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Dwivedi Y, editor. The Neurobiological Basis of Suicide. Boca Raton (FL): CRC Press/Taylor & Francis; 2012.

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The Neurobiological Basis of Suicide.

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Chapter 5Role of the Endocannabinoid System in the Neurobiology of Suicide

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5.1. INTRODUCTION

In the past decade, remarkable advances have been made in cannabinoid (CB) research. The brain endocannabinoid (eCB) system modulates several neurobiological processes and its dysfunction is suggested to be involved in the pathophysiology of mood and drug use disorders. The CB1 receptor–mediated signaling, in particular, has been shown to play a critical role in the neural circuitry that mediates mood, motivation, and emotional behaviors. This chapter presents the data pertaining to the involvement of the eCB system in depression, suicide, and alcohol addiction.

5.2. NEURONAL CIRCUITRY THAT MEDIATES MOOD, COGNITION, AND REWARD

Several brain regions are involved in the regulation of mood and are targets of stress and stress hormones (Manji et al. 2001; McEwen 2005; Heimer and Van Hoesen 2006). Prefrontal cortex, in particular, is believed to be an important cortical area participating in the brain circuitry that regulates mood. It is involved in working memory, extinction of learning, and executive functions, and it might become dysfunctional in mood disorders (Manji et al. 2001). The stress-induced impairment in the executive function might also contribute to suicide vulnerability. The postmortem and neuroimaging studies have revealed physiological abnormalities in multiple areas of prefrontal cortex and its linked brain regions in patients with major depression (Manji et al. 2001; Sibille et al. 2004). Alterations in glucose metabolism, and reduced activity and volume of prefrontal cortex, have been shown in depressed patients (Drevets 2000; Manji et al. 2001). The treatment of depression appears to reverse some of these abnormalities (Drevets 2000; Drevets et al. 2002). In addition, the development of depression and/or impulsivity is often associated with injuries to prefrontal cortex and could also lead to behavioral inhibition, altered decision making, and emotional disturbance (Mann 2003; Bechara and Van Der Linden 2005), which have been impaired in patients with depression and suicidal behavior. Among other cortical regions, dorsolateral prefrontal cortex (DLPFC) is critically involved in decision making and in spatial working memory (Krawczyk 2002; Huettel et al. 2006). The spatial working memory is important for maintaining decision goals, considering options, and integrating the two processes to predict future outcomes and probabilities of meeting goals (Krawczyk 2002). An impairment in decision making, due to altered mood, might be a neuropsychological risk factor for suicidal behavior. In addition to prefrontal cortex, ventral striatum is an important component of the reward circuitry. Nucleus accumbens, a region of ventral striatum, contributes to the motivational salience of stimuli and reward-dependent behaviors through reciprocal cortical and subcortical connections (Berridge and Robinson 2003). The dysfunction of ventral striatum could contribute to drug addiction, possibly by affecting impulsive decision making (Kalivas and Volkow 2005; Eisch et al. 2003). It might also lead to anhedonia (an inability to experience pleasure from previously pleasurable activities), a major symptom of depression. Notably, the stimulation of nucleus accumbens is shown to alleviate anhedonia in treatment-resistant human depression (Schlaepfer et al. 2008). Taken together, the dysfunction of these brain regions and associated structures could predispose an individual to drug addiction, depression, and suicidality.

5.3. MONOAMINE HYPOTHESIS OF DEPRESSION AND SUICIDE

Although there have been considerable advances in our understanding of the neurobiology of depression, this disorder remains a major cause of suicide in the present society. Previous biological studies on depression and suicide have most frequently focused on the monoamine neurotransmitter pathways in prefrontal cortex, especially serotonin (5-HT) and norepinephrine (NE). Most of the studies support the hypothesis of a deficiency in 5-HT neurotransmission in the pathophysiology of major depressive and suicidal behavior (Arango et al. 2002; Caspi et al. 2003; Mann 2003). Also, alterations in the 5-HT system are likely to be independently associated with depression and suicide (Arango et al. 2002).

Among therapeutic agents, antidepressants are the most widely used drugs for the treatment of depression-related disorders. They exert their therapeutic action through elevation of the synaptic content of monoamine neurotransmitters, mainly 5-HT and NE. However, the mood-elevating effects of antidepressants can occur after a prolonged administration. This suggests that enhancement of serotonergic or noradrenergic neurotransmission per se is not sufficient for the clinical benefits. While currently available treatments are inadequate in many patients, the search for an additional biological substrate(s) that could be a therapeutic target(s) for depressive behavior is continuing. Indeed, there is accumulating evidence to suggest that the eCB system is involved in the regulation of mood, motivation, and emotional behavior.

