Conditioned place preference and locomotor activity in response to methylphenidate, amphetamine and cocaine in mice lacking dopamine D4 receptors

Methylphenidate (MP) and amphetamine (AMPH) are the most frequently prescribed medications for the treatment of attention-deficit/hyperactivity disorder (ADHD). Both drugs are believed to derive their therapeutic benefit by virtue of their dopamine (DA)-enhancing effects, yet an explanation for the observation that some patients with ADHD respond well to one medication but not to the other remains elusive. The dopaminergic effects of MP and AMPH are also thought to underlie their reinforcing properties and ultimately their abuse. Polymorphisms in the human gene that codes for the DA D4 receptor (D4R) have been repeatedly associated with ADHD and may correlate with the therapeutic as well as the reinforcing effects of responses to these psychostimulant medications. Conditioned place preference (CPP) for MP, AMPH and cocaine were evaluated in wild-type (WT) mice and their genetically engineered littermates, congenic on the C57Bl/6J background, that completely lack D4Rs (knockout or KO). In addition, the locomotor activity in these mice during the conditioning phase of CPP was tested in the CPP chambers. D4 receptor KO and WT mice showed CPP and increased locomotor activity in response to each of the three psychostimulants tested. D4R differentially modulates the CPP responses to MP, AMPH and cocaine. While the D4R genotype affected CPP responses to MP (high dose only) and AMPH (low dose only) it had no effects on cocaine. Inasmuch as CPP is considered an indicator of sensitivity to reinforcing responses to drugs these data suggest a significant but limited role of D4Rs in modulating conditioning responses to MP and AMPH. In the locomotor test, D4 receptor KO mice displayed attenuated increases in AMPH-induced locomotor activity whereas responses to cocaine and MP did not differ. These results suggest distinct mechanisms for D4 receptor modulation of the reinforcing (perhaps via attenuating dopaminergic signalling) and locomotor properties of these stimulant drugs. Thus, individuals with D4 receptor polymorphisms might show enhanced reinforcing responses to MP and AMPH and attenuated locomotor response to AMPH.Fil: Thanos, P. K.. NIAAA Intramural Program; Estados Unidos. Brookhaven National Laboratory; Estados Unidos. Universidad de Buenos Aires; ArgentinaFil: Bermeo, C.. Brookhaven National Laboratory; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires; ArgentinaFil: Suchland, K. L.. Oregon Health & Science University; Estados UnidosFil: Wang, G. J.. Brookhaven National Laboratory; Estados UnidosFil: Grandy, David K.. Oregon Health & Science University; Estados UnidosFil: Volkow, N. D.. NIAAA Intramural Program; Estados Unido

Dynamic multilateral markets

We study dynamic multilateral markets, in which players' payoffs result from intra-coalitional bargaining. The latter is modeled as the ultimatum game with exogenous (time-invariant) recognition probabilities and unanimity acceptance rule. Players in agreeing coalitions leave the market and are replaced by their replicas, which keeps the pool of market participants constant over time. In this infinite game, we establish payoff uniqueness of stationary equilibria and the emergence of endogenous cooperation structures when traders experience some degree of (heterogeneous) bargaining frictions. When we focus on market games with different player types, we derive, under mild conditions, an explicit formula for each type's equilibrium payoff as the market frictions vanish

Unexpected relaxation dynamics of a self-avoiding polymer in cylindrical confinement

We report extensive simulations of the relaxation dynamics of a self-avoiding polymer confined inside a cylindrical pore. In particular, we concentrate on examining how confinement influences the scaling behavior of the global relaxation time of the chain, t, with the chain length N and pore diameter D. An earlier scaling analysis based on the de Gennes blob picture led to t ~ N^2D^(1/3). Our numerical effort that combines molecular dynamics and Monte Carlo simulations, however, consistently produces different t-results for N up to 2000. We argue that the previous scaling prediction is only asymptotically valid in the limit N >> D^(5/3) >> 1, which is currently inaccessible to computer simulations and, more interestingly, is also difficult to reach in experiments. Our results are thus relevant for the interpretation of recent experiments with DNA in nano- and micro-channels.Comment: 10 pages, 11 figure

Conical defects in growing sheets

A growing or shrinking disc will adopt a conical shape, its intrinsic geometry characterized by a surplus angle $se$ at the apex. If growth is slow, the cone will find its equilibrium. Whereas this is trivial if $se <= 0$, the disc can fold into one of a discrete infinite number of states if $se$ is positive. We construct these states in the regime where bending dominates, determine their energies and how stress is distributed in them. For each state a critical value of $se$ is identified beyond which the cone touches itself. Before this occurs, all states are stable; the ground state has two-fold symmetry.Comment: 4 pages, 4 figures, LaTeX, RevTeX style. New version corresponds to the one published in PR

Shear flow effects on phase separation of entangled polymer blends

We introduce an entanglement model mixing rule for stress relaxation in a polymer blend to a modified Cahn-Hilliard equation of motion for concentration fluctuations in the presence of shear flow. Such an approach predicts both shear-induced mixing and demixing, depending on the relative relaxation times and plateau moduli of the two components

A point process framework for modeling electrical stimulation of the auditory nerve

