Synaptic Depression Via Mglur1 Positive Allosteric Modulation Suppresses Cue-Induced Cocaine Craving

Cue-induced cocaine craving is a major cause of relapse in abstinent addicts. In rats, cue-induced craving progressively intensifies (incubates) during withdrawal from extended-access cocaine self-administration. After ~1 month of withdrawal, incubated craving is mediated by Ca(2+)-permeable AMPA receptors (CP-AMPARs) that accumulate in the nucleus accumbens (NAc). We found that decreased mGluR1 surface expression in the NAc preceded and enabled CP-AMPAR accumulation. Thus, restoring mGluR1 transmission by administering repeated injections of an mGluR1 positive allosteric modulator (PAM) prevented CP-AMPAR accumulation and incubation, whereas blocking mGluR1 transmission at even earlier withdrawal times accelerated CP-AMPAR accumulation. In studies conducted after prolonged withdrawal, when CP-AMPAR levels and cue-induced craving are high, we found that systemic administration of an mGluR1 PAM attenuated the expression of incubated craving by reducing CP-AMPAR transmission in the NAc to control levels. These results suggest a strategy in which recovering addicts could use a systemically active compound to protect against cue-induced relapse

A comparison of patient pain and visual outcome using topical anesthesia versus regional anesthesia during cataract surgery

Yoshikatsu Hosoda, Shoji Kuriyama, Yoko Jingami, Hidetsugu Hattori, Hisako Hayashi, Miho Matsumoto Department of Ophthalmology, Otsu Red-Cross Hospital, Otsu, Japan Purpose: The purpose of this study was to compare the level of patient pain during the phacoemulsification and implantation of foldable intraocular lenses while under topical, intracameral, or sub-Tenon lidocaine.Patients and methods: This was a retrospective study. Three hundred and one eyes subjected to cataract surgery were included in this study. All eyes underwent phacoemulsification surgery and intraocular lens implantation using topical, sub-Tenon, or intracameral anesthesia. The topical group received 4% lidocaine drops, and the intracameral group received a 0.1–0.2 cc infusion of 1% preservative-free lidocaine into the anterior chamber through the side port combined with topical drops of lidocaine. The sub-Tenon group received 2% lidocaine. Best-corrected visual acuity, corneal endothelial cell loss, and intraoperative pain level were evaluated. Pain level was assessed on a visual analog scale (range 0–2).Results: There were no significant differences in visual outcome and corneal endothelial cell loss between the three groups. The mean pain score in the sub-Tenon group was significantly lower than that in the topical and intracameral groups (P=0.0009 and P=0.0055, respectively). In 250 eyes without high myopia (<-6D), there were no significant differences in mean pain score between the sub-Tenon and intracameral groups (P=0.1417). No additional anesthesia was required in all groups.Conclusion: Intracameral lidocaine provides sufficient pain suppressive effects in eyes without high myopia, while sub-Tenon anesthesia is better for cataract surgery in eyes with high myopia. Keywords: cataract, anesthesia, topical, intracameral, sub-Teno

Structures of the extracellular regions of the group II/III metabotropic glutamate receptors

Metabotropic glutamate receptors play major roles in the activation of excitatory synapses in the central nerve system. We determined the crystal structure of the entire extracellular region of the group II receptor and that of the ligand-binding region of the group III receptor. A comparison among groups I, II, and III provides the structural basis that could account for the discrimination of group-specific agonists. Furthermore, the structure of group II includes the cysteine-rich domain, which is tightly linked to the ligand-binding domain by a disulfide bridge, suggesting a potential role in transmitting a ligand-induced conformational change into the downstream transmembrane region. The structure also reveals the lateral interaction between the two cysteine-rich domains, which could stimulate clustering of the dimeric receptors on the cell surface. We propose a general activation mechanism of the dimeric receptor coupled with both ligand-binding and interprotomer rearrangements

Structural views of the ligand-binding cores of a metabotropic glutamate receptor complexed with an antagonist and both glutamate and Gd(3+)

Crystal structures of the extracellular ligand-binding region of the metabotropic glutamate receptor, complexed with an antagonist, (S)-(α)-methyl-4-carboxyphenylglycine, and with both glutamate and Gd(3+) ion, have been determined by x-ray crystallographic analyses. The structure of the complex with the antagonist is similar to that of the unliganded resting dimer. The antagonist wedges the protomer to maintain an inactive open form. The glutamate/Gd(3+) complex is an exact 2-fold symmetric dimer, where each bi-lobed protomer adopts the closed conformation. The surface of the C-terminal domain contains an acidic patch, whose negative charges are alleviated by the metal cation to stabilize the active dimeric structure. The structural comparison between the active and resting dimers suggests that glutamate binding tends to induce domain closing and a small shift of a helix in the dimer interface. Furthermore, an interprotomer contact including the acidic patch inhibited dimer formation by the two open protomers in the active state. These findings provide a structural basis to describe the link between ligand binding and the dimer interface