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CB1 Cannabinoid Receptors and Aggression
Chapter 77
CB1 Cannabinoid Receptors and Aggression: Relationship to Cannabis Use Marta Rodríguez-Arias, José Miñarro, M. Carmen Arenas, María A. Aguilar Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de València, Valencia, Spain
Abbreviations 2-AG 2-Arachidonoylglycerol 5-HT Serotonin AA Arachidonic acid AEA N-Arachidonoylethanolamine or anandamide AMT/AT Anandamide and 2-arachidonoylglycerol membrane transporter ASPD Antisocial personality disorder CB1-KO Mice lacking the CB1 receptor DAG Diacylglycerol DAGL Diacylglycerol lipase ECS Endogenous cannabinoid system FAAH Fatty acid amide hydrolase GABA γ-Aminobutyric acid GPR G-Protein-coupled receptor MA Monoamine MAGL Monoacylglycerol lipase MAPK Mitogen-activated protein kinase MAR Monoamine receptor NADA N-Arachidonoyldopamine NAPE N-Arachidonylphosphatidylethanolamine NAT N-Acyltransferase OA Oleic acid OEA Oleoylethanolamide PA Palmitic acid PEA Palmithylethanolamide Ph Chol Phosphatidylcholine Ph Eth Phosphatidylethanolamine PKA Protein kinase A PK−/−/TauVLW mice Parkin-null, human tau-overexpressing PK−/−/TauVLW PLC Phospholipase C PLD Phospholipase D PPAR Peroxisome proliferator-activated receptor PPARα Peroxisome proliferator-activated receptor α SUD Substance use disorder TAG Triacylglycerol
THC Δ9-Tetrahydrocannabinol TRPA1 Transient receptor potential ankyrin 1 TRPV1 Transient receptor potential channel type V1
INTRODUCTION The relationship between drug use and violent behavior has been firmly established through a great number of studies (see reviews Boles & Miotto, 2003; Chermack et al., 2010; Friedman, 1998). Substance use disorder is considered a common risk factor for perpetration of violence (Barrett, Teesson, & Mills, 2014), since it contributes more to violent behavior than any other mental health disorder (Pulay et al., 2008). Violent behavior can be necessary to gain access to drugs, to acquire the resources to purchase a drug, or to resolve disputes in the illegal and unregulated drug market. Violence and drug use can be results of the same factor, including personality traits such as high novelty seeking. Finally, drugs can increase the likelihood of aggression by exerting a direct effect on the subject (Hoake & Steward, 2003). In this line, drugs of abuse induce a state of intoxication (pharmacological effect), can provoke brain damage after prolonged use (neurotoxic effects), and induce extreme discomfort when abruptly discontinued after chronic use (withdrawal effects). Aggression can be generally defined as behavior that inflicts harm and injury or threatens to do so (Berkowitz, 1993). According to Baron’s definition (Baron & Richardson, 1994) aggression is any form of behavior whose goal is the harming or injuring of another living being who is motivated to avoid such treatment. In the literature, animal studies involving drug administration and laboratory measures tend to use the term aggression. On the other hand, research concerning individuals who have come into contact with law enforcement after drug consumption tend to use the term ‘‘violence” to denote aggression between two or more human beings involving physical harm or injury. Human aggression can be classified as defensive, premeditated, or impulsive–hostile (Vitiello & Stoff, 1997). This last type is linked to biological and environmental causes and is thus the most easily induced by consumption of drugs of abuse (Coccaro, Lee, & Kavoussi, 2010).
Neuropathology of Drug Addictions and Substance Misuse, Volume 1. http://dx.doi.org/10.1016/B978-0-12-800213-1.00077-8 Copyright © 2016 Elsevier Inc. All rights reserved.
