Differential Regulation of Synaptic Inputs by Constitutively Released Endocannabinoids and Exogenous Cannabinoids

Hentges, Shane T.; Low, Malcolm J.; Williams, John T.

doi:10.1523/jneurosci.2769-05.2005

Cited by 129 publications

(117 citation statements)

References 36 publications

(40 reference statements)

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“…In hippocampal slices, application of the endocannabinoid uptake inhibitor AM404 [N-(4-hydroxyphenyl)-arachidonamide] depressed IPSCs and occluded DSI (Wilson and Nicoll, 2001), and the COX-2 inhibitor meloxicam induced a gradual depression of field EPSPs (Slanina and Schweitzer, 2005). In the hypothalamic arcuate nucleus, application of AM251 increased the amplitude of IPSCs in proopiomelanocortin neurons (Hentges et al, 2005). These authors reasoned their results as the presence of constitutive endocannabinoid tone, in agreement with the present study.…”

Section: Discussionsupporting

confidence: 91%

Presynaptic Monoacylglycerol Lipase Activity Determines Basal Endocannabinoid Tone and Terminates Retrograde Endocannabinoid Signaling in the Hippocampus

Hashimotodani¹,

Ohno‐Shosaku²,

Kano³

2007

J. Neurosci.

167

165

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Endocannabinoids function as retrograde messengers and modulate synaptic transmission through presynaptic cannabinoid CB1 receptors. The magnitude and time course of endocannabinoid signaling are thought to depend on the balance between the production and degradation of endocannabinoids. The major endocannabinoid 2-arachidonoylglycerol (2-AG) is hydrolyzed by monoacylglycerol lipase (MGL), which is shown to be localized at axon terminals. In the present study, we investigated how MGL regulates endocannabinoid signaling and influences synaptic transmission in the hippocampus. We found that MGL inhibitors, methyl arachidonoyl fluorophosphonate and arachidonoyl trifluoromethylketone, caused a gradual suppression of cannabinoid-sensitive IPSCs in cultured hippocampal neurons. This suppression was reversed by blocking CB1 receptors and was attenuated by inhibiting 2-AG synthesis, indicating that MGL scavenges constitutively released 2-AG. We also found that the MGL inhibitors significantly prolonged the suppression of both IPSCs and EPSCs induced by exogenous 2-AG and depolarization-induced suppression of inhibition/excitation, a phenomenon known to be mediated by retrograde endocannabinoid signaling. In contrast, inhibitors of other endocannabinoid hydrolyzing enzymes, fatty acid amide hydrolase and cyclooxygenase-2, had no effect on the 2-AG-induced IPSC suppression. These results strongly suggest that presynaptic MGL not only hydrolyzes 2-AG released from activated postsynaptic neurons but also contributes to degradation of constitutively produced 2-AG and prevention of its accumulation around presynaptic terminals. Thus, the MGL activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus.

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Section: Discussionsupporting

confidence: 91%

Presynaptic Monoacylglycerol Lipase Activity Determines Basal Endocannabinoid Tone and Terminates Retrograde Endocannabinoid Signaling in the Hippocampus

Hashimotodani¹,

Ohno‐Shosaku²,

Kano³

2007

J. Neurosci.

167

165

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“…This is consistent with the view that MCH cells may integrate signals from both leptins and endocannabinoids (Jo et al, 2005). Another possibility by which cannabinoids might modulate feeding is by inhibiting arcuate nucleus proopiomelanocortin (POMC) neurons that are involved in the repression of food intake; however, cannabinoids reduced GABA synaptic inhibition of POMC cells, potentially raising POMC neuron activity (Hentges et al, 2005). Because POMC neurons are thought to reduce food intake, a CB1R-mediated excitation of these cells is less likely to explain the enhancement of energy stores evoked by cannabinoids in the hypothalamus.…”

Section: Mechanisms Of Action In Mch and Hypocretin Neuronssupporting

confidence: 85%

Cannabinoids Excite Hypothalamic Melanin-Concentrating Hormone But Inhibit Hypocretin/Orexin Neurons: Implications for Cannabinoid Actions on Food Intake and Cognitive Arousal

