UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Herbal cannabis, smoked in the form of marihuana or hashish, is the most common illicit drug consumed in the Western world. In the brain, cannabinoids interact with neuronal CB1 receptors, thereby producing a marked reduction of motor activity. Here, we report that the motor depressant effect produced by the cannabinoid receptor agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]trans-4-(3-hydroxypropyl)cyclohexanol (CP55,940) is attenuated by genetic inactivation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), which is abundantly expressed in the medium spiny neurons of the striatum. Point mutation of Thr34, the protein kinase A (PKA) phosphorylation site of DARPP-32, produces a similar reduction in the effect of the CB1 agonist. In contrast, point mutation of Thr75, a site on DARPP-32 specifically phosphorylated by cyclin-dependent kinase 5, does not affect the behavioral response to CP55,940. Activation of CB1 receptors, either by an agonist or by inhibition of reuptake of endogenous cannabinoids, stimulates phosphorylation at Thr34, thereby converting DARPP-32 into an inhibitor of protein phosphatase-1. Genetic inactivation either of dopamine D2 receptors or of adenosine A2A receptors reduces the phosphorylation of DARPP-32 at Thr34 and the motor depression produced by CP55,940. Our data indicate that a considerable proportion of the psychomotor effect of cannabinoids can be accounted for by a signaling cascade in striatal projection neurons involving PKA-dependent phosphorylation of DARPP-32, achieved via modulation of dopamine D2 and adenosine A2A transmission.
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PMID:Cannabinoid action depends on phosphorylation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa at the protein kinase A site in striatal projection neurons. 1616 25

Globus pallidus neurons receive GABAergic input from the caudate-putamen via the striatopallidal pathway. Anatomical studies indicate that many CB(1) cannabinoid receptors are localized on terminals of striatopallidal axons. Accordingly, the hypothesis of the present work was that activation of CB(1) receptors presynaptically inhibits neurotransmission between striatopallidal axons and globus pallidus neurons. In sagittal mouse brain slices, striatopallidal axons were electrically stimulated in the caudate-putamen, and the resulting GABAergic inhibitory postsynaptic currents (IPSCs) were recorded in globus pallidus neurons. The synthetic cannabinoid receptor agonists R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl] pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)-methanone mesylate (WIN55212-2) and (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxy-propyl)-cyclohexanol (CP55940) decreased the amplitude of IPSCs. The CB(1) receptor antagonist rimonabant prevented the inhibition by WIN55212-2, pointing to involvement of CB(1) receptors. Depolarization of globus pallidus neurons induced a weak and short-lasting suppression of IPSCs [i.e., depolarization-induced suppression of inhibition (DSI) occurred]. Prevention of DSI by rimonabant indicates that endocannabinoids released from the postsynaptic neurons acted on CB(1) receptors to suppress synaptic transmission. WIN55212-2 did not modify currents in globus pallidus neurons elicited by GABA released from its chemically bound ("caged") form by a flash pulse, suggesting that WIN55212-2 depressed neurotransmission presynaptically. For studying the mechanism of the inhibition of GABA release, terminals of striatopallidal axons were labeled with a calcium-sensitive fluorescent dye. WIN55212-2 depressed the action potential-evoked increase in axon terminal calcium concentration. The results show that activation of CB(1) receptors by exogenous and endogenous cannabinoids leads to presynaptic inhibition of neurotransmission between striatopallidal axons and globus pallidus neurons. Depression of the action potential-evoked calcium influx into axon terminals is the probable mechanism of this inhibition.
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PMID:Effects of exogenous and endogenous cannabinoids on GABAergic neurotransmission between the caudate-putamen and the globus pallidus in the mouse. 1621 80

