Although phencyclidine and ketamine are used to model a hypoglutamate theory of schizophrenia, their selectivity for NMDA receptors has been questioned. To determine the affinities of phencyclidine, ...ketamine, dizocilpine and LSD for the functional high-affinity state of the dopamine D2 receptor, D2High, their dissociation constants (Ki) were obtained on 3Hdomperidone binding to human cloned dopamine D2 receptors. Phencyclidine had a high affinity for D2High with a Ki of 2.7 nM, in contrast to its low affinity for the NMDA receptor, with a Ki of 313 nM, as labeled by 3Hdizocilpine on rat striatal tissue. Ketamine also had a high affinity for D2High with a Ki of 55 nM, an affinity higher than its 3100 nM Ki for the NMDA sites. Dizocilpine had a Ki of 0.3 nM at D2High, but a Kd of 1.8 nM at the NMDA receptor. LSD had a Ki of 2 nM at D2High. Because the psychotomimetics had higher potency at D2High than at the NMDA site, the psychotomimetic action of these drugs must have a major contribution from D2 agonism. Because these drugs have a combined action on both dopamine receptors and NMDA receptors, these drugs, when given in vivo, test a combined hyperdopamine and hypoglutamate theory of psychosis.
This review addresses two questions. First, why does clozapine apparently occupy low levels of dopamine D2 receptors in patients, in contrast to all other antipsychotic drugs which occupy 70-80% of ...brain dopamine D2 receptors? Second, what is the receptor basis of action of antipsychotic drugs which elicit low levels of Parkinsonism? Antipsychotic doses of clozapine occupy between 0% and 50% of D2 receptors, as measured in patients by a variety of radioligands. It has recently been found, however, that the percent occupancy of a receptor by a drug depends on the radioligand used to measure that receptor. Based on this new finding, this review concludes that clozapine clinically occupies high levels of D2 receptors in the absence of any radioligand. This occupancy is estimated to be of the order of 70-80% in the dopamine-rich region of the human striatum, and even higher in the limbic D2-containing regions which are low in endogenous synaptic dopamine. This conclusion arises from two different approaches. One approach is to relate the reported clozapine occupancies in the human striatum with the dissociation constants of the various radioligands at the D2 receptor. This relation extrapolates to approximately 70-80% occupancy by clozapine when clozapine competes with endogenous dopamine at the D2 receptor. The second approach is to calculate the D2 occupancy of each antipsychotic drug, using the average spinal fluid concentration and the correct dissociation constant of the antipsychotic, thereby revealing that all antipsychotic drugs, including clozapine, occupy approximately 70-80% of dopamine D2 receptors in the human striatum, and possibly higher in the limbic regions. As determined by the new dissociation constants, antipsychotic drugs which elicit Parkinsonism (trifluperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than dopamine to D2, while those antipsychotic drugs which elicit little or no Parkinsonism (melperone, seroquel, perlapine, clozapine, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjustment, but may dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than that found with the traditional tightly bound antipsychotic drugs.
A half-cell superconducting rf electron gun is designed to provide 0.5 A, 2 MeV beam for the Brookhaven National Laboratory R&D Energy Recovery Linac. Total rf power of 1 MW must be delivered to beam ...to meet the beam current and energy specifications, resulting in very strong coupling. Two opposing fundamental power couplers (FPCs) are employed to minimize the transverse kick to beam traversing the structure and to halve the power through the coupler. A single-window coaxial coupler has been designed to meet the average power and rf coupling requirements. The coupler features a planar beryllia rf window for better handling high thermal stresses and a “pringle”-shaped tip of the antenna for enhancing rf coupling. Two FPCs have been fabricated and tested in preparation for the gun cryomodule assembly. A room-temperature test stand was used for conditioning couplers in full reflection regime with variable phase of the reflecting wave. The couplers were tested up to 250 kW in pulse mode and 125 kW in cw mode at different settings of the reflecting wave phase to expose all rf surfaces along the couplers to high fields. Several multipacting barriers were encountered and successfully processed away. The rf power levels, at which multipacting was found, match well those found in computer simulations.
Large transport aircraft with electrified propulsion systems require MW-class electric machines that have higher efficiency and power-to-weight ratio than existing machines. Superconducting machines ...are being evaluated as potential solutions. This paper presents a method to optimize the electromagnetic design of a partially superconducting machine in terms of these metrics and the approximate fuel burn of the aircraft. The optimization is based on 2D electromagnetic finite element simulations, a prediction of the superconducting coils' critical current, and geometry relations that design the superconducting coils based on dependent variables while constraining the total cost of superconductor and ensuring adequate space for structure. The design process is completed by (1) a 3D electromagnetic finite element simulation to improve the prediction of torque and assess magnetic flux leakage, (2) refinement of the superconductor width for each individual racetrack coil, and (3) evaluating inverter-produced stator current harmonics on eddy current losses in the rotor.
