Mutation of SLC35D3 causes metabolic syndrome by impairing dopamine signaling in striatal D1 neurons

Funding: This work was partially supported by grants from National Basic Research Program of China (2013CB530605; 2014CB942803), from National Natural Science Foundation of China 1230046; 31071252; 81101182) and from Chinese Academy of Sciences (KSCX2-EW-R-05, KJZD-EW-L08). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Étude du mécanisme de la libération somatodendritique de dopamine

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Postnatal development of glutamatergic receptormediated excitatory postsynaptic currents and their modulations by ach and dopamine in nucleus accumbens

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Rôle des neuromodulateurs dans les fonctions visuelles : l'angiotensine II et la dopamine

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Étude de la caractérisation de récepteurs à la sérotonine et dopamine potentiellement impliqués dans la mémoire et l'apprentissage d'Aplysia californica

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Étude du mécanisme d'inhibition de la libération de dopamine par les autorécepteurs D2

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Étude du mécanisme de facilitation de la libération de dopamine par la neurotensine

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Étude du mécanisme de la libération somatodendritique de dopamine

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Postnatal development of glutamatergic receptormediated excitatory postsynaptic currents and their modulations by ach and dopamine in nucleus accumbens

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Rôle des neuromodulateurs dans les fonctions visuelles : l'angiotensine II et la dopamine

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Étude de la caractérisation de récepteurs à la sérotonine et dopamine potentiellement impliqués dans la mémoire et l'apprentissage d'Aplysia californica

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Étude du mécanisme d'inhibition de la libération de dopamine par les autorécepteurs D2

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Étude du mécanisme de facilitation de la libération de dopamine par la neurotensine

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Role of Dopamine D2 Receptors in the Consolidation of Amphetamine-Cue Memory in Conditioned Activity in Rats

The neurotransmitter dopamine (DA) plays an essential role in reward-related incentive learning, whereby neutral stimuli gain the ability to elicit approach and other responses. In an incentive learning paradigm called conditioned activity, animals receive a stimulant drug in a specific environment over the course of several days. When then placed in that environment drug-free, they generally display a conditioned hyperactive response. Modulating DA transmission at different time points during the paradigm has been shown to disrupt or enhance conditioning effects. For instance, blocking DA D2 receptors before sessions generally impedes the acquisition of conditioned activity. To date, no studies have examined the role of D2 receptors in the consolidation phase of conditioned activity; this phase occurs immediately after acquisition and involves the stabilization of memories for long-term storage. To investigate this possible role, I trained Wistar rats (N = 108) in the conditioned activity paradigm produced by amphetamine (2.0 mg/kg, intraperitoneally) to examine the effects of the D2 antagonist haloperidol (doses 0.10, 0.25, 0.50, 0.75, 1.0, & 2.0 mg/kg, intraperitoneally) administered 5 min after conditioning sessions. Two positive control groups received haloperidol 1 h before conditioning sessions (doses 1.0 mg/kg and 2.0 mg/kg). The results revealed that post-session haloperidol at all doses tested did not disrupt the consolidation of conditioned activity, while pre-session haloperidol at 2.0 mg/kg prevented acquisition, with the 1.0 mg/kg group trending toward a block. Additionally, post-session haloperidol did not diminish activity during conditioning days, unlike pre-session haloperidol. One possible reason for these findings is that the consolidation phase may have begun earlier than when haloperidol was administered, since the conditioned activity paradigm uses longer learning sessions than those generally used in consolidation studies. Future studies may test if conditioned activity can be achieved with shorter sessions; if so, haloperidol would then be re-tested at an earlier time point. D2 receptor second messenger systems may also be investigated in consolidation. Since drug-related incentive stimuli can evoke cravings in those with drug addiction, a better understanding of the mechanisms of incentive learning may lead to the development of solutions for these individuals.

Novel free fatty acid receptor 1 (GPR40) agonists based on 1,3,4-thiadiazole-2-carboxamide scaffold

Free fatty acid receptor 1 (FFA1), previously known as GPR40 is a G protein-coupled receptor and a new target for treatment of type 2 diabetes. Two series of FFA1 agonists utilizing a 1,3,4-thiadiazole-2-caboxamide scaffold were synthetized. Both series offered significant improvement of the potency compared to the previously described 1,3,4-thiadiazole-based FFA1 agonists and high selectivity for FFA1. Molecular docking predicts new aromatic interactions with the receptor that improve agonist potency. The most potent compounds from both series were profiled for in vitro ADME properties (plasma and metabolic stability, LogD, plasma protein binding, hERG binding and CYP inhibition). One series suffered very rapid degradation in plasma and in presence of mouse liver microsomes. However, the other series delivered a lead compound that displayed a reasonable ADME profile together with the improved FFA1 potency.