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Upregulation of CB1 Receptors and Agonist-Stimulated [35S] Molecular Psychiatry (2004) 9, 184–190 &2004 Nature Publishing Group All rights reserved 1359-4184/04 $25.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE Upregulation of CB1 receptors and agonist-stimulated [35S]GTPcS binding in the prefrontal cortex of depressed suicide victims BL Hungund1,2,3,5, KY Vinod2,5, SA Kassir1, BS Basavarajappa1,2, R Yalamanchili2, TB Cooper1,2,3, JJ Mann1,3 and V Arango1,3,4 1New York State Psychiatric Institute, New York, NY, USA; 2Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA; 3Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA; 4Department of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA Endogenous and exogenous cannabinoids (CBs) acting through the CB1 receptors have been implicated in the regulation of several behavioral and neuroendocrine functions. Modulation of endocannabinoidergic system by ethanol in mouse brain, and the association of suicide and mood disorders with alcoholism suggest possible involvement of the cannabinoidergic system in the pathophysiology of depression and suicide. Therefore, the present study was undertaken to examine the levels of CB1 receptors and mediated signaling in the dorsolateral prefrontal cortex (DLPFC) of subjects with major depression who had died by suicides 3 35 (depressed suicides, DS). [ H]CP-55,940 and CB1 receptor-stimulated [ S]GTPcS binding sites were analyzed in membranes obtained from DLPFC of DS (10) and matched normal controls (10). Upregulation (24%, Po0.0001) of CB1 receptor density (Bmax) was observed in DS (644.6748.8 fmol/mg protein) compared with matched controls (493.3752.7 fmol/mg protein). However, there was no significant alteration in the affinity of receptor (DS; 1.1470.08 vs 7 control; 1.12 0.10 nM). Higher density of CB1 receptors in DS (38%, Po0.001) was also 35 demonstrated by Western blot analysis. The CB1 receptor-stimulated [ S]GTPcS binding was significantly greater (45%, Po0.001) in the DLPFC of DS compared with matched controls. The observed upregulation of CB1 receptors with concomitant increase in the CB1 receptor- mediated [35S]GTPcS binding suggests a role for enhanced cannabinoidergic signaling in the prefrontal cortex of DS. The cannabinoidergic system may be a novel therapeutic target in the treatment of depression and/or suicidal behavior. Molecular Psychiatry (2004) 9, 184–190. doi:10.1038/sj.mp.4001376 35 Keywords: CB1 receptor; [ S]GTPgS binding; depression; suicide; prefrontal cortex Introduction of the cannabinoidergic system in health and disease is just beginning to emerge.5,6 Cannabinoid (CB) receptors received their name Significant progress has been made in characteriz- as those receptors that bind cannabinoidergic ing CB receptors both centrally and peripherally, and drugs, such as 9-tetrahydrocannabinol (D9-THC), in studying the role of second messenger systems at derived from Cannabis sativa and its biologically the cellular level. To date, two types of CB receptors, 9 7,8 active synthetic analogs. D -THC is the major CB1 and CB2, have been identified and have been psychoactive component in marijuana extracts shown to belong to G-protein coupled receptor and can produce a multiplicity of effects in (GPCR) family. Two endogenous cannabimimetic humans, including alterations in mood, percep- substances, characterized to be N-arachidonyl etha- tion, cognition and memory.1–4 Marijuana nolamide (AEA/anandamide) and 2-arachidonylgly- is currently the most widely abused drug second cerol (2-AG), were discovered and shown to act as 9,10 to alcohol. However, the functional significance agonists for CB receptors. The CB1 receptor is distributed primarily in neural tissue, whereas CB2 receptor is expressed mainly in the peripheral immune system.11,12 These receptors exhibit seven Correspondence: Dr BL Hungund, Nathan Kline Institute for transmembrane domains, linked to Gi/o protein to 13 Psychiatric Research, Bldg 39, 140 Old Orangeburg Road, inhibit adenylyl cyclase. Interestingly, the CB1 Orangeburg, NY 10962, USA; receptor is one of the most abundant neuromodula- E-mail: [email protected] tory receptors in the brain and is expressed predomi- 5BLH and KYV contributed equally to this work. Received 20 January 2003; revised 7 March 2003; accepted 10 nantly in the cerebral cortex, hippocampus, March 2003 cerebellum and basal ganglia.14–16 CB1 receptors-mediated signaling in brain of DS BL Hungund et al 185 Numerous studies have implicated alterations in The study was conducted with approval from the several receptors and G-protein function in the NYSPI Institutional Review Board. Dorsolateral pre- pathophysiology of various neurological and psychia- frontal cortex postmortem samples (Brodmann area 9) tric disorders. Decreased CB1 receptor binding in from 10 normal controls (age range: 15–79 years) were neurodegenerative diseases related to extrapyramidal studied with a matched group of 10 subjects who had function has been reported.17 Alterations in the a lifetime diagnosis of major depression and died by serotonergic (for a review see, Arango et al18) and suicide (age range: 13–77 years). The groups com- adrenergic19 receptors in the pathophysiology of prised pairs of depressed suicides (DS) and control depression and suicidal behavior are well documen- cases matched for age, sex, postmortem interval (PMI) 20 ted. Recently, Dean et al, reported increased CB1 and ethnic group. There were nine pairs of caucasians receptor density in dorsolateral prefrontal cortex and one pair of African-Americans (2nd pair in Table (DLPFC) in schizophrenia. 