5.4. eCB SYSTEM IN THE CENTRAL NERVOUS SYSTEM

The eCB system consists of endogenous CB receptor agonists (i.e., eCBs), CB receptors, and proteins that are involved in the metabolism and regulation of eCBs. eCBs are a class of lipid mediators, including amides, esters, and ethers of long-chain polyunsaturated fatty acids. The first eCB was isolated from porcine brain in 1992 and was characterized to be arachidonoyl ethanolamide (AEA) (Devane et al. 1992). This compound was later named anandamide, derived from the Indian Sanskrit word ananda, which means inner bliss. Subsequently, the second eCB, 2-arachidonoylglycerol (2-AG), was discovered in 1994 (Mechoulam et al. 1995; Sugiura et al. 1995). 2-AG is present at higher level in the mammalian central nervous system (CNS) compared with AEA (Blankman et al. 2007). 2-AG and AEA act as full and partial agonists at CB1 receptor, respectively. Several other eCBs have been identified lately, and their physiological roles are yet to be understood. eCBs are abundantly present in cerebral cortex, basal ganglia, and limbic structures and exert their effects mainly through CB receptors (Matias et al. 2006). Some of these eCBs, especially AEA, also act through the vanilloid receptors (Di Marzo 1998) (Figure 5.1).

FIGURE 5.1. Structure of eCBs: (a) N-arachidonoylglycine, (b) N-arachidonoyldopamine, (c) 2-arachidonoylglyceryl ether, (d) N-arachidonoylglycerol, (e) 2-arachidonoylglycine, (f) N-arachidonoylethanolamide, and (g) 9-octadecenoamide.

FIGURE 5.1

Structure of eCBs: (a) N-arachidonoylglycine, (b) N-arachidonoyldopamine, (c) 2-arachidonoylglyceryl ether, (d) N-arachidonoylglycerol, (e) 2-arachidonoylglycine, (f) N-arachidonoylethanolamide, and (g) 9-octadecenoamide. (Adapted from Vinod, K.Y. and (more...)

There are currently two known CB receptor subtypes: CB1 and CB2. CB1 receptors are primarily localized in the CNS, whereas CB2 receptors are expressed in peripheral tissue and are mainly associated with the immune system (Howlett 2002). However, recent studies have indicated the existence of CB2 receptors in the CNS (Van Sickle et al. 2005). The tissue-specific distribution of these receptors may suggest that CB1 and CB2 play different roles in mediating exocannabinoid (exoCB)- and eCB-induced effects. The human CB1 and CB2 receptors contain 472 and 360 amino acid residues, respectively, and both are members of the G-protein-coupled receptors. These receptors possess some striking difference in biochemical and pharmacological properties, despite their high homology (44% sequence identity overall and 68% in the transmembrane regions) in their amino acid sequence (Cabral and Griffin-Thomas 2009). CB1 receptors are thought to be among the most abundant neuromodulatory G-protein-coupled receptors in the mammalian brain. They are highly expressed in cerebral cortex, hippocampus, cerebellum, and basal ganglia (Howlett 2002). These receptors are negatively coupled to adenylyl cyclase and N- and P/Q type Ca2+ channels and positively to A-type and inwardly rectifying K+ channels and mitogen-activated protein kinases through Gi/o proteins (Howlett 2002).

Presently, the regulatory mechanism of the eCB system is not clearly understood. Nevertheless, the neuroanatomical and electrophysiological studies of the mammalian CNS have provided evidence for the presynaptic localization of CB1 receptor (Howlett 2002; Wilson and Nicoll 2002). The biosynthesis of eCBs appears to occur through several pathways. For instance, the synthesis of AEA could occur via the condensation of arachidonic acid and ethanolamine, which subsequently could be released from membrane phospholipids through the activation of phospholipases. Alternatively, AEA might be synthesized by phospholipase D–mediated hydrolysis of N-arachidonoylphosphatidylethanolamine in a calcium-dependent manner (Di Marzo et al. 1994). The formation of 2-AG is calcium dependent and is mediated by the enzymes phospholipase C and diacylglycerol lipase (Blankman et al. 2007). 2-AG is translocated to the presynaptic cell, where it acts at CB1 receptor. It is later inactivated by being resorbed into the cell and mainly metabolized by monoacylglycerol lipase. However, the mechanism of eCB transport across the membrane is yet to be conclusively elucidated.

Unlike classic neurotransmitters, eCBs are not stored in intracellular compartments (i.e., synaptic vesicles). They are synthesized in the postsynaptic neurons and released into the synaptic cleft on demand by stimulus-dependent cleavage of membrane phospholipids, which then act as retrograde messengers (Wilson and Nicoll 2002). Because eCBs are lipophilic, they could also diffuse through the membrane if their levels in the synaptic cleft are higher than inside the cells. The removal of eCBs from the extracellular compartment appears to be facilitated by esterification into membrane phospholipids (Di Marzo et al. 1999). AEA can also be rapidly removed from the extracellular space through an uptake mechanism by a membrane transporter protein known as the anandamide membrane transporter. An intracellular membrane-bound enzyme, fatty acid amide hydrolase (FAAH), which is located in the somatodendritic compartments of neurons, is involved in the inactivation of AEA and related lipids (Di Marzo et al. 1994; Day et al. 2001; Deutsch et al. 2001). In the CNS, eCBs activate CB1 receptors and regulate synaptic transmission of excitatory and inhibitory circuits by modulating the release of monoamine neurotransmitters (Howlett 2002; Wilson and Nicoll 2002). This action is likely to be dependent on the localization of CB1 receptors within the excitatory or inhibitory neural circuits (Figure 5.2).

FIGURE 5.2. (See color insert.

