Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endocannabinoid (eCB) system plays central roles in the regulation of food intake and energy expenditure. Its alteration in activity contributes to the development and maintenance of obesity. Stimulation of the cannabinoid receptor type 1 (CB(1) receptor) increases feeding, enhances reward aspects of eating, and promotes lipogenesis, whereas its blockade decreases appetite, sustains weight loss, increases insulin sensitivity, and alleviates dysregulation of lipid metabolism. The hypothesis has been put forward that the eCB system is overactive in obesity. Hippocampal circuits are not directly involved in the neuronal control of food intake and appetite, but they play important roles in hedonic aspects of eating. We investigated the possibility whether or not diet-induced obesity (DIO) alters the functioning of the hippocampal eCB system. We found that levels of the two eCBs, 2-arachidonoyl glycerol (2-AG) and anandamide, were increased in the hippocampus from DIO mice, with a concomitant increase of the 2-AG synthesizing enzyme diacylglycerol lipase-alpha and increased CB(1) receptor immunoreactivity in CA1 and CA3 regions, whereas CB(1) receptor agonist-induced [(35)S]GTPgammaS binding was unchanged. eCB-mediated synaptic plasticity was changed in the CA1 region, as depolarization-induced suppression of inhibition and long-term depression of inhibitory synapses were enhanced. Functionality of CB(1) receptors in GABAergic neurons was furthermore revealed, as mice specifically lacking CB(1) receptors on this neuronal population were partly resistant to DIO. Our results show that DIO-induced changes in the eCB system affect not only tissues directly involved in the metabolic regulation but also brain regions mediating hedonic aspects of eating and influencing cognitive processes.
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PMID:Alterations in the hippocampal endocannabinoid system in diet-induced obese mice. 2044 53

Similar to dopamine (DA), cannabinoids strongly influence prefrontal cortical functions, such as working memory, emotional learning, and sensory perception. Although endogenous cannabinoid receptors (CB(1)Rs) are abundantly expressed in the prefrontal cortex (PFC), very little is known about endocannabinoid (eCB) signaling in this brain region. Recent behavioral and electrophysiological evidence has suggested a functional interplay between the dopamine and cannabinoid receptor systems, although the cellular mechanisms underlying this interaction remain to be elucidated. We examined this issue by combining neuroanatomical and electrophysiological techniques in PFC of rats and mice (both genders). Using immunoelectron microscopy, we show that CB(1)Rs and dopamine type 2 receptors (D(2)Rs) colocalize at terminals of symmetrical, presumably GABAergic, synapses in the PFC. Indeed, activation of either receptor can suppress GABA release onto layer 5 pyramidal cells. Furthermore, coactivation of both receptors via repetitive afferent stimulation triggers eCB-mediated long-term depression of inhibitory transmission (I-LTD). This I-LTD is heterosynaptic in nature, requiring glutamate release to activate group I metabotropic glutamate receptors. D(2)Rs most likely facilitate eCB signaling at the presynaptic site as disrupting postsynaptic D(2)R signaling does not diminish I-LTD. Facilitation of eCB-LTD may be one mechanism by which DA modulates neuronal activity in the PFC and regulates PFC-mediated behavior in vivo.
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PMID:Dopaminergic modulation of endocannabinoid-mediated plasticity at GABAergic synapses in the prefrontal cortex. 2050 90

Previously, a cannabinoid-dependent form of long-term depression (LTD) was discovered at the polysynaptic connection between the touch mechanosensory neuron and the S interneuron (Li and Burrell in J Comp Physiol A 195:831-841, 2009). In the present study, the physiological properties of this cannabinoid-dependent LTD were examined. Increases in intracellular calcium in the S interneuron are necessary for this form of LTD in this circuit. Calcium signals contributing to cannabinoid-dependent LTD are mediated by voltage-dependent calcium channel and release of calcium from intracellular stores. Inositol triphosphate receptors, but not ryanodine receptors, appear to mediate this store-released calcium signal. Cannabinoid-dependent LTD also requires activation of metabotropic serotonin receptors, possibly a serotonin type 2-like receptor. Finally, this form of LTD involves the stimulation of nitric oxide synthase and a decrease in cyclic adenosine monophosphate signaling, both of which appeared to be downstream of cannabinoid receptor activation. Based on these findings, the cellular signaling mechanisms of cannabinoid-dependent LTD in the leech are remarkably similar to vertebrate forms of cannabinoid-dependent synaptic plasticity.
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PMID:Properties of cannabinoid-dependent long-term depression in the leech. 2080 22

