Role of the endocannabinoid system in depression and suicide K. Yaragudri Vinod 1, 2 and Basalingappa L. Hungund 1, 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 neuropsychiatric disorder and is a major cause of suicide worldwide. The prefrontal cortex is a crucial brain region that is thought to be involved in the regulation of mood, aggression and/or impulsivity and decision making, which are altered in suicidality. Evidence of the role of the endocannabinoid (EC) system in the neurobiology of neuropsychiatric disorders is beginning to emerge. The behavioral effects of ECs are believed to be mediated through the central cannabinoid CB 1 receptor. Alterations in the levels of ECs, and in the density and coupling efficacy of CB 1 receptors, have been reported in the prefrontal cortex of depressed and alcoholic suicide victims. These findings support our hypothesis that altered EC function contributes to the pathophysiologi- cal aspects of suicidal behavior. Here, we provide a brief overview of the role of the EC system in alcoholism, depression and suicide, and discuss possible therapeutic interventions and directions for future research. Importance of the prefrontal cortex in mood and cognition The prefrontal cortex is believed to be an important cortical area that participates in a putative brain circuitry involved in the pathophysiology of depression and suicidal behavior. Neuroimaging and post-mortem studies of patients with major depression have identified neurophysiological abnormalities in multiple areas of the prefrontal cortex and its linked brain regions [1,2]. Altered glucose metabo- lism, and reduced activity and volume of the prefrontal cortex have also been indicated in depression [1,3], and treatment of depression seems to reverse some of these deficits [3,4]. Injuries to the prefrontal cortex are commonly asso- ciated with the development of depression or impulsivity and they could be involved in behavioral inhibition, deci- sion making and the expression of emotions [5,6]. These cognitive functions are impaired in patients with depres- sion and suicidal behavior. Among other cortical regions, the dorsolateral prefrontal cortex (DLPFC) is crucial for decision making and in spatial working memory [7,8]. The latter cognitive function is important for maintaining decision goals, considering options and integrating the two to predict future outcomes and probabilities of meeting goals [7]. Impaired decision-making, possibly due to altered mood and emotion, might be a neuropsychological risk factor for suicidal behavior. Monoamine hypothesis of depression and suicide Biological studies of depression and suicidality have focused most frequently on the monoamine neurotrans- mitter pathways in the prefrontal cortex, particularly 5-hydroxytryptamine (5-HT) and noradrenaline (NA). Moreover, abnormalities in the function of the 5-HT system seem to be independently associated with mood disorders and suicidal behavior [9]. The majority of these studies supports the hypothesis of there being a deficit in 5-HT neurotransmission in depression and suicide. Among therapeutic agents, antidepressants are the most widely used drugs for the treatment of depression. They exert their therapeutic action through their ability to increase the synaptic content of monoamine neurotrans- mitters (e.g. 5-HT and NA). However, antidepressants exert their mood-elevating effects only after prolonged administration, indicating that enhanced 5-HT or NA neurotransmission per se is not responsible for the clinical actions of these drugs. Whereas currently available treat- ments are inadequate in many patients, the existence of additional biological substrates could provide potential therapeutic targets. Indeed, there is a growing interest in the notion that the endocannabinoid (EC) system has a crucial role in the regulation of mood, cognition, motivation and emotional behavior. The EC system in the CNS The EC system consists of endogenous cannabinoid CB- receptor agonists (ECs), CB receptors and proteins that are involved in the regulation and metabolism of ECs. ECs are a recently discovered class of lipid mediators that includes amides, esters and ethers of long-chain polyunsaturated fatty acids. The first EC was isolated from porcine brain in 1992 and was characterized to be arachidonoyl ethanola- mide (AEA) [10]. This compound was later named ananda- mide, derived from the Sanskrit word ananda, which means ‘inner bliss’. Several other ECs have been identified recently; their pharmacological properties and physiologi- cal functions are currently being studied (Figure 1). They are found abundantly in the cerebral cortex, basal ganglia and limbic structures, and exert their effects mainly through the CB receptors [11]. Review TRENDS in Pharmacological Sciences Vol.27 No.10 Corresponding author: Hungund, B.L. (hungund@nki.rfmh.org). Available online 21 August 2006. www.sciencedirect.com 0165-6147/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2006.08.006