FIGURE 5.2

(See color insert.) Schematic illustration of the eCB system in the brain. AEA and 2-AG are synthesized in the postsynaptic membrane and then act as retrograde signaling molecules to stimulate the presynaptic CB1 receptor. This leads to the activation (more...)

5.5. ROLE OF THE eCB SYSTEM IN DEPRESSION AND SUICIDALITY

5.5.1. Human Studies

To date, a paucity of literature exists on the role of eCB system in the pathophysiology of major depression and suicide. A potential involvement of the eCB system in the neurobiology of depressive behavior has been revealed by the postmortem study of depressed suicide victims (Hungund et al. 2004). This study showed an elevation in CB1 receptor and CB1 receptor–stimulated G-protein activation in DLPFC of depressed suicide victims compared to non-psychiatric controls (Figure 5.3). Several studies have also indicated the genetic contributions to depressive disorder through family studies and molecular genetics. Furthermore, stressful life events could precipitate depressive illness in individuals with genetic predispositions (Fava and Kendler 2000; Caspi et al. 2003). In this context, the variants in the genes of CB1 receptor and FAAH enzyme might contribute to the susceptibility to mood disorders (Barrero et al. 2005; Monteleone et al. 2010). For example, the patients with Parkinson disease who have long alleles in CB receptor (CNR) 1 gene are less likely to suffer from depressive behavior (Barrero et al. 2005). Although no causal mechanism has been proved, an association of polymorphism and depressive behavior might be linked to the alterations in the expression of CB1 receptor and FAAH enzyme.

FIGURE 5.3. The saturation binding of CB1 receptor agonist, [3H]CP-55,940, to the synaptic membrane revealed a higher level of CB1 receptor density in dorsolateral prefrontal cortex of depressed suicide victims (DS) compared to normal control subjects (24%; ***p < 0.

FIGURE 5.3

The saturation binding of CB1 receptor agonist, [3H]CP-55,940, to the synaptic membrane revealed a higher level of CB1 receptor density in dorsolateral prefrontal cortex of depressed suicide victims (DS) compared to normal control subjects (24%; ***p (more...)

The prior studies have indicated an association between cannabis abuse and mood disorders. For instance, a long-term cannabis abuse alters cognition and attention, and it might lead to anhedonia that resembles the negative symptoms of schizophrenia (Emrich et al. 1997). The neurochemical studies have further shown higher levels of CB1 receptor agonist ([3H]CP-55,940) binding sites in the postmortem DLPFC (Brodmann area 9) and striatum of schizophrenic patients (Dean et al. 2001). Similarly, the levels of CB1 receptor antagonist ([3H]SR141716A) binding sites were higher in anterior cingulate cortex of schizophrenic patients (Zavitsanou et al. 2004). Conversely, a recent study reported a reduction in CB1 receptor immunoreactivity in DLPFC of schizophrenic patients (Eggan et al. 2010). These brain regions play an important role in cognitive function, particularly in relation to motivation and attention. While, exogenous CBs alter these processes, dysfunction of CB1 receptor in these brain regions might also contribute to negative symptoms of schizophrenia. In addition to alteration in CB1 receptor, eCBs are found to be elevated in cerebrospinal fluid of schizophrenic patients (Giuffrida et al. 2004). It remains to be clearly understood whether alterations in the CB1 receptor–mediated signaling in selective brain regions are linked to the symptoms of psychotic and/or mood disorders.

The neurochemical abnormalities in prefrontal cortex of depressed suicide victims, however, may not delineate whether they contribute to the pathophysiology of depression or suicide per se. In this regard, elevations in the levels of CB1 receptor and CB1 receptor–stimulated G-protein activation are shown in the postmortem prefrontal cortex of alcoholic suicide victims compared to alcoholic non-suicide subjects (Vinod et al. 2005). Consistent with the previous observation in depressed suicide victims (Hungund et al. 2004), this study further provided an association of upregulation of frontal cortical CB1 receptor with suicide (Figure 5.4). In addition, it found elevated levels of eCBs (AEA and 2-AG) in DLPFC of alcoholic suicide victims. However, it is important to note that eCBs are labile to the postmortem delay. The brain AEA levels increase approximately sevenfold by 6 h of postmortem delay. While, 2-AG levels rapidly decline within the first hour and remain relatively stable thereafter (Palkovits et al. 2008). These findings highlight the pitfall of analyzing eCB levels in the brain samples with varied postmortem intervals. Future studies are warranted to examine the brain samples of low and closely matched postmortem intervals.

FIGURE 5.4. The CB1 receptor–stimulated [35S]GTPγS binding was found to be significantly higher (34%; *** p < 0.

FIGURE 5.4

The CB1 receptor–stimulated [35S]GTPγS binding was found to be significantly higher (34%; *** p < 0.001; n = 11 in each group) in prefrontal cortical membranes of alcoholic suicide victims (AS) compared to chronic alcoholics (CA). (more...)

