect of L-DOPA a definite reciprocity arises in the neurotransmitter catabolic systems in a specific manner for each brain structure.

Salivary α-amylase and intended harsh caregiving in response to infant crying: evidence for physiological hyperreactivity.

This is the first study on adults' physiological reactivity to infant cry sounds and the association with intended harsh parenting using salivary α-amylase (sAA) as a novel and noninvasive marker of autonomic nervous system activity. The sample consisted of 184 adult twin pairs. In an experimental design, cry sounds were presented and adults' perception and their intended caregiving responses were measured. Saliva samples were collected after each cry sound. For the majority of the sample, a decrease in sAA across the cry paradigm was observed. However, adults who indicated that they would respond in a harsh way to the crying infant were significantly less likely to show a decrease in sAA. Consistent with previous studies on physiological hyperreactivity in abusive parents, these findings suggest that failure to habituate to repeated infant crying may be one of the mediating mechanisms through which excessive, inconsolable, and high-pitched infant crying triggers less optimal caregiving.

[Creatine phosphokinase in a hospitalized psychiatric population]. / Estudio de la creatinfosfokinasa en una población psiquiátrica hospitalaria.

Creatine phosphokinase (CPK) is studied in psychiatric hospitalized patients under neuroleptic treatment in order to clarify the diagnostic value of this enzyme in the neuroleptic malignant syndrome (SNM). Intramuscular drug administration was, in the present study, the only variable associated with CPK levels over 1,000 U. Other items studied, like agitation, physical restraint or illness severity can not account for this elevation. In absence of i.m. medication, levels over 1,000 U must be carefully screened in order to rule out SNM or organic pathology associated.

Multiple muscle enzyme release with psychiatric illness.

Associations (p less than .001) between serum concentrations of lactate dehydrogenase (LDH) and glutamic oxaloacetic transaminase (SGOT) were observed in physically well patients with mania (N = 100, r = .70), depression (N = 138, r = .51), chronic schizophrenia (N = 85, r = .68), and schizoaffective or atypical psychosis (N = 39, r = .52) discharged from 1978 through 1981. In contrast, there was a negligible association between these enzymes in 90 nonpsychiatric inpatient control subjects. Patients with mania (229.0 +/- 106.1 IU/l) showed significantly (t = 3.16, p less than .002, two-tailed) higher lactate dehydrogenase (LDH) levels than control subjects (191 +/- 41.7 IU/l) and a 14% incidence of abnormally high serum LDH levels vs. 1% among control subjects. Results were unchanged when patients taking neuroleptics were excluded. These results indicate that psychiatric illness, especially mania, induces release of LDH and SGOT, occasionally to unusually high levels. This is similar to previous reports of muscle creatine phosphokinase release in psychiatric patients. Presumably, these enzymes are released from skeletal muscle in association with agitation, with muscle tension, or with blood stasis and local tissue hypoxia consequent to hypoactivity.