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828 PART | IV Cannabinoids
Human and nonhuman aggressive behaviors have some common features, but animal aggression is considered less complex. Nevertheless, animal aggression is a broad category of behavior rather than a single behavioral pattern and encompasses various origins, motivations, expressions, and functions (Miczek, Faccidomo, Fish, & DeBold, 2007). In the behavioral repertoire of a given species, various acts can be classified as aggressive and have varying ethological significance depending on their functionality in the survival and reproduction of the species. Blanchard and Brain classified aggressive behavior in animals as offensive or defensive depending on the distal and proximal conditions that produce it, the topography of the behavior, and its consequences (Blanchard & Blanchard, 1977; Brain & Benton, 1979). Despite the great deal of controversy concerning the relationship between marijuana use and aggressive behavior in humans (Harris et al., 2010), relatively few studies have specifically examined the association between cannabis use and violence in humans (e.g., Dembo et al., 1987; Moore & Stuart, 2005; Myerscough & Taylor, 1985; Smith, Homish, Leonard, & Collins, 2013; Taylor et al., 1976). The acute effects of Δ9-tetrahydrocannabinol (THC) (the primary psychoactive component of cannabis) on aggressive behavior have been the most studied aspect with respect to this area, but the information obtained is controversial. Results show a biphasic effect of THC; while low doses of THC can slightly increase aggression, moderate and high doses can suppress or even eliminate this type of behavior (Myerscough & Taylor, 1985; Taylor et al., 1976). However, in all of these studies, variables that could have influenced the data obtained should be taken into consideration, such as rapid eye movement sleep deprivation, social seclusion, or pretreatment with another drug. The animal literature also largely fails to support the cannabis– violence relationship, as cannabis administration has been shown to enhance submissive behaviors and suppress attack behaviors. However, some animal studies, specifically those using Wistar rats, have associated cannabis administration with increased aggression. This chapter aims to summarize the most important results concerning the relationship between the CB1 cannabinoid type 1 receptor and aggression. First, we offer a brief review of the history and current epidemiology of cannabis consumption and an explanation of the main components and functions of the endocannabinoid system. We then review studies of the relationship between cannabis and aggression in humans and discuss the main findings regarding the effects of acute or chronic cannabis consumption or withdrawal on aggressive behavior. Finally, we focus on the effects of cannabinoids in animal models of aggression.
THE ENDOCANNABINOID SYSTEM Although cannabis has been used for thousands of years, its neurobiological mechanism of action was not discovered until 1964, when the chemical structure of its main psychoactive constituent, THC, was identified (Gaoni & Mechoulam, 1964). About 20 years later, the first cannabinoid receptor (CB1) was identified (Devane, Dysarz, Johnson, Melvin, & Howlett, 1988). In 1992, the first endogenous ligand on CB receptors—arachidonoylethanolamine (AEA; anandamide), its name originating from “ananda,” meaning “the bliss” in Sanskrit—was identified (Devane et al., 1992). These findings opened the way for research that led to the discovery of the endogenous cannabinoid system (ECS), a widely distributed modulatory system involved in multiple physiological processes (pain,
growth and development, immune function), behaviors (motor control, reproduction, sleep, eating, emotional homeostasis), learning and memory, and mental disorders (Mechoulam & Parker, 2013; Rodriguez de Fonseca, 2008; Vinod & Hungund, 2006). Endocannabinoids, together with their receptors and enzymes involved in synthesis and metabolism, constitute the ECS (see Figure 1). Endocannabinoids are signaling molecules (amides, esters, and ethers of long-chain polyunsaturated fatty acids) found in abundance in the cerebral cortex, basal ganglia, and limbic structures (Matias, Bisogno, & Di Marzo, 2006). The best known are anandamide and 2-arachidonoylglycerol (2-AG) (Mechoulam et al., 1995), but several others have been identified: N-arachidonylglycine, N-arachidonoyldopamine, 2-arachidonoylglyceryl ether (noladin ether), O-arachidonoylethanolamine (virodhamine), and 9-octadecenoamide (oleamide). The ECS centers on G-protein-coupled receptors (GPR) (Pertwee et al., 2010; Rodriguez de Fonseca, 2008). Two cannabinoid receptor subtypes have been cloned: CB1 (Matsuda, Lolait, Brownstein, Young, & Bonner, 1990), which is expressed in the brain and many peripheral tissues, and CB2 (Munro, Thomas, & Abu-Shaar, 1993), which is expressed predominantly on immune cells and damaged tissues and at low levels in the brain (Mechoulam & Parker, 2013). A yet-to-be-cloned CB3 receptor has been identified in the hippocampus. CB1 is probably the most abundant GPR to exist in the brain (Pertwee, 2010). It is presynaptically located at nerve terminals where endocannabinoids act as modulators of synaptic transmission (Howlett, 2002). These receptors are coupled negatively 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 by Gi/o proteins (Howlett, 2002). CB1 receptors are located in the cerebral cortex, basal ganglia, hippocampus, anterior cingulate cortex, and cerebellum (Herkenham, Lynn, Little, Johnson, & Melvin, 1990), where they inhibit the release of several neurotransmitters (e.g., glutamate and γ-aminobutyric acid) and stimulate dopamine release in the nucleus accumbens (Mechoulam & Parker, 2013). Synthetic CB1 receptor ligands have been developed as research tools to explore the functions of the ECS system. The hundreds of CB1 receptor agonists include WIN 55,212, HU-210, and CP 55,940. The main CB1 receptor antagonists are rimonabant (SR141716A), AM251, and AM281. Genetic knockout mice that lack CB1 receptors (or other proteins related to the ECS system, e.g., CB2, fatty acid amide hydrolase (FAAH), monoacylglycerol lipase, etc.) have also been developed with this objective in mind.
CANNABIS AND AGGRESSION IN HUMANS Cannabis was historically suspected of instigating a wide variety of aggressive behaviors, which led to it being considered a social ‘‘menace’’ and to its prohibition (Hoaken & Stewart, 2003). In 1993, after reviewing the scientific literature, the US National Research Council recognized that short-term use of cannabis inhibited aggressive behavior in humans, while long-term use could promote violence (Friedman, 1998). Today, the findings of observational research in humans are largely mixed, with studies showing positive (Arseneault, Moffitt, Caspi, Taylor, & Silva, 2000; Barrett et al., 2014; Harris et al., 2010; Moore et al., 2008; Morris, TenEyck, Barnes, & Kovandzic, 2014), negative (Arendt et al., 2007), or nonexistent (Lejoyeux et al., 2013; Macdonald, Erickson, Wells, Hathaway, & Pakula, 2008) associations between marijuana and violence.
CB1 Receptors and Aggression Chapter | 77 829
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FIGURE 1 The endocannabinoid system. The two main endocannabinoids, anandamide and 2-AG, are synthesized in the postsynaptic nerve terminal. Anandamide is produced by hydrolysis of the membrane phospholipid N-arachidonylphosphatidylethanolamine, which is catalyzed by the enzyme phospholipase D. The synthesis of N-arachidonylphosphatidylethanolamine is mediated by an uncloned enzyme—N-acyltransferase—which detaches an arachidonate moiety from phospholipids (e.g., phosphatidylcholine) and transfers it to the primary amino group of phosphatidylethanolamine. 2-AG is produced by the metabolism of diacylglycerol by specific diacylglycerol lipases. The second messenger diacylglycerol is produced by hydrolysis of phospholipids or triglycerides such as triacylglycerol by phospholipase C. Anandamide and 2-AG, as well as other endocannabinoids such as palmithylethanolamide (PEA) and oleoylethanolamide (OEA), act mainly through the CB1 and CB2 receptors, although other receptors have been identified as targets of endocannabinoids (a new uncloned CB3 receptor, the GPR119 and GPR55 orphan receptors, the vanilloid VR1 receptor, and the peroxisome proliferator-activated receptor α). Endocannabinoids function as retrograde signaling molecules that inhibit the release of classical anterograde neurotransmitters by presynaptic terminals (such as monoamines) and bind with their receptor (monoamine receptor). After the activation of presynaptic CB1 receptors (by anandamide, 2-AG, or THC), different signal transduction mechanisms are stimulated. Via G inhibitory proteins, endocannabinoids inhibit adenylyl cyclase activity and subsequently reduce cAMP, leading to reduced activity of protein kinases such as protein kinase A and mitogen-activated protein kinase (MAPK) and to the modulation of ion channels (stimulation of potassium and inhibition of calcium channels) and inhibition of neurotransmitter release. The activity of endocannabinoids is limited by a transporter that takes up AEA and 2-AG into the postsynaptic cell. AEA, PEA, and OEA are degraded by the enzyme fatty acid amidohydrolase to ethanolamide plus arachidonic, oleic, or palmitic acids. 2-AG is degraded by the enzyme monoacylglycerol lipase to arachidonic acid plus glycerol.