In addition to prefrontal cortex, ventral striatum is likely to contribute to the mediation of pleasurable responses and its dysfunction could lead to anhedonia. In this regard, levels of CB1 receptors and CB1 receptor–stimulated G-protein activation were shown to be significantly higher in the postmortem ventral striatum of alcoholic suicide compared to alcoholic subjects (Vinod et al. 2010). These results suggest that suicide is linked to an upregulation of CB1 receptors in ventral striatum. This upregulation might be the result of a feedback mechanism in response to a lower level of AEA and is consistent with higher activity of FAAH enzyme in alcoholic suicide compared to alcoholic subjects (Vinod et al. 2010). It remains to be seen if such changes also exist in DLPFC of alcoholic suicide victims. Nevertheless, the previous study revealed an elevation in CB1 receptors and G-protein activation (Figure 5.4) in DLPFC but not in occipital cortex of alcoholic suicide victims (Vinod et al. 2005), suggesting a region-specific dysfunction of eCB signaling. Further studies are required to examine the eCB system in the brain of depressed suicide victims compared to non-suicide depressed subjects. This would determine whether the pathophysiological features of depression and suicide have overlapping dysfunction in the eCB system. It is also important to examine whether dysfunction of the eCB system in other brain regions is associated with the pathophysiology of depression and/or suicide. The comorbidity of other psychiatric disorders and drugs of abuse with suicidal behavior (Suominen et al. 1996; Rich et al. 1998; Kessler et al. 1999; Potash et al. 2000) are potential confounding factors. In addition, changes in mood (e.g., stress and anxiety) at the time of suicidal act could also affect the brain eCB system because the previous studies have shown the involvement of the eCB system in stress and anxiety-related disorders (Patel et al. 2004; Vinod and Hungund 2006; Mangieri and Piomelli 2007; Patel and Hillard 2008; Steiner et al. 2008b; Kamprath et al. 2009).

Some of the previous studies have suggested the utility of CB1 receptor antagonist/inverse agonist for the treatment of depressive behavior. Although rimonabant (SR141716) and other CB1 receptor antagonists had therapeutic potentials in treating obesity and other pathological conditions, recent clinical studies have reported adverse effects of rimonabant. Rimonabant at a dose of 20 mg/day is shown to increase depressive behavior (Christensen et al. 2007). Recently, the U.S. Food and Drug Administration (FDA) has also reported an increase in risk of depression and suicidal ideations during treatment with rimonabant (FDA briefing document, 2007).

5.5.2. Animal Studies

Pharmacological studies in rodents have revealed a critical role of the eCB system in depressive-like behavior. For instance, an anandamide uptake inhibitor, AM404, and CB1 receptor agonist, HU-210, have been shown to exert antidepressant-like responses in the rat forced swim test (Hill and Gorzalka 2005). In addition, an increase in AEA level through inhibition of FAAH enzyme had a similar effect (Gobbi et al. 2005). A long-term exposure (20 days) of adolescent rats to CB1 receptor agonist, WIN 55,212-2 (0.2 and 1 mg/kg), is also shown to exert depressive-like behavior (Bambico et al. 2010b) and cognitive dysfunction (O’Shea et al. 2004, 2006). Moreover, an overexpression of CB2 receptor has recently been linked to a reduction in depressive-like behavior in mice (Garcia-Gutierrez et al. 2010), suggesting an antidepressant-like effect via enhancement of the CB receptor signaling pathway. The underlying mechanism by which CBs exert their antidepressant properties is not clearly understood. Nevertheless, the monoamine systems of the midbrain serve an important adaptive function in response to stress, and long-term alterations in their activity might contribute to the development of depression (Manji et al. 2001; Arango et al. 2002). A key component in the action of clinically effective antidepressants is their ability to increase the levels of central monoamine neurotransmitters. In this regard, exoCBs, and an inhibitor of FAAH (URB597), have been shown to increase the firing activity of serotonergic and noradrenergic neurons (Muntoni et al. 2006). The CB1 receptor agonist, WIN 55,212-2, also elevates NE levels in frontal cortex of rats (Oropeza et al. 2005). Furthermore, CB1 receptor partial agonist, Δ9-THC, is found to increase dopamine (DA) and glutamate levels in prefrontal cortex (Pistis 2002). In agreement with previously described findings, a long-term treatment with rimonabant is shown to elicit depression-like phenotype and decrease 5-HT levels in frontal cortex (Beyer et al. 2010).

An important insight into the role of eCB system in regulation of mood is derived from the studies revealing the effect of antidepressants on the components of eCB system. A long-term treatment with tranylcypromine (a monoamine oxidase inhibitor) and fluoxetine (a selective 5-HT reuptake inhibitor) has been shown to significantly increase CB1 receptor density in the prefrontal cortex (Hill et al. 2008). A chronic treatment with fluoxetine (10 mg/kg/day) also enhanced the CB1 receptor–mediated inhibition of adenylyl cyclase in prefrontal cortex (Mato et al. 2010). Interestingly, fluoxetine treatment completely reverses the increase in the CB1 receptor signaling in prefrontal cortex, following olfactory bulbectomy in rat (Rodriguez-Gaztelumendi et al. 2009). In addition, downregulation of eCB signaling in nucleus accumbens, which occurs after chronic unpredicted stress, could be reversed following fluoxetine treatment (Wang et al. 2010). These findings suggest that monoaminergic neurotransmission could regulate the eCB system and is indicative of a role of the cortical and accumbal eCB system in mood disorder and its treatment.

