Maytal Shabat-Simon

Repeated Electrical Stimulation of Reward-Related Brain Regions Affects Cocaine But Not “Natural” Reinforcement

Drug addiction is associated with long-lasting neuronal adaptations including alterations in dopamine and glutamate receptors in the brain reward system. Treatment strategies for cocaine addiction and especially the prevention of craving and relapse are limited, and their effectiveness is still questionable. We hypothesized that repeated stimulation of the brain reward system can induce localized neuronal adaptations that may either potentiate or reduce addictive behaviors. The present study was designed to test how repeated interference with the brain reward system using localized electrical stimulation of the medial forebrain bundle at the lateral hypothalamus (LH) or the prefrontal cortex (PFC) affects cocaine addiction-associated behaviors and some of the neuronal adaptations induced by repeated exposure to cocaine. Repeated high-frequency stimulation in either site influenced cocaine, but not sucrose reward-related behaviors. Stimulation of the LH reduced cue-induced seeking behavior, whereas stimulation of the PFC reduced both cocaine-seeking behavior and the motivation for its consumption. The behavioral findings were accompanied by glutamate receptor subtype alterations in the nucleus accumbens and the ventral tegmental area, both key structures of the reward system. It is therefore suggested that repeated electrical stimulation of the PFC can become a novel strategy for treating addiction.

Vaccination as a novel approach for treating depressive behavior.

BACKGROUND Depressive behavior in animals is often associated with reduced levels of brain-derived neurotrophic factor (BDNF) and impaired neurogenesis in the hippocampus. Recent studies showed that T cells recognizing central nervous system (CNS)-specific antigens can regulate adult hippocampal neurogenesis and expression of BDNF. On the basis of these findings, we hypothesized that controlling CNS specific immune activity by immunization with a myelin-related peptide may have an antidepressant effect. METHODS We investigated the impact of immunization with a CNS related peptide, on the behavioral and cellular outcomes of chronic mild stress (CMS; an animal model for depression) in rats. RESULTS Immunization with a weak agonist of a myelin-derived peptide ameliorated depressive behavior such as anhedonia (measured by sucrose preference), induced by CMS in rats. The behavioral outcome was accompanied by restoration of hippocampal BDNF levels and neurogenesis. CONCLUSIONS The results of this study introduce a novel approach of immunization with CNS-related antigens as a therapeutic means for fighting depression. Vaccination, as an antidepressant therapy, may invoke several molecular and cellular pathways that are known to be regulated by antidepressant drugs. Therefore, we suggest that immune-based therapies should be considered for treatment of depression.

Dissociation between Rewarding and Psychomotor Effects of Opiates: Differential Roles for Glutamate Receptors within Anterior and Posterior Portions of the Ventral Tegmental Area

The rewarding effects of drugs of abuse are thought to be dependent on the mesocorticolimbic dopamine system, which originates in the ventral tegmental area (VTA) and projects into the nucleus accumbens (NAC) and other forebrain regions. Heroin, by inhibiting GABAergic interneurons in the VTA, induces local dopaminergic activation and release in the NAC terminals. The role of other basic neurotransmitter systems, such as glutamate in the VTA, in mediating the rewarding effect of addictive drugs, is less established. We explored whether blockade of glutamate receptors in subregions of the VTA modulate the rewarding properties and/or the development of psychomotor changes induced by opiates. Administration of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; an AMPA/kainate receptor antagonist) into the anterior VTA blocked the rewarding effects of opiates in both the conditioned place preference and the self-administration paradigms without affecting the gradual increase of the psychomotor response to opiates. In contrast, administration of CNQX into the posterior VTA did not affect the rewarding properties of opiates, but blocked the initial sedative effect of opiates and the gradual increase of the psychomotor response to the drug. These findings suggest a critical role for glutamate receptors in the VTA in opiate reward, as well as behavioral and anatomical dissociation between the rewarding and psychomotor effects of opiates.

Chronic exposure to Δ9-tetrahydrocannabinol downregulates oxytocin and oxytocin-associated neurophysin in specific brain areas

Cannabinoids are widely abused drugs. Our goal was to identify genes modulated by Delta9-tetrahydrocannabinol (Delta9-THC) treatment. We found that chronic administration of Delta9-THC (1.5 mg/kg/day, i.p.; 7 days) to rats, downregulates the expression of oxytocin-neurophysin (OT-NP) mRNA and of OT and oxytocin-associated NP (NPOT) immunoreactivity in nucleus accumbens (NAc) and ventral tegmental area (VTA), brain areas involved in reward and addiction. Real-time PCR revealed a 60% and 53% reduction of OT-NP mRNA in NAc and VTA, respectively, under chronic treatment, while no changes were observed in NAc after 24 h. Immunohistochemistry showed a large decrease in number of OT and NPOT-stained fibers in NAc (by 59% and 52%, respectively) and VTA (by 50% and 56%, respectively). No changes in cell staining were observed in the paraventricular nucleus and supraoptic nucleus. As OT is known to inhibit development of drug tolerance and attenuate withdrawal symptoms, we suggest that OT downregulation could play a role during the establishment of the chronic effects of Delta9-THC.

