Decynium-22 Enhances SSRI-Induced Antidepressant-Like Effects in Mice: Uncovering Novel Targets to Treat Depression.

Decynium-22 Enhances SSRI-Induced Antidepressant-Like Effects in Mice: Uncovering Novel Targets to Treat Depression.

J Neurosci. 2013 Jun 19; 33(25): 10534-43
Horton RE, Apple DM, Owens WA, Baganz NL, Cano S, Mitchell NC, Vitela M, Gould GG, Koek W, Daws LC

Mood disorders cause much suffering and lost productivity worldwide, compounded by the fact that many patients are not effectively treated by currently available medications. The most commonly prescribed antidepressant drugs are the selective serotonin (5-HT) reuptake inhibitors (SSRIs), which act by blocking the high-affinity 5-HT transporter (SERT). The increase in extracellular 5-HT produced by SSRIs is thought to be critical to initiate downstream events needed for therapeutic effects. A potential explanation for their limited therapeutic efficacy is the recently characterized presence of low-affinity, high-capacity transporters for 5-HT in brain [i.e., organic cation transporters (OCTs) and plasma membrane monoamine transporter], which may limit the ability of SSRIs to increase extracellular 5-HT. Decynium-22 (D-22) is a blocker of these transporters, and using this compound we uncovered a significant role for OCTs in 5-HT uptake in mice genetically modified to have reduced or no SERT expression (Baganz et al., 2008). This raised the possibility that pharmacological inactivation of D-22-sensitive transporters might enhance the neurochemical and behavioral effects of SSRIs. Here we show that in wild-type mice D-22 enhances the effects of the SSRI fluvoxamine to inhibit 5-HT clearance and to produce antidepressant-like activity. This antidepressant-like activity of D-22 was attenuated in OCT3 KO mice, whereas the effect of D-22 to inhibit 5-HT clearance in the CA3 region of hippocampus persisted. Our findings point to OCT3, as well as other D-22-sensitive transporters, as novel targets for new antidepressant drugs with improved therapeutic potential. HubMed – depression


Acetylcholine encodes long-lasting presynaptic plasticity at glutamatergic synapses in the dorsal striatum after repeated amphetamine exposure.

J Neurosci. 2013 Jun 19; 33(25): 10405-26
Wang W, Darvas M, Storey GP, Bamford IJ, Gibbs JT, Palmiter RD, Bamford NS

Locomotion and cue-dependent behaviors are modified through corticostriatal signaling whereby short-term increases in dopamine availability can provoke persistent changes in glutamate release that contribute to neuropsychiatric disorders, including Parkinson’s disease and drug dependence. We found that withdrawal of mice from repeated amphetamine treatment caused a chronic presynaptic depression (CPD) in glutamate release that was most pronounced in corticostriatal terminals with a low probability of release and lasted >50 d in treated mice. An amphetamine challenge reversed CPD via a dopamine D1-receptor-dependent paradoxical presynaptic potentiation (PPP) that increased corticostriatal activity in direct pathway medium spiny neurons. This PPP was correlated with locomotor responses after a drug challenge, suggesting that it may underlie the sensitization process. Experiments in brain slices and in vivo indicated that dopamine regulation of acetylcholine release from tonically active interneurons contributes to CPD, PPP, locomotor sensitization, and cognitive ability. Therefore, a chronic decrease in corticostriatal activity during withdrawal is regulated around a new physiological range by tonically active interneurons and returns to normal upon reexposure to amphetamine, suggesting that this paradoxical return of striatal activity to a more stable, normalized state may represent an additional source of drug motivation during abstinence. HubMed – depression


Isotemporal Substitution Analysis for Physical Activity, Television Watching, and Risk of Depression.

Am J Epidemiol. 2013 Jun 19;
Mekary RA, Lucas M, Pan A, Okereke OI, Willett WC, Hu FB, Ding EL

The isotemporal substitution model (ISM) was previously developed as a methodology to study the time-substitution effects of 1 type of activity for another in a data setting with continuous outcomes. To demonstrate the application of ISM with a dichotomous outcome, we prospectively examined the associations of different activities with various activity displacements with depression risk among 32,900 US women from the Nurses’ Health Study who were free from depressive symptoms at baseline (in 1996). During a 10-year follow-up, 5,730 incident depression cases were documented. Results from the ISMs indicated that for each physical activity, differences in magnitude of effects of each activity type were observed, dependent on the activity being displaced/substituted. Notably, an isotemporal substitution gradient was found for television watching, in which its association with depression risk varied by its substitution for slow-, average-, or brisk-paced walking in a gradient toward high depression risk when television watching replaced a faster walking pace (relative risk = 1.18, 95% confidence interval: 1.05, 1.31). Conversely, no association with depression was found for replacement of television watching with 60 minutes/day of slow walking, whereas a lower depression risk (relative risk = 0.85, 95% confidence interval: 0.76, 0.95) was found when 60 minutes/day of brisk walking replaced 60 minutes/day of television watching. Thus, the ISM could offer a more meaningful alternative to the standard nonsubstitution models to support public health recommendations. HubMed – depression


Association between cancer stigma and depression among cancer survivors: a nationwide survey in Korea.

Psychooncology. 2013 Jun 20;
Cho J, Choi EK, Kim SY, Shin DW, Cho BL, Kim CH, Koh DH, Guallar E, Bardwell WA, Park JH

OBJECTIVE: Cancer patients are more likely to experience depression than the general population. This study aims to evaluate the possible association between cancer stigma and depression among cancer patients. METHODS: As a part of the Korean government’s program to develop comprehensive supportive care, we conducted a nationwide survey in 2010 at the National Cancer Center and in nine regional cancer centers across Korea. Cancer stigma was assessed by using a set of 12 questions grouped in three domains-impossibility of recovery, stereotypes of cancer patients, and experience of social discrimination. Depression was measured by using the Hospital Anxiety and Depression Scale. RESULTS: A total of 466 cancer patients were included in the study. Over 30% of the cancer survivors had negative attitudes toward cancer and held stereotypical views of themselves: about 10% of the participants experienced social discrimination due to cancer, and 24.5% reported clinically significant depressive symptoms. Patients who had or experienced cancer stigma were 2.5 times more likely to have depression than patients with positive attitudes. CONCLUSIONS: Regardless of highly developed medical science and increased survivorship, cancer survivors had cancer stigmas, and it was significantly associated with depression. IMPACT: Our findings emphasize the need for medical societies and health professionals to pay more attention to cancer stigma that patients are likely to experience during treatment. Copyright © 2013 John Wiley & Sons, Ltd. HubMed – depression