Regional brain volume changes following chronic antipsychotic administration are mediated by the dopamine D2 receptor.

BACKGROUND: Neuroanatomical alterations are well established in patients suffering from schizophrenia, however the extent to which these changes are attributable to illness, antipsychotic drugs (APDs), or their interaction is unclear. APDs have been extremely effective for treatment of positive symptoms in major psychotic disorders. Their therapeutic effects are mediated, in part, through blockade of D2-like dopamine (DA) receptors, i.e. the D2, D3 and D4 dopamine receptors. Furthermore, the dependency of neuroanatomical change on DA system function and D2-like receptors has yet to be explored. METHODS: We undertook a preclinical longitudinal study to examine the effects of typical (haloperidol (HAL)) and atypical (clozapine (CLZ)) APDs in wild type (WT) and dopamine D2 knockout (D2KO) mice over 9-weeks using structural magnetic resonance imaging (MRI). RESULTS: Chronic typical APD administration in WT mice was associated with reductions in total brain (p = 0.009) and prelimbic area (PL) (p = 0.02) volumes following 9-weeks, and an increase in striatal volume (p = 0.04) after six weeks. These APD-induced changes were not present in D2KOs, where, at baseline, we observed significantly smaller overall brain volume (p < 0.01), thinner cortices (q < 0.05), and enlarged striata (q < 0.05). Stereological assessment revealed increased glial density in PL area of HAL treated wild types. Interestingly, in WT and D2KO mice, chronic CLZ administration caused more limited changes in brain structure. CONCLUSIONS: Our results present evidence for the role of D2 DA receptors in structural alterations induced by the administration of the typical APD HAL and that chronic administration of CLZ has a limited influence on brain structure.

Optimization of a molecular mechanics force field for polyoxometalates based on a genetic algorithm.

A stochastic technique based on genetic algorithms was implemented to develop new force fields by optimizing molecular mechanics (MM) parameters. These force fields have been optimized for inorganic compounds such as polyoxometalates (POMs) and especially for type-I polymolybdate and polytungstate clusters. Focussing on the methodology of the development of the force fields, they were tested for the prediction of structural parameters, comparing the MM optimized structures with the geometry obtained after an optimization based on density functional theory. Results show that the genetic algorithm converges toward an optimum combination of parameters which successfully reproduces POMs structures with a high degree of accuracy.

Modeling the interactions between polyoxometalates and their environment.

To develop a force field suitable both for polyoxometalates (POMs) and organic cations, the Merck molecular force field 94x (MMFF94x) has been selected to describe the counterions used in POMs synthesis and has been combined with our force field optimized for type-II POMs with electrostatic and Van der Waals interactions included in the potential. Nontransferability of force fields is well-known and, to overcome this limitation, a charge-scaling factor (SF) has been introduced and optimized to tune the POMs force field parameters and adapt them to MMFF94x. The mixed MMFF94x/POMFF-II force field has been optimized and tested on different clusters based on hepta-molybdate. To validate our mixed force field comparison of the results obtained after molecular mechanics (MM), geometry optimizations with density-functional (DFT) calculations have been performed on the smallest system of interest. This has enabled a study of the accuracy of different functionals, especially on the description of hydrogen bonding, to be made. Results are promising in terms of structural accuracy. MM geometry optimization can be used on small POM clusters, competing reasonably well with DFT. When quantum approaches increase considerably the computational cost because of the size of the system studied, MM can be used, with the small reservation that even if the charge SF introduced improves the performance of the force field, further optimizations of the nonbonded term and the model used for the atomic charges may be necessary in further studies.

Optimization of a molecular mechanics force field for type-II polyoxometalates focussing on electrostatic interactions: a case study.

In this study, we have focussed on type-II polyanions such as [M(7)O(24)](6-), and we have developed and validated optimized force fields that include electrostatic and van der Waals interactions. These contributions to the total steric energy are described by the nonbonded term, which encompasses all interactions between atoms that are not transmitted through the bonds. A first validation of a stochastic technique based on genetic algorithms was previously made for the optimization of force fields dedicated to type-I polyoxometalates. To describe the new nonbonded term added in the functional, a fixed-charged model was chosen. Therefore, one of the main issues was to analyze that which partial atomic charges could be reliably used to describe these interactions in such inorganic compounds. Based on several computational strategies, molecular mechanics (MM) force field parameters were optimized using different types of atomic charges. Moreover, the influence of the electrostatic and van der Waals buffering constants and 1,4-interactions scaling factors used in the force field were also tested, either being optimized as well or fixed with respect to the values of CHARMM force field. Results show that some atomic charges are not well adapted to CHARMM parameters and lead to unrealistic MM-optimized structures or a MM divergence. As a result, a new scaling factor has been optimized for Quantum Theory of Atoms in Molecules charges and charges derived from the electrostatic potential such as ChelpG. The force fields optimized can be mixed with the CHARMM force field, without changing it, to study for the first time hepta-anions interacting with organic molecules.