The long-term depression (LTD) of parallel fiber (PF) synapses onto Purkinje cells plays a central role in motor learning. Endocannabinoid release and LTD induction both depend upon activation of the metabotropic glutamate receptor mGluR1, require postsynaptic calcium increases, are synapse specific, and have a similar dependence on the associative activation of PF and climbing fiber synapses. These similarities suggest that endocannabinoid release could account for many features of cerebellar LTD. Here we show that LTD induction is blocked by a cannabinoid receptor (CB1R) antagonist, by inhibiting the synthesis of the endocannabinoid 2-arachidonyl glycerol (2-AG), and is absent in mice lacking the CB1R. Although CB1Rs are prominently expressed presynaptically at PF synapses, LTD is expressed postsynaptically. In contrast, a previously described transient form of inhibition mediated by endocannabinoids is expressed presynaptically. This indicates that Purkinje cells release 2-AG that activates CB1Rs to both transiently inhibit release and induce a postsynaptic form of LTD.
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PMID:Endocannabinoids control the induction of cerebellar LTD. 1630 Nov 80

Previous studies have suggested that cannabinoid compounds are anticonvulsants and that these compounds depress respiratory activity. However, the anticonvulsant potential of cannabinoids and their depressive effect on respiration have not been evaluated simultaneously. In the present study, we used a brainstem-spinal cord preparation model to investigate changes in inspiratory activity and the anticonvulsant effects of a cannabinoid receptor agonist, WIN 55, 212-2, in bicuculline-induced convulsion. Application of 10 microM WIN 55, 212-2 caused no change in inspiratory activity (6.9+/- 0.89 bursts/min vs. 8.0+/- 1.3 bursts/min, not significant) and decreased bicuculline-induced seizure-like nerve activity (number of seizure-like activities in 10 min, 11+/- 7.4 bursts vs. 1.5+/- 1.6 bursts, P< 0.01; average duration of seizure-like activity, 8.9+/- 4.0 sec vs. 4.7+/- 2.1 sec, P> 0.01). Our results suggest that administration of an appropriate dose of cannabinoid receptor agonist WIN 55,212-2 has an anticonvulsant effect but does not cause respiratory depression.
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PMID:Cannabinoid suppressed bicuculline-induced convulsion without respiratory depression in the brainstem-spinal cord preparation from newborn rats. 1641 5

Behavioral and molecular methods were used to study and determine whether there is a link between depression that may be a factor in drug/alcohol addiction, and the endocannabinoid hypothesis of substance abuse. Depression is a lack of interest in the pleasurable things of life (termed anhedonia) and depressed mood. It is unknown whether CB2 cannabinoid receptors are expressed in the brain and whether they are involved in depression and substance abuse. Therefore, mice were subjected daily for 4 wk to chronic mild stress (CMS), and anhedonia was measured by the consumption of 2% sucrose solution. Behavioral and rewarding effects of abused substances were determined in the CMS and control animals. The expression of CB2 receptors and their gene transcripts was compared in the brains of CMS and control animals by Western blotting using CB2 receptor antibody and reverse transcriptase-polymerase chain reaction (RT-PCR). Furthermore, the expression and immunocytochemical identification of CB2 cannabinoid receptor in the rat brain were determined. CMS induced gender-specific aversions, which were blocked by WIN55,212-2, a nonspecific CB1 and CB2 cannabinoid receptor agonist. Direct CB2 antisense oligonucleotide microinjection into the mouse brain induced anxiolysis, indicating that CB2 or CB2-like receptors are present in the brain and may influence behavior. The major finding from these studies was the expression of CB2 receptor and its gene transcript in the mouse brain, which was enhanced by CMS. These preliminary results, if confirmed, suggest that the CB2 receptors are expressed in the mammalian brain and may be involved in depression and substance abuse.
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PMID:Methods to study the behavioral effects and expression of CB2 cannabinoid receptor and its gene transcripts in the chronic mild stress model of depression. 1650 15

