The quetiapine active metabolite N-Desalkylquetiapine and the neurotensin NTS1 receptor agonist PD149163 exhibit antidepressant-like effects on operant responding in male rats

Major depressive disorder (MDD) is the most common mood disorder in the United States and European Union; however, the limitations of clinically available antidepressant drugs have led researchers to pursue novel pharmacological treatments. Clinical studies have reported that monotherapy with the atypical antipsychotic drug quetiapine produces a rapid reduction in depressive symptoms that are apparent following one week of quetiapine treatment, and it is possible that the active metabolite N-Desalkylquetiapine, which structurally resembles an antidepressant drug, produces antidepressant effects. Neuropharmacological evaluations of the neurotensin NTS1 receptor agonist PD149163 are suggestive of antidepressant efficacy, but the effects of a NTS1 receptor agonist in an antidepressant animal model have yet to be reported. The present study examined the antidepressant-like effects of the N-Desalkylquetiapine, the neurotensin NTS1 receptor agonist PD14916, quetiapine, the tricylic antidepressant drug imipramine, the atypical antipsychotic drug risperidone, and the typical antipsychotic drug raclopride on responding in male Sprague-Dawley rats trained on a differential-reinforcement-of-low-rate (DRL) 72 s operant schedule, a procedure used for screening antidepressant drugs. Quetiapine, PD149163, risperidone, and imipramine exhibited antidepressant-like effects by increasing the number of reinforcers earned, decreasing the number of responses emitted, and shifting the interresponse time (IRT) distributions to the right. N-Desalkylquetiapine produced a partial antidepressant-like effect by decreasing the number of responses emitted and producing a rightward shift in the IRT distributions, but it did not significantly alter the number of reinforcers earned. The typical antipsychotic drug raclopride decreased both reinforcers and responses. These data suggest that N-Desalklyquetiapine likely contributes to quetiapine’s antidepressant efficacy and identifies NTS1 receptor activation as a potential novel pharmacologic strategy for antidepressant drugs

Neurotensin NTS1 and NTS2 receptor agonists produce anxiolytic-like effects in the 22-kHz ultrasonic vocalization model in rats

Neurotensin is a neuropeptide neurotransmitter that interacts with multiple neurotransmitter systems, including those regulating amygdalar function, via NTS1 and NTS2 receptors. Both receptors are expressed in the amygdala and agonists for NTS1 or NTS2 receptors have exhibited anxiolytic effects in animal models. Systemic adminstration of NTS1 receptor agonist PD149163 was recently shown to reduce footshock conditioned 22-kHz ultrasonic vocalizations in rats, suggesting that PD149163 produced an anxiolytic effect. The effects that neurotensin may have or a selective NTS2receptor agonist may have on 22-kHz vocalizations has yet to be examined. The current study evaluated the effects of intracerebroventricularly administered neurotensin (0.1–10.0 μg), PD149163 (0.1–10.0 ng), or the NTS2 receptor agonist JMV-431 (0.1–1.0 μg) on footshock conditioned 22-kHz vocalizations in male Wistar rats. Neurotensin, PD149163, and JMV-431 all significantly reduced the number 22-kHz calls. No changes in call duration were found, suggesting that non-specific drug effects do not account for the reductions in 22-kHz calls. These data support anxiolytic effects produced by activation of NTS1 or NTS2 receptors, and suggest that neurotensin plays a natural role in the expression of conditioned USVs. These data suggest that both receptor subtypes are putative pharmacologic targets

Electron-phonon interaction via Pekar mechanism in nanostructures

We consider an electron-acoustic phonon coupling mechanism associated with the dependence of crystal dielectric permittivity on the strain (the so-called Pekar mechanism) in nanostructures characterized by strong confining electric fields. The efficiency of Pekar coupling is a function of both the absolute value and the spatial distribution of the electric field. It is demonstrated that this mechanism exhibits a phonon wavevector dependence similar to that of piezoelectricity and must be taken into account for electron transport calculations in an extended field distribution. In particular, we analyze the role of Pekar coupling in energy relaxation in silicon inversion layers. Comparison with the recent experimental results is provided to illustrate its potential significance