The main reason for these discrepant results is the heterogeneity of the studies performed. First, as previously stated, human aggression is a multidimensional construct that hinders a simple definition. We have found research demonstrating an association between marijuana and delinquent behavior based on reports of marijuana consumers committing violent crimes (Arseneault et al., 2000) and exhibiting a significantly higher level of delinquent behaviors (Dembo et al., 1987) than subjects testing negative for marijuana. Conversely, White, Loeber, Stouthamer-Loeber, and Farrington (1999) found that the association between marijuana use and aggression was nonsignificant after controlling for history of aggression and alcohol use in a longitudinal study of substance use and aggression. Other studies evaluating the relation between marijuana use and violence have distinguished between nonintimate interpersonal and intimate partner violence (see review by Moore & Stuart, 2005). While mixed results were documented when nonintimate interpersonal
violence was evaluated (Moore & Stuart, 2005), studies examining the relationship between drug abuse and aggression between intimate partners revealed a significant association with marijuana, considering it an important factor in the incidence of partner aggression (Moore et al., 2008). Another reason for these relatively inconsistent findings could be the heterogeneity of the subjects assessed, which have included college students (Taylor et al., 1976), delinquents in a detention center (Dembo et al., 1987), and psychiatric patients (Arseneault et al., 2000; Barrett et al., 2014; Becker et al., 2012; Lejoyeux et al., 2013). Serious aggression in first-episode psychosis was associated with regular cannabis use (Harris et al., 2010), and posttraumatic stress disorder violence and trait aggression were associated with higher levels of cannabis use (Barrett et al., 2014). However, a lack of association between cannabis use and aggressive behavior was reported in a population of schizophrenics (Lejoyeux et al., 2013).
830 PART | IV Cannabinoids
Correlational studies support a link between cannabis use and violent behavior, but their results do not offer insight into potential causal relationships. Although cannabis use has been shown to be an independent predictor of violence at a community level (Arseneault et al., 2000), it is unclear whether it is a direct cause of violence; whether people who use cannabis are violent as a result of a third factor, such as a personality type; or whether cannabis dependence is an indirect cause of violence as a result of criminal association or crime to obtain money for the drug (Harris et al., 2010). This review principally examines studies based on psychopharmacological explanations. Multiple researchers have considered that cannabis in moderate-to-high doses reduces aggressive behavior (Hoaken & Stewart, 2003; Myerscough & Taylor, 1985). In this way, cannabis-intoxicated subjects are less likely to react aggressively (Hoaken & Stewart, 2003). This indicates that cannabis is used as a means of self-medication; indeed, in one study subjects that reported having problems controlling their violent behavior were much more likely to use cannabis to decrease aggression, as the drug helped them to relax and to decrease suspiciousness (Arendt et al., 2007). In favor of this hypothesis, a longitudinal study to assess the longterm predictive validity of antisocial personality disorder (ASPD) on criminal behavior in samples of substance abusers over a 30-year period reported a lower propensity for crime in cannabis users than in users of other stimulant drugs. Moreover, violence in ASPD patients was predicted by the absence of cannabis addiction (Fridell, Hesse, Jæger, & Kühlhorn, 2008). Marijuana use has also been related to decreased likelihood of violence with injury in interpersonal conflict incidents among men and women in substance use disorder treatment (Chermack et al., 2010). Moreover, Becker et al. (2012) observed that delinquent behavior predicted subsequent marijuana use, whereas marijuana use did not predict subsequent delinquent behavior.