Bootstrap quantification of cardiac pulsation artifact in DTI.

While several studies have shown the benefit of cardiac gating in diffusion MRI with single-shot EPI acquisition, cardiac gating is still not commonly used. This is probably because it requires additional time and many investigators may not be convinced that cardiac gating is worth the extra effort. Here, we tested a clinically feasible protocol with a minimal increase in scan time, and quantified the effect of cardiac gating under partial or full Fourier acquisition. Eight volunteers were scanned on a 3 T scanner with a SENSE 8-channel head coil. Diffusion-weighted, single-shot spin-echo EPI images were acquired along 32 gradient directions, with or without cardiac gating and with partial or full Fourier acquisition. Vectorcardiography (VCG) was used to trigger acquisition at a minimum delay (30 ms). The uncertainties of DTI derived parameters were estimated using residual bootstrap. With partial Fourier, cardiac gating reduced the uncertainties, and better efficiency in reducing DTI parameter variability was also achieved even allowing for the increase in total scan time. For full Fourier acquisition, minimum time gating slightly decreased the uncertainties but the efficiency was worse. A minimum trigger delay might not be the optimal scheme to avoid the majority of systole but it allows clinically acceptable scan times. We have demonstrated that cardiac gating, especially of partial Fourier acquisitions, can reduce the uncertainties of DTI derived parameters in a time-efficient manner.

Structural and vibrational study of [Mo7O24]6- and [W7O24]6-.

Density functional methods have been used to investigate the structure and the vibrational modes of [M7O24]6- isopolyanions of molybdenum and tungsten. Relativistic effects have been considered through the zeroth-order regular approximation (ZORA) and interactions with an aqueous environment modeled by the COSMO approach. A structural study of the two compounds has been performed, and the geometrical parameters obtained are in good agreement with experimental data. However, when the solvent is introduced in the model, deviations are found, especially for some tungsten-oxygen bonds which involve pseudoterminal oxygens. Thus, different computational strategies have been tested to reject any reliance on the COSMO model and the optimization algorithms. The variations compared to solid-state bond lengths appear to be due to the solvent. Infrared and Raman spectra have been also calculated in the gas phase and in water leading, for the first time, to a detailed assignment of the vibrational frequencies. The vibrational contributions of the aminopyridinium counterion [C5H7N2]+ have been isolated, improving the assignment of experimental spectra. Inclusion of solvent causes a shift toward lower frequencies and an increase in the intensity of the peaks. Spectra obtained using pseudo-gas-phase calculations reproduce the experimental data most satisfactorily, especially when the experiments are performed on the solid state.

Fimbria-Fornix Volume Is Associated With Spatial Memory and Olfactory Identification in Humans.

White matter pathways that surround the hippocampus comprise its afferent and efferent connections, and are therefore crucial in mediating the function of the hippocampus. We recently demonstrated a role for the hippocampus in both spatial memory and olfactory identification in humans. In the current study, we focused our attention on the fimbria-fornix white matter bundle and investigated its relationship with spatial memory and olfactory identification. We administered a virtual navigation task and an olfactory identification task to 55 young healthy adults and measured the volume of the fimbria-fornix. We found that the volume of the right fimbria-fornix and its subdivisions is correlated with both navigational learning and olfactory identification in those who use hippocampus-based spatial memory strategies, and not in those who use caudate nucleus-based navigation strategies. These results are consistent with our recent finding that spatial memory and olfaction rely on similar neural networks and structures.

Role of D3 dopamine receptors in modulating neuroanatomical changes in response to antipsychotic administration.

Clinical research has shown that chronic antipsychotic drug (APD) treatment further decreases cortical gray matter and hippocampus volume, and increases striatal and ventricular volume in patients with schizophrenia. D2-like receptor blockade is necessary for clinical efficacy of the drugs, and may be responsible for inducing these volume changes. However, the role of other D2-like receptors, such as D3, remains unclear. Following our previous work, we undertook a longitudinal study to examine the effects of chronic (9-week) typical (haloperidol (HAL)) and atypical (clozapine (CLZ)) APDs on the neuroanatomy of wild-type (WT) and dopamine D3-knockout (D3KO) mice using magnetic resonance imaging (MRI) and histological assessments in a sub-region of the anterior cingulate cortex (the prelimbic [PL] area) and striatum. D3KO mice had larger striatal volume prior to APD administration, coupled with increased glial and neuronal cell density. Chronic HAL administration increased striatal volume in both WT and D3KO mice, and reduced PL area volume in D3KO mice both at trend level. CLZ increased volume of the PL area of WT mice at trend level, but decreased D3KO PL area glial cell density. Both typical and atypical APD administration induced neuroanatomical remodeling of regions rich in D3 receptor expression, and typically altered in schizophrenia. Our findings provide novel insights on the role of D3 receptors in structural changes observed following APD administration in clinical populations.

