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Role of the Endocannabinoid System in Depression and Suicide

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Role of the Endocannabinoid System in Depression and Suicide Review TRENDS in Pharmacological Sciences Vol.27 No.10 Role of the endocannabinoid system in depression and suicide K. Yaragudri Vinod1,2 and Basalingappa L. Hungund1,2,3 1 Division of Analytical Psychopharmacology, New York State Psychiatric Institute, NY 10032, USA 2 Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA 3 Department of Psychiatry, College of Physicians and Surgeons, Columbia University, NY 10032, USA Depression is one of the most prevalent forms of two to predict future outcomes and probabilities of meeting neuropsychiatric disorder and is a major cause of suicide goals [7]. Impaired decision-making, possibly due to worldwide. The prefrontal cortex is a crucial brain region altered mood and emotion, might be a neuropsychological that is thought to be involved in the regulation of mood, risk factor for suicidal behavior. aggression and/or impulsivity and decision making, which are altered in suicidality. Evidence of the role of Monoamine hypothesis of depression and suicide the endocannabinoid (EC) system in the neurobiology of Biological studies of depression and suicidality have neuropsychiatric disorders is beginning to emerge. The focused most frequently on the monoamine neurotrans- behavioral effects of ECs are believed to be mediated mitter pathways in the prefrontal cortex, particularly through the central cannabinoid CB1 receptor. 5-hydroxytryptamine (5-HT) and noradrenaline (NA). Alterations in the levels of ECs, and in the density and Moreover, abnormalities in the function of the 5-HT system coupling efficacy of CB1 receptors, have been reported in seem to be independently associated with mood disorders the prefrontal cortex of depressed and alcoholic suicide and suicidal behavior [9]. The majority of these studies victims. These findings support our hypothesis that supports the hypothesis of there being a deficit in 5-HT altered EC function contributes to the pathophysiologi- neurotransmission in depression and suicide. cal aspects of suicidal behavior. Here, we provide a Among therapeutic agents, antidepressants are the brief overview of the role of the EC system in alcoholism, most widely used drugs for the treatment of depression. depression and suicide, and discuss possible They exert their therapeutic action through their ability to therapeutic interventions and directions for future increase the synaptic content of monoamine neurotrans- research. mitters (e.g. 5-HT and NA). However, antidepressants exert their mood-elevating effects only after prolonged Importance of the prefrontal cortex in mood and administration, indicating that enhanced 5-HT or NA cognition neurotransmission per se is not responsible for the clinical The prefrontal cortex is believed to be an important cortical actions of these drugs. Whereas currently available treat- area that participates in a putative brain circuitry involved ments are inadequate in many patients, the existence of in the pathophysiology of depression and suicidal behavior. additional biological substrates could provide potential Neuroimaging and post-mortem studies of patients with therapeutic targets. Indeed, there is a growing interest major depression have identified neurophysiological in the notion that the endocannabinoid (EC) system has a abnormalities in multiple areas of the prefrontal cortex crucial role in the regulation of mood, cognition, motivation and its linked brain regions [1,2]. Altered glucose metabo- and emotional behavior. lism, and reduced activity and volume of the prefrontal cortex have also been indicated in depression [1,3], and The EC system in the CNS treatment of depression seems to reverse some of these The EC system consists of endogenous cannabinoid CB- deficits [3,4]. receptor agonists (ECs), CB receptors and proteins that are Injuries to the prefrontal cortex are commonly asso- involved in the regulation and metabolism of ECs. ECs are ciated with the development of depression or impulsivity a recently discovered class of lipid mediators that includes and they could be involved in behavioral inhibition, deci- amides, esters and ethers of long-chain polyunsaturated sion making and the expression of emotions [5,6]. These fatty acids. The first EC was isolated from porcine brain in cognitive functions are impaired in patients with depres- 1992 and was characterized to be arachidonoyl ethanola- sion and suicidal behavior. Among other cortical regions, mide (AEA) [10]. This compound was later named ananda- the dorsolateral prefrontal cortex (DLPFC) is crucial for mide, derived from the Sanskrit word ananda, which decision making and in spatial working memory [7,8]. The means ‘inner bliss’. Several