Other studies reported no correlation with violent crime when marijuana was the only drug consumed (for review see Friedman, 1998). However, other studies have reported that marijuana use predicts later delinquent behavior, while delinquency did not predict later marijuana use in a longitudinal study of high-school students (Becker et al., 2012). Additionally, consistent marijuana use during adolescence has been related to an increase in the likelihood of being involved in intimate partner violence in young adulthood and consistent marijuana use has been associated with an increase in the odds of being the perpetrator of intimate partner violence, independent of whether there is alcohol use (Morris et al., 2014). As previously highlighted, researchers in general agree that low doses of cannabis can slightly increase aggression, but that moderate and high doses can suppress or even eliminate aggressive behavior, since marijuana use has been found to depress mental activity (Boles & Miotto, 2003; Myerscough & Taylor, 1985; Taylor et al., 1976). It is likely that cannabis temporarily inhibits aggression in the general population, whereas it increases aggression in some individuals (Smith et al., 2013). In some cases, when consumed in high doses or in an extremely potent form, marijuana can have psychoactive effects that are difficult to differentiate from those of hallucinogens such as LSD (Boles & Miotto, 2003). Additionally, other factors are likely to account for associations between marijuana use and violence, such as personality, expectancies about drug effects, and/or social contextual factors associated with general marijuana use (Chermack et al., 2010). While cannabis intoxication seems to reduce the likelihood of violence, mounting evidence associates withdrawal with an increase of aggression (Budney & Hughes, 2006; Hoaken & Stewart, 2003; Kouri, Pope, & Lukas, 1999; Moore & Stuart, 2005; Smith et al., 2013) (see Figure 2). Anger, aggression, and
CANNABIS Acute intoxicaon
Chronic consumpon
Personality trait
Depresses mental acvity (depresser of CNS)
Suppresses aggressive behavior
(impulsivity, noveltyseeking, etc.)
Cannabis withdrawal
Mental health problems (post-
traumac stress disorder, psychosis, etc.)
Criminal environment / Legal problems
Increases aggressive behavior:
inmate partner aggression, interpersonal violence, suicide
FIGURE 2 Different effects of cannabis use on aggressive behavior in humans. Depending on the pattern of cannabis consumption, increases or decreases in aggression can be observed. Depressed mental activity observed after acute consumption is associated with decreased aggression. Conversely, chronic cannabis consumption interacts with genetic and environmental factors and can increase aggression. These increases are observed particularly during withdrawal syndrome.
CB1 Receptors and Aggression Chapter | 77 831
irritability are common symptoms observed during cannabis withdrawal (Ramesh, Schlosburg, Wiebelhaus, & Lichtman, 2011; Vandrey, Budney, Hughes, & Liguori, 2008), and can persist for weeks (Budney, Moore, Vandrey, & Hughes, 2003; Kouri et al., 1999). The greatest risk of violence seems to be within the first week of abstinence and is associated with different variables. In highly controlled experimental settings, it has been observed that heavy chronic THC users are significantly more aggressive than controls and with respect to their preabstinence aggression levels at 3 and 7, but not at 28 days, of abstinence (Kouri et al., 1999). In a laboratory experiment with dependent cannabis users, withdrawalrelated angry outbursts were associated with high levels of distress (Allsop, Norberg, Copeland, Fu, & Budney, 2011). Finally, in one observational study, marijuana withdrawal symptoms were linked with current relationship aggression (but not with general aggression) among users with a history of aggression, but not among those without such a history (Smith et al., 2013). According to the authors, one explanation for the differential findings between relationship and general aggression stems from the transitive nature of marijuana withdrawal. Withdrawal symptoms peak after 2–6 days of abstinence and may last for up to 2 weeks, during which time users tend to interact more frequently with their partner than others. Moreover, as the authors of the study in question stated, these results do not exclude marijuana withdrawal as a contributing factor to general aggression in particular individuals. Chronic marijuana users may run an increased risk of aggression during periods of abstinence. Moreover, individuals who have a tendency to be aggressive are more likely to act aggressively during periods of marijuana withdrawal than other periods. This needs to be confirmed by research employing alternative approaches, such as longitudinal studies. Finally, it has been hypothesized that sensitization of CB1receptor-mediated G-protein signaling in the prefrontal cortex is one of the etiological or neuroadaptive factors in the pathophysiology of suicide, a less common form of aggression that is selfdirected (Vinod & Hungund, 2006).