The CB1 receptor antagonists and/or inverse agonists (i.e., rimonabant and AM251) have also been shown to exert antidepressant-like effects (Shearman et al. 2003; Tzavara et al. 2003; Witkin et al. 2005) similar to those of fluoxetine in various animal models of depressive behavior (Griebel et al. 2005). Such an effect was also found to be absent in CB1 receptor knockout mice treated with AM251 (Shearman et al. 2003). Furthermore, the lack of CB1 receptor is shown to induce a facilitation of serotonergic activity in dorsal raphe nucleus by increasing 5-HT extracellular levels in prefrontal cortex in mice (Aso et al. 2009). The treatment with rimonabant is shown to increase 5-HT, NE, and DA levels in prefrontal cortex (Tzavara et al. 2003; Need et al. 2006). It is interesting to note that a long-term treatment with fluoxetine decreases the expression of CB1 receptor in frontal, cingulate, and piriform cortices, without significant alterations in parietal, temporal, and occipital regions of rodents (Oliva et al. 2005; Zarate et al. 2008). An enhancement in the 5-HT neurotransmission appears to be associated with this effect. The discrepancy pertaining to the antidepressant activity and the CB1 receptor–stimulated neurotransmitter release is yet to be clearly determined. However, the dose and duration of treatment, and the brain region under investigation (e.g., prefrontal vs. frontal cortex), might be some contributing factors.

Recent studies have highlighted the modulation of the central eCB system due to stress. For instance, downregulation of the eCB system in rat hippocampus is shown following chronic unpredictable stress (Hill et al. 2005). Acute stress, however, is found to induce elevation in prefrontal cortical AEA (Fride and Sanudo-Pena 2002) and midbrain AEA and 2-AG (Hohmann et al. 2005). Although the occurrence of major depression has been linked to an increased vulnerability to stress, the impact of stress on the eCB system and how it modulates the function of other brain regions, particularly prefrontal cortex, and how it affects mood and decision making, is not clearly understood.

Immobility tests in rodents have been extensively used as measures of depressive-like symptoms. The FAAH gene deleted (FAAH-/-) mice exhibit a reduction in immobility in the forced swim and tail suspension tests, predicting antidepressant-like activity. Electrophysiological studies further revealed an increase in dorsal raphe 5-HT neural firing. These two parameters were shown to be attenuated by rimonabant (Bambico et al. 2010a,b). Behavioral studies using CB1 receptor knockout mice, however, yielded mixed results, such as both a decrease (Zimmer et al. 1999; Martin et al. 2002) and an increase (Ledent et al. 1999) in spontaneous locomotor activity. The reasons for these contrasting results are not clear. Nevertheless, use of different genetic backgrounds and dosage of the drug might be among some contributing factors. Although the effect of CNR1 gene deletion may not be behavior-specific, neuroadaptation to the receptor deletion may also play an important role. Presently, there is an inadequate understanding of the mechanisms of CBs in the regulation of mood. Whether eCBs exert their mood-altering effects through CB1-like or non-CB receptors (e.g. vanilloid) needs to be further investigated.

5.6. MODULATION OF HPA FUNCTION BY THE eCB SYSTEM

The hypothalamic–pituitary–adrenal (HPA) axis, a neuroendocrine system, plays an important role in the regulation of mood, and its dysregulation is believed to be involved in increased susceptibility to depression and suicidal behavior and in the development of alcohol addiction (Manji et al. 2001; Mann 2003; Sher 2007; Richardson et al. 2008; Steiner et al. 2008a). It is a major regulator of circulating levels of glucocorticoid hormones (cortisol in humans and corticosterone in rodents), which are found to be elevated in major depression and in response to stress. Importantly, animal studies have shown the modulation of the HPA axis by the eCB system (Patel et al. 2004; Vinod and Hungund 2006; Steiner et al. 2008a; Kamprath et al. 2009). Notably, studies have indicated the activation of the HPA axis through CB1 receptors (Di Marzo 1998; Wenger et al. 2003; Manzanares et al. 2004) by stimulating the neurons containing corticotropin-releasing factor (Rodriguez de Fonseca et al. 1997). The stimulation of CB1 receptor leads to an elevation in the levels of corticotropin and corticosterone. This increase is shown to be attenuated by rimonabant (Murphy et al. 1998; Manzanares et al. 1999). The level of adrenocorticotropin was also found to be lower in CB1 receptor knockout mice compared to wild-type mice (Uriguen et al. 2004). Conversely, the eCB signaling has also been shown to inhibit stress-induced corticosterone release via CB1 receptor in rodents (Barna et al. 2004; Patel et al. 2004). The basal and stress-induced plasma levels of adrenocorticotropin and corticosterone are also reported to be higher in CB1 receptor knockout mice, suggesting a dysfunctional HPA axis (Haller et al. 2004). Although the discrepancy between these findings is yet to be determined, they suggest an interaction between the eCB and the neuroendocrine systems. Considering a critical role of the HPA axis in the pathophysiology of depression and suicidal behavior (Pfennig et al. 2005), it appears that the eCB system might have a critical role in the regulation of mood and emotional responses that are impaired in patients with depression and suicidal behavior.