other ECs have been identified latter cognitive function is important for maintaining recently; their pharmacological properties and physiologi- decision goals, considering options and integrating the cal functions are currently being studied (Figure 1). They are found abundantly in the cerebral cortex, basal ganglia Corresponding author: Hungund, B.L. ([email protected]). and limbic structures, and exert their effects mainly Available online 21 August 2006. through the CB receptors [11]. www.sciencedirect.com 0165-6147/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2006.08.006 540 Review TRENDS in Pharmacological Sciences Vol.27 No.10 Figure 1. Structure of ECs. The structures of (a) N-arachidonylglycine, (b) N-arachidonyldopamine, (c) 2-arachidonoylglyceryl ether (noladin-ether), (d) O-arachidonoyl ethanolamine (virodhamine), (e) 2-arachidonoylglycerol, (f) N-arachidonoyl ethanolamide (anandamide) and (g) 9-octadecenoamide (oleamide) are shown. Adapted, with permission, from Ref. [58]. There are currently two known CB-receptor subtypes, circuits by modulating the release of several monoamine CB1 and CB2.CB1 receptors are localized primarily in the neurotransmitters [12,14]. The effects of ECs seem to CNS, whereas CB2 receptors are expressed peripherally depend on the localization of CB1 receptors within the and are associated mainly with the immune system [12]. excitatory or inhibitory neural circuits (Figure 2). Recent studies have also revealed the existence of CB2 receptors in the CNS [13]. The human CB1 receptor The EC system in depression and suicidality contains 472 amino acids and is a G-protein-coupled Human studies receptor (GPCR). CB1 receptors are the most abundant There is limited information available about the role neuromodulatory GPCR and are highly expressed in the of the EC system in depression and/or suicide. A possible cortex, hippocampus, cerebellum and basal ganglia [12]. role for the CB1 receptor in the pathophysiology of These receptors are coupled negatively to adenylyl cyclase depression has been revealed by post-mortem study [16], 2+ (AC), and N- and P/Q-type Ca channels, and positively to which demonstrated higher levels of CB1 receptor and + A-type and inwardly rectifying K channels and mitogen- CB1-receptor-mediated G-protein activation in the DLPFC activated protein kinases (MAPKs) by Gi/o proteins [12]. of depressed suicide victims compared with normal controls. The regulatory mechanisms that govern the EC system Furthermore, a genetic risk factor for depression in are not clearly understood at present. Nevertheless, neu- Parkinson’s disease (PD) was recently found to be associated roanatomical and electrophysiological studies of the mam- with polymorphisms of the CNR1 gene [17]. According to malian CNS have revealed that CB1 receptors are located this study, PD patients with long alleles in the CNR1 gene in the presynaptic terminals of neurons [12,14]. It has been are less susceptible to depression. Although the relationship proposed that ECs are synthesized in postsynaptic neurons between genotype and phenotypic behavior is yet to be following the stimulus-dependent cleavage of membrane established, alteration in the expression of CNR1 might phospholipids and are released into the synaptic cleft, have a greater role in the depressive disorder. where they function as retrograde messengers [14]. Sev- Recent studies, however, also indicate an association eral studies have indicated a role for the cellular uptake among cannabis abuse, mood alteration and the involve- mechanism – the AEA membrane transporter (AMT) – in ment of the EC system in the etiology of schizophrenia. For limiting the activity of ECs. An intracellular membrane- example, long-term cannabis abuse alters cognition and bound serine hydrolase, fatty acid amide hydrolase attention, and might include symptoms of anhedonia, (FAAH), which is preferentially located in the somatoden- which resemble negative symptoms of schizophrenia dritic compartments of neurons, is involved in the inacti- [18]. Post-mortem studies have also shown a higher den- vation of AEA and related lipids [15]. sity of the CB1 receptor in the prefrontal cortex, striatum In the CNS, ECs activate the CB1 receptor and regulate and anterior cingulate cortex of schizophrenics [19,20]. the synaptic transmission of excitatory and inhibitory These brain regions have a crucial role in normal cognition, www.sciencedirect.com Review TRENDS in Pharmacological Sciences Vol.27 No.10 541 Figure 2. The synaptic EC system. AEA, which is synthesized in the postsynaptic membrane, is a retrograde signaling molecule that binds to the presynaptic CB1 receptor. + 2+ This, in turn, acts upon various effectors – including AC, MAPK, and K and Ca channels – via Gai/o proteins. The inhibition of AC activity and the subsequent decrease
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