Hypocretin-1 receptors regulate the reinforcing and reward-enhancing effects of cocaine: pharmacological and behavioral genetics evidence.

Considerable evidence suggests that transmission at hypocretin-1 (orexin-1) receptors (Hcrt-R1) plays an important role in the reinstatement of extinguished cocaine-seeking behaviors in rodents. However, far less is known about the role for hypocretin transmission in regulating ongoing cocaine-taking behavior. Here, we investigated the effects of the selective Hcrt-R1 antagonist SB-334867 on cocaine intake, as measured by intravenous (IV) cocaine self-administration in rats. The stimulatory effects of cocaine on brain reward systems contribute to the establishment and maintenance of cocaine-taking behaviors. Therefore, we also assessed the effects of SB-334867 on the reward-enhancing properties of cocaine, as measured by cocaine-induced lowering of intracranial self-stimulation (ICSS) thresholds. Finally, to definitively establish a role for Hcrt-R1 in regulating cocaine intake, we assessed IV cocaine self-administration in Hcrt-R1 knockout mice. We found that SB-334867 (1-4 mg/kg) dose-dependently decreased cocaine (0.5 mg/kg/infusion) self-administration in rats but did not alter responding for food rewards under the same schedule of reinforcement. This suggests that SB-334867 decreased cocaine reinforcement without negatively impacting operant performance. SB-334867 (1-4 mg/kg) also dose-dependently attenuated the stimulatory effects of cocaine (10 mg/kg) on brain reward systems, as measured by reversal of cocaine-induced lowering of ICSS thresholds in rats. Finally, we found that Hcrt-R1 knockout mice self-administered far less cocaine than wildtype mice across the entire dose-response function. These data demonstrate that Hcrt-R1 play an important role in regulating the reinforcing and reward-enhancing properties of cocaine and suggest that hypocretin transmission is likely essential for establishing and maintaining the cocaine habit in human addicts

Stretched Exponential Relaxation in the Biased Random Voter Model

We study the relaxation properties of the voter model with i.i.d. random bias. We prove under mild condions that the disorder-averaged relaxation of this biased random voter model is faster than a stretched exponential with exponent $d/(d+\alpha)$, where $0<\alpha\le 2$ depends on the transition rates of the non-biased voter model. Under an additional assumption, we show that the above upper bound is optimal. The main ingredient of our proof is a result of Donsker and Varadhan (1979).Comment: 14 pages, AMS-LaTe

Possible loss and recovery of Gibbsianness during the stochastic evolution of Gibbs measures

We consider Ising-spin systems starting from an initial Gibbs measure $\nu$ and evolving under a spin-flip dynamics towards a reversible Gibbs measure $\mu\not=\nu$. Both $\nu$ and $\mu$ are assumed to have a finite-range interaction. We study the Gibbsian character of the measure $\nu S(t)$ at time $t$ and show the following: (1) For all $\nu$ and $\mu$, $\nu S(t)$ is Gibbs for small $t$. (2) If both $\nu$ and $\mu$ have a high or infinite temperature, then $\nu S(t)$ is Gibbs for all $t>0$. (3) If $\nu$ has a low non-zero temperature and a zero magnetic field and $\mu$ has a high or infinite temperature, then $\nu S(t)$ is Gibbs for small $t$ and non-Gibbs for large $t$. (4) If $\nu$ has a low non-zero temperature and a non-zero magnetic field and $\mu$ has a high or infinite temperature, then $\nu S(t)$ is Gibbs for small $t$, non-Gibbs for intermediate $t$, and Gibbs for large $t$. The regime where $\mu$ has a low or zero temperature and $t$ is not small remains open. This regime presumably allows for many different scenarios

Minimum entropy production principle from a dynamical fluctuation law

The minimum entropy production principle provides an approximative variational characterization of close-to-equilibrium stationary states, both for macroscopic systems and for stochastic models. Analyzing the fluctuations of the empirical distribution of occupation times for a class of Markov processes, we identify the entropy production as the large deviation rate function, up to leading order when expanding around a detailed balance dynamics. In that way, the minimum entropy production principle is recognized as a consequence of the structure of dynamical fluctuations, and its approximate character gets an explanation. We also discuss the subtlety emerging when applying the principle to systems whose degrees of freedom change sign under kinematical time-reversal.Comment: 17 page

Trapping reactions with subdiffusive traps and particles characterized by different anomalous diffusion exponents

A number of results for reactions involving subdiffusive species all with the same anomalous exponent gamma have recently appeared in the literature and can often be understood in terms of a subordination principle whereby time t in ordinary diffusion is replaced by t^gamma. However, very few results are known for reactions involving different species characterized by different anomalous diffusion exponents. Here we study the reaction dynamics of a (sub)diffusive particle surrounded by a sea of (sub)diffusive traps in one dimension. We find rigorous results for the asymptotic survival probability of the particle in most cases, with the exception of the case of a particle that diffuses normally while the anomalous diffusion exponent of the traps is smaller than 2/3.Comment: To appear in Phys. Rev.