5.7. POSSIBLE RELEVANCE OF A DYSFUNCTIONAL eCB SYSTEM TO DEPRESSION AND SUICIDE

The underlying mechanism of elevation in the levels of CB1 receptor in DLPFC of depressed suicide victims is not currently known. The upregulation of CB1 receptors because of a feedback response to low levels of eCBs in depression per se might be a possibility. This assumption is based on the findings obtained using rodent models. However, the observed sensitization of CB1 receptor and its G-protein activation, despite higher eCB levels in DLPFC of alcoholic suicide victims (Vinod et al. 2005), is of particular interest. Such a trend in the brain of depressed suicide victims could not be excluded. Although the underlying mechanism remains to be established, the changes in metabolism and uptake of eCBs appear to be responsible for altered levels of eCBs. Elevated levels of eCBs and CB1 receptors in DLPFC of suicide victims raise the following questions: what might be the mechanism that causes these changes and what are the functional consequences? Investigations into whether alterations in CB1 receptors reflect a primary pathological condition or a compensatory homeostatic adaptation in response to dysfunction in other neuronal systems remain to be elucidated.

It is important to note that the monoaminergic systems, which are involved in the regulation of mood, anxiety, reward, and impulsive behaviors, functionally interact with the eCB system (Patel et al. 2003; Vinod and Hungund 2006; Mangieri and Piomelli 2007; Kamprath et al. 2009). The cAMP response element–binding protein (CREB) pathway is also a target for several monoamine and neuromodulatory systems and is shown to play a pivotal role in neuronal plasticity associated with stress, drug addiction, and suicidal behavior (Self and Nestler 1998; Reiach et al. 1999; Dwivedi et al. 2002). Because CB1 receptors are among the most abundant neuromodulatory G-protein-coupled receptors, the alteration in their levels in prefrontal cortex and ventral striatum is likely to have a greater impact on the cAMP pathway. This appears to account for the dysfunctional cAMP-dependent protein kinase A–CREB pathway that might play a critical role in the pathophysiology of depression and suicide. Furthermore, exogenous CB (e.g., Δ9-THC) that exerts its effect mainly through CB1 receptor appears to modulate impulsive behavior (McDonald et al. 2003; Pattij and Vanderschuren 2008). In addition, AEA, is shown to elicit Δ9-THC-like discriminative and neurochemical effects (Solinas et al. 2007). Hence, the impulsive behavior, which is one of the contributing factors for suicidal behavior (Mann et al. 1999; Koller et al. 2002), might be associated with the dysfunction in the central eCB system. Importantly, ventral striatum is shown to mediate anhedonia and impulsive behavior (Eisch et al. 2003; Tremblay et al. 2005; Juckel et al. 2006; Kumar et al. 2008). Considering the reported abnormalities in CB1 receptor function in prefrontal cortex and ventral striatum of suicide victims (Hungund et al. 2004; Vinod et al. 2005), the dysfunction of eCB system in the frontocorticostriatal circuitry is likely to produce behavioral deficits associated with suicidality.

5.8. COMORBIDITY OF DRUGS OF ABUSE WITH DEPRESSION AND SUICIDAL BEHAVIOR

Psychosocial problems might contribute to suicide to some degree. However, most suicides occur in context with psychiatric illness. Mood and substance abuse disorders, in particular, are major risk factors for suicide, although clinical studies of cannabis abuse in patients with mood disorders have provided contrasting results. Recent studies have suggested the beneficial effects of CB-based drugs for the treatment of depressive behavior, while there is also a negative impact of a long-term cannabis abuse. For example, cannabis dependence is associated with increased rates of psychotic depressive symptoms and even suicidal behavior (Degenhardt et al. 2003; Friedman et al. 2004; Lynskey et al. 2004; Raphael et al. 2005). Clinical studies have also demonstrated that a short-term CB intoxication produces deficits in mood and cognition (i.e., social withdrawal with affective flattening, poor motivation, and apathy) in patients with schizophrenia (Emrich et al. 1997). Although Δ9-THC is beneficial in certain disease conditions (Manzanares et al. 2004), this psychoactive ingredient and abuse of cannabis and alcohol induce certain forms of impulsive behavior in humans (Askenazy et al. 2003; McDonald et al. 2003; Simons et al. 2005; Ramaekers et al. 2006) that might also be associated with suicidal behavior and suicide (Mann 2003; Price et al. 2009).

5.8.1. Role of eCB System in Alcohol Addiction

Besides cannabis abuse, a strong association of alcohol use disorder with depression and suicide has been shown (Friedman et al. 2004; Sher 2006). Interestingly, there is overwhelming evidence to suggest involvement of the eCB system in the regulation of alcohol-related behavior. The pharmacological manipulation of CB1 receptor function is shown to regulate alcohol-drinking behavior in rodents. For instance, CB1 receptor agonists (CP-55,940 and WIN 55,212-2) enhance alcohol-drinking behavior (Gallate et al. 1999; Colombo et al. 2004a,b; Vinod et al. 2008a). In line with these findings, a reduction in motivation to drink alcohol and relapse-like drinking behavior could be achieved by genetic deletion and antagonism of CB1 receptor function in rodents (Colombo et al. 1998; Hungund et al. 2003; Wang et al. 2003; Vinod and Hungund 2005; Malinen and Hyytia 2008; Vinod et al., 2008a, 2012; Maccioni et al. 2010). Notably, the blockade of CB1 receptor–mediated signaling specifically in nucleus accumbens is shown to suppress alcohol-drinking behavior in rats (Malinen and Hyytia 2008; Alvarez-James et al. 2009).