Huang¹,

Acuña-Goycolea²,

Liu³

et al. 2007

J. Neurosci.

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“…Both these effects are under the negative control of leptin, which is known to negatively control endocannabinoid tone in the hypothalamus (2). On the other hand, the effects of CB1 activation on ␣-melanocyte-stimulating hormone are controversial, since both inhibition and stimulation were reported in the study by Hentges et al (14), and no downstream effects of ␣-melanocyte-stimulating hormone on endocannabinoid levels were found in the hypothalamus (15).…”

mentioning

confidence: 99%

Peripheral, but Not Central, CB1 Antagonism Provides Food Intake–Independent Metabolic Benefits in Diet-Induced Obese Rats

et al. 2008

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OBJECTIVE-Blockade of the CB1 receptor is one of the promising strategies for the treatment of obesity. Although antagonists suppress food intake and reduce body weight, the role of central versus peripheral CB1 activation on weight loss and related metabolic parameters remains to be elucidated. We therefore specifically assessed and compared the respective potential relevance of central nervous system (CNS) versus peripheral CB1 receptors in the regulation of energy homeostasis and lipid and glucose metabolism in diet-induced obese (DIO) rats.RESEARCH DESIGN AND METHODS-Both lean and DIO rats were used for our experiments. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR, and euglycemic-hyperinsulinemic clamps were used for insulin sensitivity and glucose metabolism studies.RESULTS-Specific CNS-CB1 blockade decreased body weight and food intake but, independent of those effects, had no beneficial influence on peripheral lipid and glucose metabolism. Peripheral treatment with CB1 antagonist (Rimonabant) also reduced food intake and body weight but, in addition, independently triggered lipid mobilization pathways in white adipose tissue and cellular glucose uptake. Insulin sensitivity and skeletal muscle glucose uptake were enhanced, while hepatic glucose production was decreased during peripheral infusion of the CB1 antagonist. However, these effects depended on the antagonistelicited reduction of food intake.CONCLUSIONS-Several relevant metabolic processes appear to independently benefit from peripheral blockade of CB1, while CNS-CB1 blockade alone predominantly affects food intake and body weight. Diabetes 57:2977-2991, 2008 T he incidence of obesity and the metabolic syndrome have grown to epidemic proportions, making increased research efforts toward discovery of novel anti-obesity therapies increasingly important. Endocannabinoids are key modulators of feeding behavior through the activation of the CB1 receptor (1,2), which is localized in the periphery as well as in many brain areas involved in the regulation of energy homeostasis and reward processes (3,4). Recent studies (5-11) have demonstrated that blocking the activity of the endogenous cannabinoid system may be a successful strategy for the treatment of obesity and the metabolic syndrome.It is well known that CB1 receptors in the hypothalamus might regulate food intake through the disinhibition of the release of melanin-concentrating hormone from lateral hypothalamic neurons (12) and the inhibition of the release and/or expression of corticotrophin-releasing hormone in the paraventricular nucleus (13). Both these effects are under the negative control of leptin, which is known to negatively control endocannabinoid tone in the hypothalamus (2). On the other hand, the effects of CB1 activation on ␣-melanocyte-stimulating hormone are controversial, since both inhibition and stimulation were reported in the study by Hentges et al. (14), and no downstream effects of ␣-melanocyte-stimulating hormone on endocannabinoi...

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Differential Regulation of Synaptic Inputs by Constitutively Released Endocannabinoids and Exogenous Cannabinoids

Cited by 129 publications

References 36 publications

Presynaptic Monoacylglycerol Lipase Activity Determines Basal Endocannabinoid Tone and Terminates Retrograde Endocannabinoid Signaling in the Hippocampus

Presynaptic Monoacylglycerol Lipase Activity Determines Basal Endocannabinoid Tone and Terminates Retrograde Endocannabinoid Signaling in the Hippocampus

Cannabinoids Excite Hypothalamic Melanin-Concentrating Hormone But Inhibit Hypocretin/Orexin Neurons: Implications for Cannabinoid Actions on Food Intake and Cognitive Arousal

Peripheral, but Not Central, CB1 Antagonism Provides Food Intake–Independent Metabolic Benefits in Diet-Induced Obese Rats

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