Fronts in randomly advected and heterogeneous media and nonuniversality of Burgers turbulence: Theory and numerics

A recently established mathematical equivalence--between weakly perturbed Huygens fronts (e.g., flames in weak turbulence or geometrical-optics wave fronts in slightly nonuniform media) and the inviscid limit of white-noise-driven Burgers turbulence--motivates theoretical and numerical estimates of Burgers-turbulence properties for specific types of white-in-time forcing. Existing mathematical relations between Burgers turbulence and the statistical mechanics of directed polymers, allowing use of the replica method, are exploited to obtain systematic upper bounds on the Burgers energy density, corresponding to the ground-state binding energy of the directed polymer and the speedup of the Huygens front. The results are complementary to previous studies of both Burgers turbulence and directed polymers, which have focused on universal scaling properties instead of forcing-dependent parameters. The upper-bound formula can be heuristically understood in terms of renormalization of a different kind from that previously used in combustion models, and also shows that the burning velocity of an idealized turbulent flame does not diverge with increasing Reynolds number at fixed turbulence intensity, a conclusion that applies even to strong turbulence. Numerical simulations of the one-dimensional inviscid Burgers equation using a Lagrangian finite-element method confirm that the theoretical upper bounds are sharp within about 15% for various forcing spectra (corresponding to various two-dimensional random media). These computations provide a new quantitative test of the replica method. The inferred nonuniversality (spectrum dependence) of the front speedup is of direct importance for combustion modeling.Comment: 20 pages, 2 figures, REVTeX 4. Moved some details to appendices, added figure on numerical metho

Relaxation Height in Energy Landscapes: an Application to Multiple Metastable States

The study of systems with multiple (not necessarily degenerate) metastable states presents subtle difficulties from the mathematical point of view related to the variational problem that has to be solved in these cases. We introduce the notion of relaxation height in a general energy landscape and we prove sufficient conditions which are valid even in presence of multiple metastable states. We show how these results can be used to approach the problem of multiple metastable states via the use of the modern theories of metastability. We finally apply these general results to the Blume--Capel model for a particular choice of the parameters ensuring the existence of two multiple, and not degenerate in energy, metastable states

Measuring degree-degree association in networks

The Pearson correlation coefficient is commonly used for quantifying the global level of degree-degree association in complex networks. Here, we use a probabilistic representation of the underlying network structure for assessing the applicability of different association measures to heavy-tailed degree distributions. Theoretical arguments together with our numerical study indicate that Pearson's coefficient often depends on the size of networks with equal association structure, impeding a systematic comparison of real-world networks. In contrast, Kendall-Gibbons' $\tau_{b}$ is a considerably more robust measure of the degree-degree association

Quantum state estimation and large deviations

In this paper we propose a method to estimate the density matrix \rho of a d-level quantum system by measurements on the N-fold system. The scheme is based on covariant observables and representation theory of unitary groups and it extends previous results concerning the estimation of the spectrum of \rho. We show that it is consistent (i.e. the original input state \rho is recovered with certainty if N \to \infty), analyze its large deviation behavior, and calculate explicitly the corresponding rate function which describes the exponential decrease of error probabilities in the limit N \to \infty. Finally we discuss the question whether the proposed scheme provides the fastest possible decay of error probabilities.Comment: LaTex2e, 40 pages, 2 figures. Substantial changes in Section 4: one new subsection (4.1) and another (4.2 was 4.1 in the previous version) completely rewritten. Minor changes in Sect. 2 and 3. Typos corrected. References added. Accepted for publication in Rev. Math. Phy

Tunneling and Metastability of continuous time Markov chains

We propose a new definition of metastability of Markov processes on countable state spaces. We obtain sufficient conditions for a sequence of processes to be metastable. In the reversible case these conditions are expressed in terms of the capacity and of the stationary measure of the metastable states