Endocannabinoids and their receptor CB1 play key roles in brain function. Astrocytes express CB1Rs that are activated by endocannabinoids released by neurons. However, the consequences of the endocannabinoid-mediated neuron-astrocyte signaling on synaptic transmission are unknown. We show that endocannabinoids released by hippocampal pyramidal neurons increase the probability of transmitter release at CA3-CA1 synapses. This synaptic potentiation is due to CB1R-induced Ca(2+) elevations in astrocytes, which stimulate the release of glutamate that activates presynaptic metabotropic glutamate receptors. While endocannabinoids induce synaptic depression in the stimulated neuron by direct activation of presynaptic CB1Rs, they indirectly lead to synaptic potentiation in relatively more distant neurons by activation of CB1Rs in astrocytes. Hence, astrocyte calcium signal evoked by endogenous stimuli (neuron-released endocannabinoids) modulates synaptic transmission. Therefore, astrocytes respond to endocannabinoids that then potentiate synaptic transmission, indicating that astrocytes are actively involved in brain physiology.
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PMID:Endocannabinoids potentiate synaptic transmission through stimulation of astrocytes. 2113 76

The transient receptor potential TRPV1 is a nonselective cation channel that mediates pain sensations and is commonly activated by a wide variety of exogenous and endogenous, physical and chemical stimuli. Although TRPV1 receptors are mainly found in nociceptive neurons of the peripheral nervous system, these receptors have also been found in the brain, where their role is far less understood. Activation of TRPV1 reportedly regulates neurotransmitter release at several central synapses. However, we found that TRPV1 suppressed excitatory transmission in rat and mouse dentate gyrus by regulating postsynaptic function in an input-specific manner. This suppression was a result of Ca(2+)-calcineurin and clathrin-dependent internalization of AMPA receptors. Moreover, synaptic activation of TRPV1 triggered a form of long-term depression (TRPV1-LTD) mediated by the endocannabinoid anandamide in a type 1 cannabinoid receptor-independent manner. Thus, our findings reveal a previously unknown form of endocannabinoid- and TRPV1-mediated regulation of synaptic strength at central synapses.
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PMID:TRPV1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus. 2121 72

Clinical evidence in humans suggests that there is some linkage between dysfunction in the timing of circadian rhythms and certain types of depression. In animal models, Syrian hamsters have been used extensively to study the pharmacology of circadian rhythms, while rats and mice are used to screen putative anxiolytics/antidepressant compounds. It would be beneficial to be able to test anxiolytic/antidepressant compounds in hamsters in conjunction with circadian rhythm studies. Therefore, in this study, Syrian hamsters were used in three experimental paradigms to evaluate anxiety: the elevated plus maze, the t-tube, and the open field Thatcher-Britton conflict test. Diazepam, tested with 2mg/kg and 5mg/kg intraperitoneal injections, was found to induce anxiolytic activity in each of the three tests. Hamsters were more likely to spend time in the open arms in the plus maze, displayed more exploratory behavior in the t-tube, and were quicker to enter a brightly lit exposed field in the Thatcher-Britton conflict test following injections of diazepam. Diazepam (2mg/kg) was also tested at three times during the 24-h day in the elevated plus maze: at the beginning and end of the lights-on period (Zeitgeber times 23 and 11, respectively) and once in the dark just before the room lights came on (Zeitgeber time 20). Diazepam induced anxiolytic activity only at Zeitgeber 23. Therefore, the following known and putative anxiolytic compounds were also evaluated in each of the three tests at Zeitgeber 23: citalopram, the neurokinin(1) receptor antagonists GR205171 and vestipitant, the corticotropin releasing factor(1) receptor antagonist CP154526, the cannabinoid receptor(1) agonist CP55940, the serotonin(6) receptor antagonist SB399885, and the metabotropic glutamate receptor(5) antagonists fenobam and MTEP. Vestipitant displayed some anxiolytic activity in the elevated plus maze, but this effect was not confirmed with GR205171. None of the other compounds displayed any anxiolytic activity in the tests. Nevertheless, the present results with diazepam - together with a few reports from other laboratories, indicate that the elevated plus maze may be a suitable procedure for evaluating the actions of anxiolytic compounds in Syrian hamsters. In view of current interest in novel classes of psychotropic agent interacting with diverse GABA(A) receptor recognition sites, further characterization appears justified.
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PMID:The benzodiazepine diazepam demonstrates the usefulness of Syrian hamsters as a model for anxiety testing: evaluation of other classes of anxiolytics in comparison to diazepam. 2109 64