RELATION BETWEEN AGGRESSION AND CB1 RECEPTOR IN ANIMAL STUDIES Numerous experimental studies have highlighted the involvement of the endocannabinoid system in the control of emotional behavior (for review see Valverde & Torrens, 2012). However, few studies have used animal models to specifically address the relationship between CB1 receptors and aggression. Most of those that have done so have shown that stimulation of this receptor decreases aggression, although blockade or absence of the CB1 receptor can also decrease aggression in several circumstances. In a series of studies performed in the 1970s, Miczek and coworkers studied the effects of acute or chronic THC administration in mice and rats. Acute THC administration decreased offensive aggression in dominant animals, but also altered the submissive reaction of subordinate subjects (Miczek, 1978; Miczek & Barry, 1977). However, after chronic administration of THC for 5–8 weeks, 25–70% of previously “nonkiller” rats presented mouse-killing (Miczek, 1976). Sativex®, a mixture of THC (a stimulant of both CB1 and CB2 receptors) and cannabidiol, has been approved for the treatment of spasticity in multiple sclerosis. In comparison with vehicle-treated
PK−/−/TauVLW mice (parkin-null, human tau-overexpressing PK−/−/TauVLW, a model of complex frontotemporal dementia, parkinsonism, and lower motor neuron disease), Sativex®-treated animals show a significant improvement in abnormal behaviors related to stress, such as auto- and heteroaggressive behavior and stereotypes (Casarejos et al., 2013). In the study in question, there was a significant reduction in self-injury facial masks, which was very severe in vehicle-treated PK−/−/TauVLW mice and very mild in Sativex®-treated littermates. Repeated administration of psychostimulants and cannabinoids can elicit so-called behavioral sensitization, a gradually increased behavioral response to a drug. Landa, Slais, and Sulcova (2006) demonstrated that the CB1 receptor was involved in the development of sensitization to the antiaggressive effects of methamphetamine. Pretreatment with the CB1 agonist methanandamide resulted in cross-sensitization to this methamphetamine antiaggressive effect, whereas pretreatment with a CB2 agonist, JWH015, did not. Combined pretreatment with methamphetamine plus a CB1 antagonist (AM251) suppressed this sensitization. Among the countless consequences of stress in animals and in humans, evidence suggests that endocannabinoid transmission in the brain is altered. Indeed, stress has been shown to alter endocannabinoid content in several brain areas, including the amygdala, striatum, and prefrontal cortex (Rademacher et al., 2008). Activation of the endocannabinoid system during stress modulates complex responses such as stress-induced analgesia, escaping behavior, suppression of reproductive behavior, and sensitivity to natural reward. A social defeat stress paradigm was shown to cause a dramatic rearrangement of the CB1 receptor in the striatum (Rossi et al., 2008). However, Moise Eisenstein, Astarita, Piomelli, and Hohmann (2008) observed that neither unconditioned nor conditioned social defeat in the Syrian hamster depended on CB1 receptor activation, blockade of CB1, or inhibition of FAAH-altered conditioned defeat behavior. In line with this, Griebel, Stemmelin, and Scatton (2005) observed that the CB1 antagonist rimonabant did not affect flight or risk assessment when mice were able to escape from the oncoming rat. In contrast, when escape was not possible, the CB1 antagonist decreased defensive threat and attack reactions. The forced-contact test is thought to be particularly stressful for animals because of the impossibility of escape and unavoidable confrontation with the threat stimulus. Similar to the acute blockade of CB1 receptors by rimonabant, permanent deletion of the CB1 receptor gene (CB1−/−) in mice led to a profile of reduced defensiveness, suggesting that said receptor plays an important role in the expression of this particular set of behaviors. Genetically modified mice lacking the CB1 receptor behave normally under basal conditions, but can display altered behavior under adverse environmental conditions (for review see Valverde & Torrens, 2012). Experiments with CB1-knockout (CB1-KO) mice have revealed anxiogenic- and depressive-like phenotypes. To date, only two studies have evaluated the social and aggressive profile of CB1-KO mice. Martin, Ledent, Parmentier, Maldonado, and Valverde (2002) used the resident–intruder paradigm, in which aggressive behavior by a resident toward an intruder represents the species-typical repertoire of offensive aggressive acts and postures. In this paradigm, males living in a pair with a female or isolated for several weeks attack an intruder/opponent that is placed in their home cage (Rodriguez-Arias, Aguilar, & Simon, 2005). In Martin’s study, resident CB1-KO mice were significantly more