Perioperative COX-2 and β-Adrenergic Blockade Improves Metastatic Biomarkers in Breast Cancer Patients in a Phase-II Randomized Trial

Purpose: Translational studies suggest that excess perioperative release of catecholamines and prostaglandins may facilitate metastasis and reduce disease-free survival. This trial tested the combined perioperative blockade of these pathways in breast cancer patients. Experimental Design: In a randomized placebo-controlled biomarker trial, 38 early-stage breast cancer patients received 11 days of perioperative treatment with a β-adrenergic antagonist (propranolol) and a COX-2 inhibitor (etodolac), beginning 5 days before surgery. Excised tumors and sequential blood samples were assessed for prometastatic biomarkers. Results: Drugs were well tolerated with adverse event rates comparable with placebo. Transcriptome profiling of the primary tumor tested a priori hypotheses and indicated that drug treatment significantly (i) decreased epithelial-to-mesenchymal transition, (ii) reduced activity of prometastatic/proinflammatory transcription factors (GATA-1, GATA-2, early-growth-response-3/EGR3, signal transducer and activator of transcription-3/STAT-3), and (iii) decreased tumor-infiltrating monocytes while increasing tumor-infiltrating B cells. Drug treatment also significantly abrogated presurgical increases in serum IL6 and C-reactive protein levels, abrogated perioperative declines in stimulated IL12 and IFNγ production, abrogated postoperative mobilization of CD16− “classical” monocytes, and enhanced expression of CD11a on circulating natural killer cells. Conclusions: Perioperative inhibition of COX-2 and β-adrenergic signaling provides a safe and effective strategy for inhibiting multiple cellular and molecular pathways related to metastasis and disease recurrence in early-stage breast cancer. Clin Cancer Res; 23(16); 4651–61. ©2017 AACR.

Beneficial Effect of Glatiramer Acetate Treatment on Syndecan-1 Expression in Dextran Sodium Sulfate Colitis

Syndecan-1, the most abundant heparan sulfate proteoglycan in the gastrointestinal tract, is reduced in the regenerative epithelium in inflammatory bowel disease (IBD). This study explored the effects of the immunomodulator glatiramer acetate (GA; Copaxone) treatment on syndecan-1 expression in dextran sodium sulfate (DSS)-induced colitis. Acute and chronic colitis was induced in C57BL/6 mice by 2 and 1.5% DSS in tap water, respectively. GA was applied subcutaneously, 2 mg per mouse per day, starting on the day of DSS induction until the mice were sacrificed. Syndecan-1 expression was assessed by immunohistochemistry. The effect of adoptive transfer of GA-specific T cells as an organ-specific therapy also was evaluated. Syndecan-1 expression was significantly lower in both colitis groups compared with that in naive mice (p < 0.0001). GA attenuated clinical scores and pathological manifestations of colitis and led to the reinstatement of normal levels of syndecan-1. After adoptive transfer, GA-specific cells homed to the surface epithelium of the distal colon, accompanied by the augmentation of syndecan-1 staining in their vicinity. We concluded that syndecan-1 expression is reduced in DSS-induced colitis and could be a potential prognostic factor in IBD. Treatment with GA exerts not only an anti-inflammatory effect but also a possible beneficial effect in stabilizing the intestinal epithelium barrier and tissue repair in DSS colitis. GA may be applied as a novel drug for IBD, shifting treatment from immunosuppression toward immunomodulation.

Objective Physiological Measurements but Not Subjective Reports Moderate the Effect of Hunger on Choice Behavior

Hunger is a powerful driver of human behavior, and is therefore of great interest to the study of psychology, economics, and consumer behavior. Assessing hunger levels in experiments is often biased, when using self-report methods, or complex, when using blood tests. We propose a novel way of objectively measuring subjects’ levels of hunger by identifying levels of alpha-amylase (AA) enzyme in their saliva samples. We used this measure to uncover the effect of hunger on different types of choice behaviors. We found that hunger increases risk-seeking behavior in a lottery-choice task, modifies levels of vindictiveness in a social decision-making task, but does not have a detectible effect on economic inconsistency in a budget-set choice task. Importantly, these findings were moderated by AA levels and not by self-report measures. We demonstrate the effects hunger has on choice behavior and the problematic nature of subjective measures of physiological states, and propose to use reliable and valid biologically based methods to overcome these problems.

Abstract # 1731 Perioperative COX-2 inhibition and beta-adrenoceptor blockade in breast cancer patients improve markers of immunity and reduce inflammation and primary tumor epithelial-to-mesenchymal transition (EMT)

Preclinical research has implicated excess perioperative release of catecholamines and prostaglandins in mediating the metastasis-promoting effects of stress and surgery. This study reports the first clinical test of combined blockade of these pathways using the beta-adrenergic blocker, propranolol, and the COX-2 inhibitor, etodolac. In a double-blind placebo-controlled clinical trial, 36 breast cancer patients were randomized to an 11-day oral drug treatment beginning five days before surgery. Blood samples were taken before treatment (T1), on the mornings before and after surgery (T2&T3), and after treatment cessation (T4), and excised tumors were collected. No adverse effects of drug treatment were reported. Among other findings, in the placebo group, (i) serum IL-6 and CRP levels increased before surgery (T2), and (ii) stimulated IL-12 and IFN γ levels were reduced by stress and surgery (T2&T3). Both effects were blocked and further reversed by the drug treatment. Transcriptome analyses of excised tumor tissue identified 368 genes showing >1.20-fold differential expression as a function of drug treatment. Bioinformatics analyses based on a priory hypotheses indicated decreased tumor expression of several pro-metastatic gene programs, including inflammatory and epithelial-to-mesenchymal transition (EMT). Flow cytometry showed that drug treatment also abolished a postoperative (T3) circulating influx of immature-proinflammatory monocytes (CD14++CD16-), and enhanced perioperative (T2&T3) expression levels of CD11a on NK cells. These findings suggest pro-immune, anti-inflammatory, and potential anti-metastatic effects of this novel and safe therapy.