Dominant mutations of the P/Q‐type Ca2+ channel (CACNA1A) underlie several human neurological disorders, including episodic ataxia type 2, familial hemiplegic migraine 1 (FHM1) and spinocerebellar ...ataxia 6, but have not been found previously in the mouse. Here we report the first dominant ataxic mouse model of Cacna1a mutation. This Wobbly mutant allele of Cacna1a was identified in an ethylnitrosourea (ENU) mutagenesis dominant behavioral screen. Heterozygotes exhibit ataxia from 3 weeks of age and have a normal life span. Homozygotes have a righting reflex defect from postnatal day 8 and later develop severe ataxia and die prematurely. Both heterozygotes and homozygotes exhibit cerebellar atrophy with focal reduction of the molecular layer. No obvious loss of Purkinje cells or decrease in size of the granule cell layer was observed. Real‐time polymerase chain reaction revealed altered expression levels of Cacna1g, Calb2 and Th in Wobbly cerebella, but Cacna1a messenger RNA and protein levels were unchanged. Positional cloning revealed that Wobbly mice have a missense mutation leading to an arginine to leucine (R1255L) substitution, resulting in neutralization of a positively charged amino acid in repeat III of voltage sensor segment S4. The dominance of the Wobbly mutation more closely resembles patterns of CACNA1A mutation in humans than previously described mouse recessive mutants (tottering, leaner, rolling Nagoya and rocker). Positive‐charge neutralization in S4 has also been shown to underlie several cases of human dominant FHM1 with ataxia. The Wobbly mutant thus highlights the importance of the voltage sensor and provides a starting point to unravel the neuropathological mechanisms of this disease.
Previous studies reported that music therapy (MT) exerts a positive effect on many medical and neuropsychiatric disorders. The use of MT has been proposed also for patients with severe mental ...illnesse (SMI), altrough further studies are still needed. The aim of the present study was to evaluate the effects on a structured MT program on clinical and social functioning indices of patient with SMI, hospitalized in an psychiatric emergency ward. The MT intervention followed the Benenzon model of MT and was delivered biweekly to 61 patients consecutively admittted to the psychiatric emergency ward. Subjects who did not complete the two-week MT intervention (N=45) were considered as the control group. all subjects were administred the Brief Psychiatric Rating Scale (BPRS) to evaluate the general psychopatology, the Hospital Anxiety And Depression Scale (HADS) for affective symptomatology, the Clinical Global Impression Scale (CGI-S) for severity of symptoms and the Global Assestment of Functioning (GAF) for psychosocial functioning. A repeated measures analysis of variance revealed that patients who unerwent the MT intervention had a statistically significant reduction of general and affective psychopatology scores and of symptoms severity with respect to the control group, after observation period. Our result are in line with previous studies confirming that MT may exert positive effects on psychopatology (in particular, on affective symptomatology) of patient with SMI, and extend this observation to an emergency setting, with short period of hospital stay.
Schizophrenia is a major psychiatric disorder which is hypothesized to result from abnormal neurodevelopment or neural changes in adulthood and possibly associated with altered gene expression. To ...search for genes overexpressed in schizophrenia, cDNA library subtractive hybridization experiments between post-mortem human frontal cerebral cortices from schizophrenia individuals and neurological controls were carried out. One of the genes over-expressed in schizophrenia was identified as Nogo (also known as reticulon 4, RTN4, NI 250, or RTN-X), a myelin-associated protein which inhibits the outgrowth of neurites and nerve terminals. The elevated expression of Nogo mRNA in schizophrenia was confirmed by quantitative reverse transcription-polymerase chain reaction studies: 16.5 pg Nogo cDNA/μg total RNA in schizophrenia, and 10.2 pg Nogo cDNA/μg total RNA in controls (
n=7;
P=0.01,
t-test for
n<30). To identify possible polymorphisms in this gene, the Nogo nucleotide sequence was determined in a series of schizophrenia and control samples. The Nogo mRNA was found to contain a CAA insert polymorphism in the 3′-untranslated region. The prevalence of individuals homozygous for this CAA insert was significantly higher in schizophrenia compared to controls in genomic DNA samples extracted from post-mortem brain and blood samples: 17/81 or 21% in schizophrenia and 2/61 or 3% in controls (
P=0.0022,
χ
2- and Fisher’s exact-tests). Because the 3′-untranslated regions of eukaryotic genes are known to regulate gene expression, the increased frequency of the Nogo CAA insert in schizophrenia may contribute to abnormal regulation of Nogo gene expression, and may indicate a role for Nogo in disturbed neurodevelopment in schizophrenia.
OBJECTIVE: In an attempt to understand the basis of early relapse after antipsychotic withdrawal, the objective of this study was to determine whether the low occupancy of dopamine D2 receptors by ...clozapine and by quetiapine, as seen by brain imaging, could arise from a rapid release of some of the D2-bound clozapine or quetiapine by the brain imaging compounds and by the action of a physiological concentration of dopamine. METHOD: Human cloned D2 receptors were first pre-equilibrated with the 3Hantipsychotic drug, after which raclopride, iodobenzamide, or dopamine (at the physiological concentration in the synapse) was added, and the time course of release of the 3Hantipsychotic from the D2 receptor was measured. RESULTS: Within 5 minutes, low concentrations of raclopride and iodobenzamide displaced appreciable amounts of 3Hclozapine and 3Hquetiapine from the D2 receptors but, during the course of 1 hour, did not displace any of the other antipsychotic 3Hligands. 3HClozapine and 3Hquetiapine, moreover, were displaced by dopamine (100 nM) at least 100 times faster than the other antipsychotic 3Hligands. CONCLUSIONS: Clozapine and quetiapine are loosely bound to the D2 receptor, and the injected radioactive ligand at its peak concentration may displace some of the D2-bound antipsychotic drug, resulting in apparently low D2 occupancies. Therefore, under clinical brain imaging conditions with 11Craclopride, D2 occupancies by clozapine and by quetiapine may be higher than currently estimated. These considerations may result in high levels of the D2 receptors being occupied by therapeutic doses of clozapine or quetiapine. The rapid release of clozapine and quetiapine from D2 receptors by endogenous dopamine may contribute to low D2 receptor occupancy and to early clinical relapse upon withdrawal of these medications.
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