Preliminary clinical studies, however, have reported the inability of rimonabant to reduce alcohol drinking in alcohol-dependent subjects (Soyka et al. 2008; George et al. 2010). It remains to be examined if different dosage or other CB1 receptor antagonists have beneficial effects in alcohol dependence. The activation of CB1 receptor through an increase in endogenous AEA is also reported to enhance alcohol-drinking behavior. In this regard, the genetic deletion (Basavarajappa et al. 2006; Blednov et al. 2007; Vinod et al. 2008b) and the pharmacological inhibition of FAAH (Blednov et al. 2007; Vinod et al. 2008b) have been shown to enhance motivation to drink alcohol in mice. Prefrontal cortex is also likely to play a critical role in motivation to drink more alcohol. For example, an increase in alcohol self-administration is evident when rats are given an injection of FAAH inhibitor, URB597, into prefrontal cortex (Hansson et al. 2007). The biochemical studies have further suggested that a difference in CB1 receptor function is likely a contributing factor for variation in alcohol-seeking behavior. In this context, higher levels of CB1 receptors are correlated with greater alcohol-drinking behavior (Vinod et al. 2008a, 2012). Lower expression and activity of FAAH in prefrontal cortex in alcohol-preferring rats is also likely to be linked with increased alcohol consumption (Hansson et al. 2007).

An increased vulnerability to alcohol abuse in humans is suggested to be the result of polymorphisms in the genes of CB1 receptor (Schmidt et al. 2002; Zuo et al. 2007) and FAAH, and reduced expression and activity of FAAH (Sipe et al. 2002; Chiang et al. 2004). In addition, a relationship between CNR1 gene and attention-deficit hyperactivity disorder is also reported in alcoholic patients (Ponce et al. 2003). Some of these patients also exhibit suicidal behavior (Johann et al. 2005; Kenemans et al. 2005) that appears to be associated with impulsive behavior and impairment in the decision-making process. It remains to be established whether this polymorphism is related to the alterations in CB1 receptor levels. Nevertheless, these studies clearly indicate a role of the eCB system in alcohol addiction and underscore the importance of corticostriatal dysfunction of the eCB system in motivation/impulsive behavior.

The aggressive and impulsive behaviors are likely to be linked to alcohol addiction and suicide (Rich et al. 1998; Potash et al. 2000; Roy 2000; Koller et al. 2002; Preuss et al. 2002; Makhija and Sher 2007). Notably, the addiction to alcohol in humans is associated with the dysfunction in the brain eCB system. For instance, CB1 receptor levels were found to be significantly lower in postmortem ventral striatum of chronic alcoholic individuals compared to the healthy control group (Vinod et al. 2010), suggesting that alcohol dependence is associated with downregulation of CB1 receptors (Figure 5.5). The lower levels of CB1 receptors in chronic alcoholics is consistent with the studies in rodents showing downregulation of CB1 receptors by a long-term alcohol exposure (Basavarajappa et al. 1998; Ortiz et al. 2004; Vinod and Hungund 2006; Mitrirattanakul et al. 2007; Vinod et al. 2012). The FAAH activity was also found to be reduced in ventral striatum of chronic alcoholics compared to healthy controls (Vinod et al. 2010). While FAAH is a key degrading enzyme of AEA, a decrease in its activity might eventually elevate AEA level in chronic alcoholics and vice versa. Indeed, previous studies in rodents have shown an increase in AEA content in striatum and “limbic” brain by chronic alcohol exposure (Gonzalez et al. 2004; Vinod 2006) through reduction in the activity of FAAH (Vinod and Hungund 2006). Thus, repeated alcohol consumption could desensitize the CB1 receptor function in ventral striatum of alcohol-dependent patients as a consequence of a compensatory adaptation to increased AEA. It is inferred from these studies that the impaired eCB function might confer a phenotype of high voluntary alcohol intake. An association of the eCB system with alcohol addiction, and the existence of a high incidence rate of suicide in cannabis and alcohol abusers, indicate that dysfunction of the eCB system might be one of the major contributing factors for suicidal behavior. Although the available literature points to the existence of a strong association among suicide with many neuropsychiatric and substance use disorders, the nature of such a relation is complex and might vary depending on the disorder in question and the substance used. A causative relationship among drug abuse, depression, and suicidality is yet to be clearly established.

FIGURE 5.5. CB1 receptor levels were found to be lower in the membranes isolated from ventral striatum of chronic alcoholics (CA, 74%, ***p < 0.

FIGURE 5.5

CB1 receptor levels were found to be lower in the membranes isolated from ventral striatum of chronic alcoholics (CA, 74%, ***p < 0.0001; (A)) and alcoholic suicide victims (AS, 48%, **p < 0.001; (A)) compared to normal controls (n = 9 (more...)

