Natural reward and drugs of abuse converge upon the mesolimbic system which mediates motivation and reward behaviors. Drugs induce neural adaptations in this system, including transcriptional, morphological, and synaptic changes, which contribute to the development and expression of drug-related memories and addiction. Previously, it has been reported that sexual experience in male rats, a natural reward behavior, induces similar neuroplasticity in the mesolimbic system and affects natural reward and drug-related behavior. The current study determined whether sexual experience causes long-lasting changes in mating, or ionotropic glutamate receptor trafficking or function in the nucleus accumbens (NAc), following 3 different reward abstinence periods: 1 day, 1 week, or 1 month after final mating session. Male Sprague Dawley rats mated during 5 consecutive days (sexual experience) or remained sexually naïve to serve as controls. Sexually experienced males displayed facilitation of initiation and performance of mating at each time point. Next, intracellular and membrane surface expression of N-methyl-D-aspartate (NMDA: NR1 subunit) and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA: GluA1, GluA2 subunits) receptors in the NAc was determined using a bis(sulfosuccinimidyl)suberate (BS3) protein cross-linking assay followed by Western Blot analysis. NR1 expression was increased at 1 day abstinence both at surface and intracellular, but decreased at surface at 1 week of abstinence. GluA2 was increased intracellularly at 1 week and increased at the surface after 1 month of abstinence. Finally, whole-cell patch clamp electrophysiological recordings determined reduced AMPA/NMDA ratio of synaptic currents in NAc shell neurons following stimulation of cortical afferents in sexually experienced males after all reward abstinence periods. Together, these data show that sexual experience causes long-term alterations in glutamate receptor expression and function in the NAc. Although not identical, this sex experience-induced neuroplasticity has similarities to that caused by psychostimulants, suggesting common mechanisms for reinforcement of natural and drug reward.

Activation of Group I metabotropic glutamate receptors (mGluRs) activates signaling cascades, resulting in calcium release from intracellular stores, ERK1/2 activation, and long term changes in synaptic activity that are implicated in learning, memory, and neurodegenerative diseases. As such, elucidating the molecular mechanisms underlying Group I mGluR signaling is important for understanding physiological responses initiated by the activation of these receptors. In the current study, we identify the multifunctional scaffolding protein spinophilin as a novel Group I mGluR-interacting protein. We demonstrate that spinophilin interacts with the C-terminal tail and second intracellular loop of Group I mGluRs. Furthermore, we show that interaction of spinophilin with Group I mGluRs attenuates receptor endocytosis and phosphorylation of ERK1/2, an effect that is dependent upon the interaction of spinophilin with the C-terminal PDZ binding motif encoded by Group I mGluRs. Spinophilin knock-out results in enhanced mGluR5 endocytosis as well as increased ERK1/2, AKT, and Ca 2؉ signaling in primary cortical neurons. In addition, the loss of spinophilin expression results in impaired mGluR5-stimulated LTD. Our results indicate that spinophilin plays an important role in regulating the activity of Group I mGluRs as well as their influence on synaptic activity.Glutamate is the main excitatory neurotransmitter in the central nervous system. The actions of glutamate are mediated via two types of receptors: ionotropic glutamate receptors, which are ligand-gated cation channels, and metabotropic glutamate receptors, which are G protein-coupled receptors (GPCRs) 2 (1, 2). Activation of mGluRs produces long term changes in synaptic plasticity, including long term potentiation and long term depression (LTD) (3, 4). Consequently, mGluRs have been implicated in both memory and learning as well as neurodegenerative disorders, such as Alzheimer and Parkinson diseases (5). The mechanism by which Group I mGluR signaling contributes to neurodegenerative disease remains unclear. However, genetic deletion of mGluR5 has been shown to improve cognitive performance and reduce Alzheimer disease-like pathology in an APPswe/PS1⌬E9 mouse model of Alzheimer disease (6). Multiple protein partners have been shown to interact with Group I mGluRs to alter their signaling and trafficking (7,8). Recently, via a tandem affinity purification proteomic screen with the mGluR1a C-terminal tail, our laboratory has discovered a novel Group I mGluR-interacting protein, protein phosphatase 1, regulatory subunit 9B (spinophilin/neurabin II). Spinophilin is a multifunctional synaptic scaffolding protein that is compartmentalized to the heads of dendritic spines and interacts with protein phosphatases (PP1␣ and -␥) and F-actin (9 -11). It also encodes three putative Src homology 3 domains, a GPCR-binding domain, a PDZ (PSD95/Disc Large/zona occludens) domain, three coiled-coiled domains, and a potential leucine/isoleucine zipper motif (12).Spinophilin is recruited...

Glioblastoma (GBM) is the leading cause of high fatality cancer arising within the adult brain. Electrotherapeutic approaches offer new promise for GBM treatment by exploiting innate vulnerabilities of cancer cells to low intensity electric fields. This report describes the preclinical outcomes of a novel electrotherapeutic strategy called Intratumoral Modulation Therapy (IMT) that uses an implanted stimulation system to deliver sustained, titratable, low intensity electric fields directly across GBM-affected brain regions. This pilot technology was applied to in vitro and animal models demonstrating significant and marked reduction in tumor cell viability and a cumulative impact of concurrent IMT and chemotherapy in GBM. No off target neurological effects were observed in treated subjects. Computational modeling predicted IMT field optimization as a means to further bolster treatment efficacy. This sentinel study provides new support for defining the potential of IMT strategies as part of a more effective multimodality treatment platform for GBM.