Palatable food has reinforcing effects on feeding and accelerates obesity. Alteration of food-related behavior in obesity may promote maintenance of obesity. The ventral tegmental area (VTA) of the midbrain is important for food reward. However, it is unknown whether activity of VTA neurons is altered in diet-induced obesity. In this study, we examined VTA neuronal activity using an electrophysiological technique in diet-induced obese mice. Male 4-week-old mice were fed a high-fat diet or a standard diet for 5–6 weeks. Mice fed a high-fat diet gained greater body weight with heavier visceral fat compared with those fed a standard diet. Brain slice preparations were obtained from the lean and obese mice. Spontaneous activity of VTA neurons was recorded extracellularly. We found a negative correlation between firing frequency (FF) and action potential (AP) current duration in lean and obese mice VTA neurons. VTA neurons were classified as group-1 neurons (FF <5.0 Hz and AP current duration >1.2 msec) or group-2 neurons (FF ≧5.0 Hz and AP current duration ≦1.2 msec). FF, AP current duration, and firing regularity of VTA group-1 neurons were similar between lean and obese mice. Obese mice VTA group-2 neurons had a lower FF and shorter AP current duration compared with lean mice. In conclusion, obesity minimally affects VTA group-1 neurons, which are presumed to be dopaminergic, but decreases excitability of VTA group-2 neurons, which are presumed to be GABAergic. This differential effect may contribute to the pathophysiology of reward-related feeding in obesity.

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IntroductionA large-scale clinical trial, the Sequence Trial Alternatives to Relieve Depression (STAR*D) study, concluded that about one-third of the studied patients with major depressive disorder remitted during the initial treatment with selective serotonin reuptake inhibitors and that approximately half of the remitted subjects relapsed over a 1-year follow-up. The development of new therapeutic approaches with potent efficacy and good tolerability for the treatment of depressive disorders is of great importance. Adult hippocampal neurogenesis has been proposed to be important for understanding and treating depression and anxiety. The present study aimed to elucidate whether or not 5-hydroxytryptamine 1A (5-HT1A) receptor partial agonists have a potential therapeutic effect for the treatment of depressive and anxiety disorders, from the standpoint of neurogenesis.MethodsMale Sprague–Dawley rats were subcutaneously administered a vehicle or tandospirone (TDS) (1 or 10 mg/kg) once daily for 14 days. The effects of chronic TDS treatment on neurogenesis were evaluated on the day after the last injection. The quantification of hippocampal neurogenesis was estimated using immunostaining with doublecortin (DCX), a marker protein of newborn neurons.ResultsChronic TDS treatment resulted in a significant increase in the number of DCX-positive cells per volume of dentate gyrus in a dose-dependent manner.ConclusionThe results strongly suggest that 5-HT1A receptor partial agonists would be useful and beneficial in the treatment of depressive and anxiety disorders through increased hippocampal neurogenesis.Electronic supplementary materialThe online version of this article (doi:10.1007/s40120-013-0015-0) contains supplementary material, which is available to authorized users.

Rivastigmine (Riv) is a potent and selective cholinesterase (acetylcholinesterase, AChE and butyrylcholinesterase, BuChE) inhibitor developed for the treatment of Alzheimer’s disease (AD). To elucidate whether Riv causes neuronal differentiation, we examined its effect on nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. At concentrations of 0–100 μM, Riv was non-toxic in PC12 cells. Riv caused dose-dependent (10–100 μM) enhancement of NGF-induced neurite outgrowth, which was completely inhibited by the TrkA antagonist GW-441756. By contrast, Riv-mediated enhancement of neurite outgrowth was not blocked by the acetylcholine receptor antagonists, scopolamine and hexamethonium. However, the sigma-1 receptor (Sig-1R) antagonist NE-100 and sigma-2 receptor (Sig-2R) antagonist SM-21 each blocked about half of the Riv-mediated enhancement of NGF-induced neurite outgrowth. Interestingly, the simultaneous application of NE-100 and SM-21 completely blocked the enhancement of NGF-induced neurite outgrowth by Riv. These findings suggest that both Sig-1R and Sig-2R play important roles in NGF-induced neurite outgrowth through TrkA and that Riv may contribute to neuronal repair via Sig-1R and Sig-2R in AD therapy.

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