The present study evaluates the pharmacological profile of the new neutral cannabinoid CB1 receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole -LH-21- on feeding behavior and alcohol self-administration in rats, two behaviors inhibited by cannabinoid CB1 receptor antagonists. Administration of LH-21 (0.03, 0.3 and 3 mg/kg) to food-deprived rats resulted in a dose-dependent inhibition of feeding. Subchronic administration of LH-21 reduced food intake and body weight gain in obese Zucker rats. Acute effects on feeding were not associated with anxiety-like behaviors, or induction of complex motor behaviors such as grooming or scratching sequences, usually observed after central administration of cannabinoid receptor blockers with inverse agonist properties. LH-21 did not markedly reduce alcohol self-administration (30% reduction observed only at a high dose of 10 mg/kg). This pharmacological pattern partially overlaps that of the reference cannabinoid CB1 receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, SR141716A, (0.3, 1 and 3 mg/kg) that reduced feeding and alcohol self-administration with similar efficacy. In vitro analysis of blood-brain barrier permeability using a parallel artificial membrane permeation assay demonstrated that LH-21 has lower permeation through membranes than SR141716A. That was confirmed in vivo by studies showing lower potency of peripherally injected LH-21 when compared to SR141716A to antagonize motor depression induced by intracerebroventricular administration of the CB1 agonist CP55,940. The neutral antagonist profile and the lower penetration into the brain of LH-21 favour this class of antagonists with respect to reference inverse agonists for the treatment of obesity because they potentially will display reduced side effects.
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PMID:Antiobesity effects of the novel in vivo neutral cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole--LH 21. 1675 May 44

(1) The treatment of obesity is based on calorie reduction and moderate physical activity. (2) Rimonabant, a CB1 cannabinoid receptor antagonist, is marketed in Europe for the adjuvant treatment of obesity, in combination with a low-calorie diet and physical exercise. (3) Four double-blind placebo-controlled trials involving about 6500 patients show that, when combined with a low-calorie diet, rimonabant 20 mg/day leads to an average weight loss of 4 or 5 kg more than placebo after one year of treatment. This is similar to the weight loss reported with orlistat (indirect comparison). Effects on the lipid profile are similar to those reported with sibutramine. (4) Rimonabant has not been shown to reduce morbidity or mortality. Patients regain the weight they lost within about 9 months after rimonabant withdrawal. (5) Three placebo-controlled trials have evaluated rimonabant in smoking cessation. The available results (a single conference abstract) are inconclusive. In early 2006 the FDA and the European Medicines Agency refused to approve rimonabant for this use. (6) Adverse effects mentioned in published clinical trials of rimonabant include mental disorders (anxiety, depression), neurological disorders (dizziness) and gastrointestinal disorders (nausea, diarrhoea). No postmarketing safety data are available. The possible long-term adverse effects of rimonabant are unknown. (7) In practice, when drug therapy is considered for weight loss, it seems unwise to prescribe rimonabant: this new drug has only limited symptomatic effects and its adverse effects, especially in the long term, are poorly documented.
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PMID:Rimonabant: new drug. Obesity: loss of a few kilos, many questions. 1697 39

Fatty acid amide hydrolase (FAAH) is the enzyme responsible for the rapid degradation of fatty acid amides such as the endocannabinoid anandamide. Inhibition of FAAH activity has been suggested as a therapeutic approach for the treatment of chronic pain, depression and anxiety, through local activation of the cannabinoid receptor CB1. We have developed a high throughput screening assay for identification of FAAH inhibitors using a novel substrate, decanoyl 7-amino-4-methyl coumarin (D-AMC) that is cleaved by FAAH to release decanoic acid and the highly fluorescent molecule 7-amino-4-methyl coumarin (AMC). This assay gives an excellent signal window for measuring FAAH activity and, as a continuous assay, inherently offers improved sensitivity and accuracy over previously reported endpoint assays. The assay was validated using a panel of known FAAH inhibitors and purified recombinant human FAAH, then converted to a 384 well format and used to screen a large library of compounds (>600,000 compounds) to identify FAAH inhibitors. This screen identified numerous novel FAAH inhibitors of diverse chemotypes. These hits confirmed using a native FAAH substrate, anandamide, and had very similar rank order potency to that obtained using the D-AMC substrate. Collectively these data demonstrate that D-AMC can be successfully used to rapidly and effectively identify novel FAAH inhibitors for potential therapeutic use.
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PMID:A high throughput fluorescent assay for measuring the activity of fatty acid amide hydrolase. 1708 80

