The endocannabinoid system as possible target for the treatment of obesity related disorders: beyond cannabinoid receptors

Worldwide, obesity is one of the most diffused pathologies. Several lines of recent evidence link obesity with a higher risk of neurological pathologies such as anxiety and depression; this consideration stems from the observation that palatable food consumption becomes sometimes necessary to overcome negative mental states, thus sustaining the vicious circle of “food addiction”. Endogenous acylethanolamides (such as anandamide, oleoylethanolamide, palmitoylethanolamide) might play a key role in this scenario since they participate to the mechanisms regulating both reward and mood tone. The present study aims to explore whether the abstinence from a palatable diet, after a long-term ad libitum consumption of it, might produce alterations of the emotional reactivity and mood tone and whether the pharmacological inhibition of fatty acid amide hydrolase (FAAH) by PF-3845 treatment (which causes an increase of acylethanolamide tone) might ameliorate such alterations. We used a rat model of diet-induced obesity based on a cafeteria-style diet. After the first 40 days of extended exposure to cafeteria diet, rats underwent an abstinence period of 28 days. During this period, animals were separated in two different groups: one group was chronically treated with PF-3845 (10 mg/kg, intraperitoneally) and the other group was treated with vehicle (ethanol/tween80/saline 5/5/90). At the end of the treatment rats were subjected to behavioral tests such as the open field test, the elevated plus maze and the forced swimming test and then were sacrificed. Brains were collected to investigate markers of monoaminergic transmission, endocannabinoid tone and inflammation in different brain areas implicated in reward, anxiety and depression. To meet this aim we used different experimental approaches including immunofluorescence, HPLC and western blot analysis. Pearson correlations tests were also conducted to correlate behavioural parameters to monoamine tissue levels in the different brain areas, as well as to investigate monoaminergic and endocannabinoid protein correlations throughout the different brain areas analysed. Our results demonstrate that long term abstinence from a palatable diet might impact both mood and reward processes: in particular, animals subjected to cafeteria diet withdrawal show an anxiety-like behavior and a depressive-like phenotype. Moreover, several neurochemical alterations are also detected in key brain areas involved in the control of mood and reward processes. These include alterations of the expression of proteins partaking to the endocannabinoid system and to the inflammatory-response, alterations in the monoaminergic tone. The repeated administration of the FAAH inhibitor PF-3845 during the abstinence period exerts an anxiolytic and antidepressant effect in abstinent rats and is effective in normalizing protein expression variations and monoamine content alterations in almost all brain areas analyzed. Pearson correlation tests display pattern variations both consequently to diet abstinence and pharmacological treatment. The results obtained from the present study are important in evidencing that palatable food exposure and subsequent abstinence can cause neuroadaptive changes that turn into the development of depression and anxiety, raising the importance of these comorbidities in obesity and palatable food consumption. Most importantly, we observe that enhancing the endogenous tone of acylethanolamides and endocannabinoids by blocking their enzymatic degradation might represent a novel protective strategy for psychiatric comorbidities in obese subjects

Quantum Conductivity for Metal-Insulator-Metal Nanostructures

We present a methodology based on quantum mechanics for assigning quantum conductivity when an ac field is applied across a variable gap between two plasmonic nanoparticles with an insulator sandwiched between them. The quantum tunneling effect is portrayed by a set of quantum conductivity coefficients describing the linear ac conductivity responding at the frequency of the applied field and nonlinear coefficients that modulate the field amplitude at the fundamental frequency and its harmonics. The quantum conductivity, determined with no fit parameters, has both frequency and gap dependence that can be applied to determine the nonlinear quantum effects of strong applied electromagnetic fields even when the system is composed of dissimilar metal nanostructures. Our methodology compares well to results on quantum tunneling effects reported in the literature and it is simple to extend it to a number of systems with different metals and different insulators between them

Surface Plasmon Excitation of Second Harmonic light: Emission and Absorption

We aim to clarify the role that absorption plays in nonlinear optical processes in a variety of metallic nanostructures and show how it relates to emission and conversion efficiency. We define a figure of merit that establishes the structure's ability to either favor or impede second harmonic generation. Our findings suggest that, despite the best efforts embarked upon to enhance local fields and light coupling via plasmon excitation, nearly always the absorbed harmonic energy far surpasses the harmonic energy emitted in the far field. Qualitative and quantitative understanding of absorption processes is crucial in the evaluation of practical designs of plasmonic nanostructures for the purpose of frequency mixing

Low-damping epsilon-near-zero slabs: nonlinear and nonlocal optical properties

We investigate second harmonic generation, low-threshold multistability, all-optical switching, and inherently nonlocal effects due to the free-electron gas pressure in an epsilon-near-zero (ENZ) metamaterial slab made of cylindrical, plasmonic nanoshells illuminated by TM-polarized light. Damping compensation in the ENZ frequency region, achieved by using gain medium inside the shells' dielectric cores, enhances the nonlinear properties. Reflection is inhibited and the electric field component normal to the slab interface is enhanced near the effective pseudo-Brewster angle, where the effective \epsilon-near-zero condition triggers a non-resonant, impedance-matching phenomenon. We show that the slab displays a strong effective, spatial nonlocality associated with leaky modes that are mediated by the compensation of damping. The presence of these leaky modes then induces further spectral and angular conditions where the local fields are enhanced, thus opening new windows of opportunity for the enhancement of nonlinear optical processes

Gain assisted harmonic generation in near-zero permittivity metamaterials made of plasmonic nanoshells

We investigate enhanced harmonic generation processes in gain-assisted, near-zero permittivity metamaterials composed of spherical plasmonic nanoshells. We report the presence of narrow-band features in transmission, reflection and absorption induced by the presence of an active material inside the core of the nanoshells. The damping-compensation mechanism used to achieve the near-zero effective permittivity condition also induces a significant increase in field localization and strength and, consequently, enhancement of linear absorption. When only metal nonlinearities are considered, second and third harmonic generation efficiencies obtained by probing the structure in the vicinity of the near-zero permittivity condition approach values as high as for irradiance value as low as . These results clearly demonstrate that a relatively straightforward path now exists to the development of exotic and extreme nonlinear optical phenomena in the KW/cm2 rang