1). This distribution reflects the ethnic make-up of The increased levels of endocannabinoids and Allegheny County, where the samples were collected. downregulation of CB1 receptor in response to There were no significant differences in age, sex and chronic ethanol intake in mouse brain suggest PMI distribution between DS and control subjects. modulation of the endocannabinoidergic system by The demographic variables, such as sex, age, PMI and alcohol21,22 (for a review, see Hungund et al23). The cause of death, as well as toxicology results, are mood and cognition altering ability of exogenous summarized in Table 1. The Coroner determined the cannabinoids and alcohol, and the association be- cause of death and reached the verdict of suicide. tween depression, suicide and alcohol abuse raise the Toxicological analyses were performed on all the question whether endogenous cannabinoidergic sys- cases, ruling out recent consumption of substance of tem plays any role in the etiology of depression and abuse or psychoactive medication except in three suicidal behavior. Therefore, to address this question, samples where an anxiolytic drug (n ¼ 1) and ethanol we studied the density of CB1 receptors and CB1 (n ¼ 3) were detected. Two individuals received receptor-mediated [35S]GTPgS binding in prefrontal lidocaine as part of resuscitation efforts at the cortex of subjects with major depression who had emergency room. All cases were free of neuropathol- died by suicides. Further studies of the role of the ogy. Both suicides and controls were examined cannabinoidergic system in various neuropsychiatric psychiatrically by structured interviews with family disorders would be of great interest. members and/or close friends. The psychiatric diag- noses were made according to DSM-III-R criteria.25 The psychological autopsies revealed that all suicide Materials and methods victims had a lifetime diagnosis of major depression Human brain tissue and all controls were free of psychopathology. The Brain samples of prefrontal cortex were obtained from samples were coded to mask investigators to the autopsy material derived from the brain tissue diagnostic group of all subjects. All the assays were collection of the Department of Neuroscience at the carried out in a paired design under the same New York State Psychiatric Institute (NYSPI) and experimental conditions. Columbia University, NY, USA. All tissue used in this study was provided by the Allegheny County Coroner Membrane preparation in accordance with protocols approved by the Brain tissue (B1 g) was homogenized in 20 volumes Institutional Review Board of the University of of ice-cold TME buffer (50 mM Tris-HCl, 3 mM MgCl2 Pittsburgh. Brains were collected and bisected at and 1 mM of EDTA, pH 7.4) containing 0.32 M sucrose autopsy. The right hemispheres were cut coronally and freshly added protease inhibitor cocktail. The into 1.5-cm thick sections. Blocks were placed on a homogenate was centrifuged at 1000 g for 10 min at glass slide, immersed in freon (À201C) and stored at 41C. The resulting supernatant was then centrifuged À801C in tightly sealed, thick plastic bags until at 22 000 g for 20 min. The pellet was dissolved in sectioning. After a control and suicide were matched, TME buffer and recentrifuged at 22 000 g for 20 min. coronal sections (20 mm) from the hemicerebrum were The final pellet, dissolved in TME buffer, was made taken from a level just anterior to the genu of the aliquots and stored at –801C until the assay. corpus callosum with a large format Leica Cryopoly- cut cryostat. Interleaved sections every 200 mm were Determination of protein content sectioned at 50 mm and stained with cresylecht violet The protein content of the membrane fraction was for cytoarchitectonics. Once the sectioning was determined by Lowry’s method26 using bovine serum completed, Brodmann area 9 was identified using albumin (BSA) as the standard. Protein content of the gyral and sulcal landmarks, cytoarchitecture and a membrane, also normalized by silver staining, was standardized coronal atlas (Robert Perry and Edward used for Western blot analysis. Bird, personal communication), as previously de- scribed.24 Tissue from Brodmann area 9 (B1.5 g) was [3H]CP-55,940 binding assay dissected frozen, the white matter was removed as An aliquot of membrane (100 mg protein) was incu- much as possible, and tissue returned immediately to bated with TME buffer, [3H]CP-55,940 (0.05–5.0 nM) –801C until membrane preparation.
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