Absence of bimodal peak spacing distribution in the Coulomb blockade regime

Using exact diagonalization numerical methods, as well as analytical arguments, we show that for the typical electron densities in chaotic and disordered dots the peak spacing distribution is not bimodal, but rather Gaussian. This is in agreement with the experimental observations. We attribute this behavior to the tendency of an even number of electrons to gain on-site interaction energy by removing the spin degeneracy. Thus, the dot is predicted to show a non trivial electron number dependent spin polarization. Experimental test of this hypothesis based on the spin polarization measurements are proposed.Comment: 13 pages, 3 figures, accepted for publication in PRL - a few small change

Mesoscopic fluctuations of the ground state spin of a small metal particle

We study the statistical distribution of the ground state spin for an ensemble of small metallic grains, using a random-matrix toy model. Using the Hartree Fock approximation, we find that already for interaction strengths well below the Stoner criterion there is an appreciable probability that the ground state has a finite, nonzero spin. Possible relations to experiments are discussed.Comment: 4 pages, RevTeX; 1 figure included with eps

Density Modulations and Addition Spectra of Interacting Electrons in Disordered Quantum Dots

We analyse the ground state of spinless fermions on a lattice in a weakly disordered potential, interacting via a nearest neighbour interaction, by applying the self-consistent Hartree-Fock approximation. We find that charge density modulations emerge progressively when r_s >1, even away from half-filling, with only short-range density correlations. Classical geometry dependent "magic numbers" can show up in the addition spectrum which are remarkably robust against quantum fluctuations and disorder averaging.Comment: 4 pages, 3 eps figure

Ground-state energy and spin in disordered quantum dots

We investigate the ground-state energy and spin of disordered quantum dots using spin-density-functional theory. Fluctuations of addition energies (Coulomb-blockade peak spacings) do not scale with average addition energy but remain proportional to level spacing. With increasing interaction strength, the even-odd alternation of addition energies disappears, and the probability of non-minimal spin increases, but never exceeds 50%. Within a two-orbital model, we show that the off-diagonal Coulomb matrix elements help stabilize a ground state of minimal spin.Comment: 10 pages, 2 figure

Thermodynamic magnetization of a strongly correlated two-dimensional electron system

We measure thermodynamic magnetization of a low-disordered, strongly correlated two-dimensional electron system in silicon. Pauli spin susceptibility is observed to grow critically at low electron densities - behavior that is characteristic of the existence of a phase transition. A new, parameter-free method is used to directly determine the spectrum characteristics (Lande g-factor and the cyclotron mass) when the Fermi level lies outside the spectral gaps and the inter-level interactions between quasiparticles are avoided. It turns out that, unlike in the Stoner scenario, the critical growth of the spin susceptibility originates from the dramatic enhancement of the effective mass, while the enhancement of the g-factor is weak and practically independent of the electron density.Comment: As publishe

On the computation of zone and double zone diagrams

Classical objects in computational geometry are defined by explicit relations. Several years ago the pioneering works of T. Asano, J. Matousek and T. Tokuyama introduced "implicit computational geometry", in which the geometric objects are defined by implicit relations involving sets. An important member in this family is called "a zone diagram". The implicit nature of zone diagrams implies, as already observed in the original works, that their computation is a challenging task. In a continuous setting this task has been addressed (briefly) only by these authors in the Euclidean plane with point sites. We discuss the possibility to compute zone diagrams in a wide class of spaces and also shed new light on their computation in the original setting. The class of spaces, which is introduced here, includes, in particular, Euclidean spheres and finite dimensional strictly convex normed spaces. Sites of a general form are allowed and it is shown that a generalization of the iterative method suggested by Asano, Matousek and Tokuyama converges to a double zone diagram, another implicit geometric object whose existence is known in general. Occasionally a zone diagram can be obtained from this procedure. The actual (approximate) computation of the iterations is based on a simple algorithm which enables the approximate computation of Voronoi diagrams in a general setting. Our analysis also yields a few byproducts of independent interest, such as certain topological properties of Voronoi cells (e.g., that in the considered setting their boundaries cannot be "fat").Comment: Very slight improvements (mainly correction of a few typos); add DOI; Ref [51] points to a freely available computer application which implements the algorithms; to appear in Discrete & Computational Geometry (available online