832 PART | IV Cannabinoids
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FIGURE 3 Aggressive behavior displayed by mice lacking the CB1 receptor in a social interaction test. Means ± SEM of accumulated times (in seconds) for threat (blue) and attack (pink) behaviors of group- or singly housed CB1-KO and WT adult mice during the social interaction test (n = 10–15 mice per group). Differences with respect to group-housed WT mice, *p < 0.05, **p < 0.01, ***p < 0.001. Modified with permission from Rodriguez-Arias et al. (2013).
aggressive toward intruders than wild-type animals, although this difference disappeared after successive encounters. In a more recent study performed in our laboratory we studied the aggressive behavior of CB1-KO mice by means of another paradigm, namely, intermale aggression (Rodriguez-Arias et al., 2013). We employed an ethological model of intermale aggression in which an experimental adult mouse is group housed or isolated for 28 days and is then confronted with a conspecific that has been housed in groups and rendered anosmic with zinc sulfate 1 day before the test. This opponent mouse induces an attack reaction in its opponent but does not outwardly provoke or defend itself, since it cannot perceive a pheromone that is present in the urine of the experimental animals. However, the opponent mouse elicits aggressive behavior in mice with a normal sense of smell. The agonistic encounter takes place in a neutral area, and both offensive and defensive behaviors are evaluated. Our results suggested that the CB1 receptor played a relevant role in the regulation of aggressive behavior. First, we observed that grouped CB1-KO mice showed more aggression than their wild-type (WT) counterparts, spending more time in threat and attack, needing less time to perform the first aggressive behavior, and showing longer aggressive interactions during the social interaction test (see Figure 3). However, when WT or CB1-KO mice were housed in isolation, a procedure that has been shown to facilitate the display of aggression in laboratory mice (Rodriguez-Arias et al., 2005), no differences were observed. These KO mice presented differences in serotonin (5-HT), a key neurotransmitter system involved in aggression control. 5-HT in the mammalian central nervous system is derived mainly from dorsal and medial raphe. Inhibition of the metabolism of monoamines renders 5-HT and other monoamines more available in the brain. However, CB1-KO mice seem to better metabolize 5-HT, as they show higher levels of catechol-O-methyltransferase (COMT) in the raphe nucleus and amygdala. Gene expression of
monoamine oxidase A was also increased in the amygdala. This may have reduced 5-HT levels, which could have been related with the elevated concentration of 5-HT1Br observed in these mice. In the same study, we tested the antiaggressive effect of the CB1 agonist Arachidonyl-2’-chloroethylamide (ACEA), and observed how it significantly decreased aggressive behaviors in isolated, highly aggressive mice (see Figure 4).
CONCLUSIONS The relationship between cannabis use and aggressive behavior, although widely studied in humans and in animal models, is a subject that requires clarification, as there are many confounding variables that need to be taken into consideration. As a general conclusion, we can affirm that acute cannabis use does not lead to increases in aggressive behavior, but rather has the opposite effect. However, under different circumstances, such as high stress, contrasting effects can be seen; for example, withdrawal syndrome after discontinuation of chronic cannabis use is one of the most strongly associated with heightened aggression. Pharmacological studies in animal models do not generally support the hypothesis that cannabis induces aggression. Studies performed in mice lacking the CB1 receptor confirm this lack of a relation.