Model-based studies of auditory nerve responses to electrical stimulation can provide insight into the functioning of cochlear implants. Ideally, these studies can identify limitations in sound processing strategies and lead to improved methods for providing sound information to cochlear implant users. To accomplish this, models must accurately describe auditory nerve spiking while avoiding excessive complexity that would preclude large-scale simulations of populations of auditory nerve fibers and obscure insight into the mechanisms that influence neural encoding of sound information. In this spirit, we develop a point process model of the auditory nerve that provides a compact and accurate description of neural responses to electric stimulation. Inspired by the framework of generalized linear models, the proposed model consists of a cascade of linear and nonlinear stages. We show how each of these stages can be associated with biophysical mechanisms and related to models of neuronal dynamics. Moreover, we derive a semi-analytical procedure that uniquely determines each parameter in the model on the basis of fundamental statistics from recordings of single fiber responses to electric stimulation, including threshold, relative spread, jitter, and chronaxie. The model also accounts for refractory and summation effects that influence the responses of auditory nerve fibers to high pulse rate stimulation. Throughout, we compare model predictions to published physiological data and explain differences in auditory nerve responses to high and low pulse rate stimulation. We close by performing an ideal observer analysis of simulated spike trains in response to sinusoidally amplitude modulated stimuli and find that carrier pulse rate does not affect modulation detection thresholds.Comment: 1 title page, 27 manuscript pages, 14 figures, 1 table, 1 appendi

The cross-entropy method for continuous multi-extremal optimization

In recent years, the cross-entropy method has been successfully applied to a wide range of discrete optimization tasks. In this paper we consider the cross-entropy method in the context of continuous optimization. We demonstrate the effectiveness of the cross-entropy method for solving difficult continuous multi-extremal optimization problems, including those with non-linear constraints

Conformations, Transverse Fluctuations and Crossover Dynamics of a Semi-Flexible Chain in Two Dimensions

We present a unified scaling description for the dynamics of monomers of a semiflexible chain under good solvent condition in the free draining limit. We consider both the cases where the contour length $L$ is comparable to the persistence length $\ell_p$ and the case $L\gg \ell_p$. Our theory captures the early time monomer dynamics of a stiff chain characterized by $t^{3/4}$ dependence for the mean square displacement(MSD) of the monomers, but predicts a first crossover to the Rouse regime of $t^{2\nu/{1+2\nu}}$ for $\tau_1 \sim \ell_p^3$, and a second crossover to the purely diffusive dynamics for the entire chain at $\tau_2 \sim L^{5/2}$. We confirm the predictions of this scaling description by studying monomer dynamics of dilute solution of semi-flexible chains under good solvent conditions obtained from our Brownian dynamics (BD) simulation studies for a large choice of chain lengths with number of monomers per chain N = 16 - 2048 and persistence length $\ell_p = 1 - 500$ Lennard-Jones (LJ) units. These BD simulation results further confirm the absence of Gaussian regime for a 2d swollen chain from the slope of the plot of $\langle R_N^2 \rangle/2L \ell_p \sim L/\ell_p$ which around $L/\ell_p \sim 1$ changes suddenly from $\left(L/\ell_p \right) \rightarrow \left(L/\ell_p \right)^{0.5}$, also manifested in the power law decay for the bond autocorrelation function disproving the validity of the WLC in 2d. We further observe that the normalized transverse fluctuations of the semiflexible chains for different stiffness $\sqrt{\langle l_{\bot}^2\rangle}/L$ as a function of renormalized contour length $L/\ell_p$ collapse on the same master plot and exhibits power law scaling $\sqrt{\langle l_{\bot}^2\rangle}/L \sim (L/\ell_p)^\eta$ at extreme limits, where $\eta = 0.5$ for extremely stiff chains ($L/\ell_p \gg 1$), and $\eta = -0.25$ for fully flexible chains.Comment: 14 pages, 18 figure

Hall-Effect Sign Anomaly and Small-Polaronic Conduction in (La_{1-x}Gd_x)_{0.67}Ca_{0.33}MnO_3

The Hall coefficient of Gd-doped La_{2/3}Ca_{1/3}MnO_3 exhibits Arrhenius behavior over a temperature range from 2T_c to 4T_c, with an activation energy very close to 2/3 that of the electrical conductivity. Although both the doping level and thermoelectric coefficient indicate hole-like conduction, the Hall coefficient is electron-like. This unusual result provides strong evidence in favor of small-polaronic conduction in the paramagnetic regime of the manganites.Comment: 11 pages, 4 figures, uses revtex.st

Static and dynamic properties of large polymer melts in equilibrium

We present a detailed study of the static and dynamic behavior of long semiflexible polymer chains in a melt. Starting from previously obtained fully equilibrated high molecular weight polymer melts [{\it Zhang et al.} ACS Macro Lett. 3, 198 (2014)] we investigate their static and dynamic scaling behavior as predicted by theory. We find that for semiflexible chains in a melt, results of the mean square internal distance, the probability distributions of the end-to-end distance, and the chain structure factor are well described by theoretical predictions for ideal chains. We examine the motion of monomers and chains by molecular dynamics simulations using the ESPResSo++ package. The scaling predictions of the mean squared displacement of inner monomers, center of mass, and relations between them based on the Rouse and the reptation theory are verified, and related characteristic relaxation times are determined. Finally we give evidence that the entanglement length $N_{e,PPA}$ as determined by a primitive path analysis (PPA) predicts a plateau modulus, $G_N^0=\frac{4}{5}(\rho k_BT/N_e)$, consistent with stresses obtained from the Green-Kubo relation. These comprehensively characterized equilibrium structures, which offer a good compromise between flexibility, small $N_e$, computational efficiency, and small deviations from ideality provide ideal starting states for future non-equilibrium studies.Comment: 13 pages, 10 figures, to be published in J. Chem. Phys. (2016