The relationship between bone and nervous system has been considered based on clinical observations such as Reflex Sympathetic Dystrophy (RSD) or ectopic bone formation associated with spinal cord injury. Sympathtic nervous tone has been reported to control both bone formation and bone resorption. Unloading induces bone loss due to an increase in bone resorption and decrease in bone formation. Both of these two arms are shown to be influenced by sympathetic tone. In addition, cannabinoid receptor has been observed to be involved in regulation of bone mass. Psychiatric diseases such as depression has also been suggested to linked to the alteration in the levels of bone mass. These observations together point to importance of the relationship between bone mass and nervous system.
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PMID:[Control of bone remodeling by nervous system. Nervous system and bone]. 2112 31

Since Rimonabant was withdrawn in Europe in 2008 because of its substantial CNS risk factors including depression and anxiety, the development of anti-obesity drugs targeting CB1R in the brain has been suspended and/or terminated globally. Instead, developing peripherally restricted CB1R antagonists is actively pursued in the hope that not only could they eliminate any CNS adverse effects observed with Rimonabant, but also maintain therapeutic benefits in metabolic syndrome, including obesity, type 2 diabetes, and non-alcoholic fatty liver diseases. In this review, we summarized the most recent advances that have been made on this area, with particular emphasis on various synthetic approaches, whereby the increase in polarity, water solubility and polar surface area were centralized on, toward potential peripheral-acting CB1 antagonists.
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PMID:A new perspective of cannabinoid 1 receptor antagonists: approaches toward peripheral CB1R blockers without crossing the blood-brain barrier. 2151 Aug 37

Depression and anxiety are among the leading causes of societal burden. Abnormalities in 5-hydroxytryptamine (5-HT; serotonin) neurotransmission are known to be associated with depressive and anxiety symptoms. The rostral projections of brainstem dorsal (DRN) and median (MRN) raphe nuclei are the main sources of forebrain 5-HT. The expression, turnover and distribution of tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme in 5-HT biosynthesis in the DRN and MRN are complex, in keeping with the existence of different subpopulations of 5-HT neurons in this area. In the present study, we measured the expression of TPH2 mRNA in the DRN and MRN using in situ hybridization in three genetically modified mouse models, all relevant to depression and anxiety, and matched wild-type controls. Our results show quantitative modifications in TPH2 mRNA expression in the three main subregions of the DRN as well as the MRN in relation to changes in serotonergic, glutamatergic and endocannabinoid neurotransmission systems. Thus, there were significant decreases in TPH2 transcript levels in 5-HT transporter (5-HTT)-/- mutant mice, whereas increases were observed in the vesicular glutamate transporter 1 hemi knock out (VGLUT1+/-) and cannabinoid receptor 1 mutant (CB1R-/-) mice. Based on these findings, we suggest that TPH2 mRNA expression is under the influence of multiple messenger systems in relation to presynaptic and/or postsynaptic feedback control of serotonin synthesis that, 5-HTT, VGLUT1 and CB1R seem to be involved in these feedback mechanisms. Finally, our data are in line with previous reports suggesting that TPH2 activity within different raphe subregions is differentially regulated under specific conditions.
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PMID:Altered expression of neuronal tryptophan hydroxylase-2 mRNA in the dorsal and median raphe nuclei of three genetically modified mouse models relevant to depression and anxiety. 2170 53

Changes in food availability alter the output of hypothalamic nuclei that underlie energy homeostasis. Here, we asked whether food deprivation impacts the ability of GABA synapses in the dorsomedial hypothalamus (DMH), an important integrator of satiety signals, to undergo activity-dependent changes. GABA synapses in DMH slices from satiated rats exhibit endocannabinoid-mediated long-term depression (LTD(GABA)) in response to high-frequency stimulation of afferents. When CB1Rs are blocked, however, the same stimulation elicits long-term potentiation (LTP(GABA)), which manifests presynaptically and requires heterosynaptic recruitment of NMDARs and nitric oxide (NO). Interestingly, NO signaling is required for eCB-mediated LTD(GABA). Twenty-four hour food deprivation results in a CORT-mediated loss of CB1R signaling and, consequently, GABA synapses only exhibit LTP(GABA). These observations indicate that CB1R signaling promotes LTD(GABA) and gates LTP(GABA). Furthermore, the satiety state of an animal, through regulation of eCB signaling, determines the polarity of activity-dependent plasticity at GABA synapses in the DMH.
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PMID:Endocannabinoids gate state-dependent plasticity of synaptic inhibition in feeding circuits. 2183 36


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