Long-term changes in synaptic efficacy produced by high-frequency stimulation (HFS) of glutamatergic afferents to the rat dorsolateral striatum exhibit heterogeneity during early stages of postnatal development. Whereas HFS most often induces striatal long-term potentiation (LTP) in rats postnatal day 12 (P12)-P14, the same stimulation tends to induce long-term depression (LTD) at ages P16-P34. Previous studies have shown that striatal LTD induction depends on retrograde endocannabinoid signaling and activation of the CB1 cannabinoid receptor. It is also known that levels of one of the primary endogenous CB1 receptor agonists, anandamide (AEA), increases during development in whole-brain samples. In the present study, we sought to determine whether this developmental increase in AEA also takes place in striatal tissue and whether increased AEA levels contribute to the postnatal switch in the response to HFS. We observed a pronounced increase in striatal levels of AEA, but not the other major endogenous cannabinoid 2-arachidonoylglycerol (2-AG), during the postnatal period characterized by the switch from LTP to LTD. Furthermore, application of synthetic AEA during HFS in field recordings of slices from P12-P14 rats allowed for induction of LTD whereas blocking the CB1 receptor during HFS in animals P16-P34 resulted in expression of LTP. However, blocking 2-AG synthesis with the DAG-lipase inhibitor tetrahydrolipstatin did not alter HFS-induced striatal LTD. In addition, synaptic depression produced by a synthetic CB1 agonist was similar across development. Together, these findings suggest that the robust developmental increase in striatal AEA may be the key factor in the emergence of HFS-induced striatal LTD.
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PMID:Anandamide regulates postnatal development of long-term synaptic plasticity in the rat dorsolateral striatum. 1732 38

For over a decade, until recently, it was thought that marijuana acts by activating brain-type cannabinoid receptors called CB1, and that a second type called CB2 cannabinoid receptor was found only in peripheral tissues. Neuronal CB2 receptors in the brain had been controversial. We reported the discovery and functional presence of CB2 cannabinoid receptors in the mammalian brain that may be involved in depression and drug abuse and this was supported by reports of identification of neuronal CB2 receptors that are involved in emesis. RT-PCR, immunoblotting, hippocampal cultures, immunohistochemistry, transmission electron microscopy, and stereotaxic techniques with behavioral assays were used to determine the functional expression of CB2 cannabinoid receptors in the rat brain and mouse brain exposed to chronic mild stress or treated with abused drugs. RT-PCR analyses supported the expression of brain CB2 receptor transcripts at levels much lower than those of CB1 receptors. In situ hybridization revealed CB2 mRNA in cerebellar neurons of wild-type but not of CB2 knockout mice. Abundant CB2 receptor immunoreactivity (iCB2) in neuronal and glial processes was detected in the brain. The effect of direct CB2 antisense oligonucleotide injection into the brain and treatment with JWH015 in motor function and plus-maze tests also demonstrated the functional presence of CB2 cannabinoid receptors in the central nervous system. In humans, there was a high incidence of Q63R polymorphism in the CB2 gene in Japanese alcoholics and depressed subjects. Contrary to the prevailing view that CB2 cannabinoid receptors are restricted to peripheral tissues and predominantly in immune cells, we demonstrated that CB2 cannabinoid receptors and their gene transcripts are widely distributed in the brain. This multifocal expression of iCB2 in the brain suggests that CB2 receptors may play broader roles than previously anticipated and may therefore be exploited as new targets in the treatment of depression and substance abuse.
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PMID:Neuropsychobiological evidence for the functional presence and expression of cannabinoid CB2 receptors in the brain. 1735 7

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