5.8.2. Neurobiology of Alcohol Addiction Involving the eCB System

The dopaminergic neurotransmitter system in prefrontal cortex and ventral striatum has long been implicated in the drug-reinforcing mechanism. The mesolimbic dopaminergic system mainly consists of dopaminergic neurons whose cell bodies are located in ventral tegmental area and project terminals into nucleus accumbens, frontal cortex, amygdala, and septal area. This neuronal circuitry is likely to be involved in the process that mediates the reward mechanisms of various drugs of abuse, including alcohol (Koob 1992). Alcohol is shown to elevate extracellular DA levels in nucleus accumbens, which may increase the hedonic experience. Thus, accumbal DA may play a role in the development of addiction to alcohol. The eCB system also seems to contribute to this effect. For example, pharmacological blockade and deletion of CB1 receptor gene reduce the acute alcohol-induced release of DA in nucleus accumbens in mice (Hungund et al. 2003). In addition, alcohol consumption is shown to increase AEA content in limbic forebrain (Gonzalez et al. 2004), which appears to activate mesolimbic dopaminergic transmission by increasing DA release in nucleus accumbens. In this regard, an intravenous administration of AEA and methanandamide (a stable derivative of AEA) and pharmacological inhibition of FAAH with URB597 (which increases the brain levels of AEA) have been shown to increase DA in the shell region of nucleus accumbens (Solinas et al. 2006). On the contrary, antagonism of CB1 receptor function reduces DA release in nucleus accumbens (Tanda et al. 1999), indicating a critical role for the AEA–CB1 receptor signaling in mediating a reward effect of alcohol (Hungund et al., 2003; Vinod et al. 2008b) through the stimulation of the mesolimbic dopaminergic system. The persistent drug use might be linked to repeated activation of the mesolimbic DA system, which could enhance the incentive value of the drug of abuse. The alcohol-induced changes in the function of the accumbal DA and eCB systems might lead to the progression from reward to addiction. This might provide one of the mechanistic explanations for the pathophysiology of alcohol addiction.

5.9. CONCLUSION

One of the important tasks in psychiatry is to protect patients from their suicidal behavior. Preventive strategies could be improved by increasing our knowledge of the neurochemical abnormalities underlying this disorder. An increase in CB1 receptor levels is associated with suicide, whereas alcohol dependence is linked to the downregulation of these receptors. The changes in eCB levels might, in turn, explain differences in the CB1 receptor function in alcohol dependence, depression, and suicide. The dysfunction in the CB1 receptor–mediated signaling in frontocorticostriatal circuitry might be one of the etiological factors involved in the pathophysiology of suicide, in addition to depression and alcohol addiction. Based on preclinical studies, the antagonists of CB1 receptor appear to have therapeutic potential in the treatment of alcohol addiction. While majority of studies suggest hypoactivity of the CB1 receptor–mediated signaling in the pathophysiology of depressive behavior. Because depression is one of the major risk factors for suicide, a deficiency of this signaling might contribute to suicidal behavior. An abnormal interaction of the eCB system with the HPA axis and monoamine neurotransmitter systems might also constitute, at least in part, the underlying pathophysiology of depression and suicidal behavior. While many drugs are currently available for the treatment of these neuropsychiatric disorders, they only partially ameliorate the symptoms and elicit significant adverse effects. The data provided in this chapter support the notion that the eCB system might be an additional target for the development of a drug against alcohol use, depression, and suicidal behavior.

Although the focus of this chapter has been on the eCB system, it is important to note that its role might constitute just one facet of a very complex mental illness. A further study on the functional interactions between the eCB system and other monoamine neurotransmitter systems will be essential in understanding a given mental disorder. Numerous questions and contradictory findings exist in the field of CB research. An important question to consider is how a single CB1 receptor accounts for several of these behavioral manifestations. It is quite possible that activation of multiple signaling pathways by the CB1 receptor and/or existence of subtypes of CB or CB1 receptors in the CNS might account for the heterogeneity. Whether the dysfunction of the eCB system is directly associated with the pathophysiology of depression and suicide or if they are part of neuroadaptative changes in response to alteration in some other neuronal substrates still remains to be examined. Future studies should also focus on the effects (beneficial and adverse) of different dosage and duration of treatment of a given drug. Finally, alcohol addiction and stress-related disorders are shown to be risk factors for suicide attempts and suicide; treatment of these disorders could eventually reduce the rate of suicide.

CHEMICAL NAMES

CP-55,940: 5-(1,1-Dimethylheptyl)-2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-phenol

SR141716: N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide

AM251: 1-(2,4-Dichlorophenyl-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrozole-3-carboxamide

AM404: N-(4-Hydroxyphenyl)arachidonoylamide

HU-210: 3-(1,1-Dimethylheptyl)-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzopyran-9-methanol

Δ9-THC: Delta-9-tetrahydrocannibinol

URB597: 3´-Carbamoyl-biphenyl-3-yl-cyclohexylcarbamate

WIN 55,212-2: 2,3-Dihydro-5-methyl-3-(4-morpholinyl-methyl-pyrrolo[1,2,3-de] 1,4-benzoxazin-6yl]-1-naphthalenylmethanone mesylate

ACKNOWLEDGMENTS

The research studies cited in this chapter were partly supported by the National Institutes of Health, the National Alliance for Research on Schizophrenia and Depression, and the American Foundation for Suicide Prevention. The author is thankful to Dr. Raymond Suckow for editing this book chapter.

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