Experimental/theoretical electrostatic properties of a styrylquinoline-type HIV-1 integrase inhibitor and its progenitors.

We have established that polyhydroxylated styrylquinolines are potent inhibitors of HIV-1 integrase (IN). Among them, we have identified (E)-8-hydroxy-2-[2-(4,5-dihydroxy-3-methoxyphenyl)-ethenyl]-7-quinolinecarboxylic acid (1) as a promising lead. Previous molecular dynamics simulations and docking procedures have shown that the inhibitory activity involves one or two metal cations (Mg2+), which are present in the vicinity of the active center of the enzyme. However, such methods are generally based on a force-field approach and still remain not as reliable as ab initio calculations with extended basis sets on the whole system. To go further in this area, the aim of the present study was to evaluate the predictive ability of the electron density and electrostatic properties in the structure-activity relationships of this class of HIV-1 antiviral drugs. The electron properties of the two chemical progenitors of 1 were derived from both high-resolution X-ray diffraction experiments and ab initio calculations. The twinning phenomenon and solvent disorder were observed during the crystal structure determination of 1. Molecule 1 exhibits a planar s-trans conformation, and a zwitterionic form in the crystalline state is obtained. This geometry was used for ab initio calculations, which were performed to characterize the electronic properties of 1. The electron densities, electrostatic potentials, and atomic charges of 1 and its progenitors are here compared and analyzed. The experimental and theoretical deformation density bond peaks are very comparable for the two progenitors. However, the experimental electrostatic potential is strongly affected by the crystal field and cannot straightforwardly be used as a predictive index. The weak difference in the theoretical electron densities between 1 and its progenitors reveals that each component of 1 conserves its intrinsic properties, an assumption reinforced by a 13C NMR study. This is also shown through an excellent correlation of the atomic charges for the common fragments. The electrostatic potential minima in zwitterionic and nonzwitterionic forms of 1 are discussed in relation with the localization of possible metal chelation sites.

Modelling the circularly and linearly polarised spectrum of [Ni(en)3]2+.

The relative intensity and band shapes of the low energy spin-allowed transitions in the linearly polarised and circular dichroism spectrum of [Ni(en)(3)](2+) have been calculated using a time-dependent density functional theory approach. The effect of the trigonal ligand-field is minimal and no splitting of the bands is predicted by the simulations or observed experimentally. The 'd-d' transitions of the [Ni(en)(3)](2+) ion are electric dipole allowed but gain much of their intensity through Herzberg-Teller vibronic coupling. Its CD spectrum is dominated by the low energy band, which gains its rotatory strength through the magnetic dipole-allowed character of the parent octahedral transition and the electric dipole character due to the trigonal field. The simulation of the spectrum incorporates the contribution from all inducing vibrational modes with significant involvement of the {NiN(6)} unit. Vibrations which are centred on the chelate rings are not important in generating intensity, reflecting the localised d-d' character of the transitions. Simulated linearly polarised and circular dichroism spectra of such an open-shell system are presented for the first time and predict the essential elements of the experimental spectra.

Electronic properties of 3,3'-dimethyl-5,5'-bis(1,2,4-triazine): towards design of supramolecular arrangements of N-heterocyclic Cu(I) complexes.

A new efficient and safe synthesis of 3,3'-dimethyl-5,5'-bis-(1,2,4-triazine) is presented. The electron-density distribution and electrostatic properties (charge, electrostatic potential) of this molecule were analyzed. These properties were derived from a high-resolution single-crystal X-ray diffraction experiment at 100 K and compared to the results obtained from ab initio DFT quantum-mechanical calculations. Comparisons of its electrostatic potential features and integrated atomic charges (quantum theory of atoms in molecules, QTAIM) have been made with those of related molecules such as bipyrimidine ligands. Two methods were used to derive integrated charges: one is based on the conventional analytical procedure and the second uses a steepest-ascent numerical algorithm. Excellent agreement was obtained between these two methods. Charges and electrostatic potential were used as predictive indices of metal chelation and discussed in the light of complexation abilities of the title compound and related molecules. The crystal structure of a Cu(I) complex of 3,3'-dimethyl-5,5'-bis(1,2,4-triazine) is reported here. In the solid state, this complex forms a three-dimensional multibranch network with open channels in which counterions and solvent molecules are located. This architecture involves both cis and trans isomers of the title compound.