APPLICATIONS TO OTHER ADDICTIONS AND SUBSTANCE MISUSE l Alcohol
is a drug that has been associated with heightened aggression and is often consumed with cannabis among adolescents and young people. l The increase in aggression observed after cannabis withdrawal must be considered when seeking to abstain from multiple drugs simultaneously (e.g., tobacco or opioids).
CB1 Receptors and Aggression Chapter | 77 833
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FIGURE 4 Effect of a single dose of the CB1 agonist ACEA. Means ± SEM of accumulated times (in seconds) for threat (blue) and attack (pink) behaviors during the social interaction test in highly aggressive isolated adult OF1 mice treated with saline or the CB1 agonist ACEA (1 or 2 mg/kg) (n = 9–12 mice per group). Differences with respect to saline-treated group-housed mice, *p < 0.05. Modified with permission from Rodriguez-Arias et al. (2013).
l The
CB1 receptors are involved in feeding behavior and mood change. l Among adolescents, cannabis use may be a means of forming relationships. l Cannabis consumption is closely associated with psychiatric illness (dual pathology). Knowledge of the relation between cannabis and aggression could be of relevance for treatment of this comorbidity.
DEFINITION OF TERMS Aggression This refers to any form of behavior directed toward the goal of harming or injuring another living being that is motivated to avoid such treatment. Animal models of aggression An animal model allows for the study of one or several aspects of a human condition. Its purpose is the study of a given phenomenon found in humans. Animal models are essential because they have a heuristic, hypothesis-generating function and provide important parallels to human aggression. CB1 receptor This is the most abundant G-protein-coupled receptor presynaptically located at nerve terminals, where endocannabinoids act as modulators of synaptic transmission. CB1 receptor agonists These are compounds that induce a change in the configuration of the CB1 receptor, producing a biological response. As example is WIN 55,212. CB1 receptor antagonists These are compounds that induce a change in the configuration of the CB1 receptor, without inducing any biological response. Examples are rimonabant and SR141716A. Correlational study This is a scientific study in which researchers investigate associations between variables. It allows us to determine which variables are related. However, the fact that two variables are related or correlated does not mean there is a causal relationship. Endocannabinoid system This is the retrograde neurotransmitter system formed by the cannabinoid receptors, endogenously produced compounds displaying significant affinity for these receptors (endocannabinoids), and enzymes involved in the synthesis and metabolism of endocannabinoids.
Longitudinal study This is a study in which researchers conduct several observations of the same subjects over a period of time, sometimes lasting many years. It is an observational study, as researchers do not interfere with their subjects. Offensive and defensive aggression The distinction between offensive and defensive aggression is based upon the distal and proximal antecedent conditions that precipitate aggression, the topography of the behavior, and its consequences. Offensive aggressive behavior between conspecifics is ritually organized, and the attack is usually directed toward less vulnerable body areas such as the back and flanks of the opponent. Defensive aggression involves attack in defense of the self in response to threatening or fear-inducing stimuli and is often accompanied by escape. Sensitization In the context of the use of drugs, sensitization refers to the increased effectiveness of a given drug with repeated administration. Substance use disorder The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), defines a substance use disorder as a cluster of cognitive, behavioral, and physiological symptoms indicating that the individual continues using the substance despite significant substance-related problems. An important characteristic of substance use disorders is an underlying change in brain circuits that may persist beyond detoxification, particularly in individuals with severe disorders Withdrawal syndrome The DSM-5 defines this as a syndrome that occurs when blood or tissue concentrations of a substance decline in an individual who has maintained prolonged heavy use of the substance. After developing withdrawal symptoms, the individual is likely to consume the substance to relieve the symptoms.
KEY FACTS OF AGGRESSION l Aggressive
behavior is influenced by genetic and environmental factors. l The amygdala, anterior cingulate cortex, and regions of the prefrontal cortex are associated with aggression control. l Aggression is elicited by excessive reactivity in the amygdala plus inadequate prefrontal regulation.
834 PART | IV Cannabinoids
l Insufficient
serotonergic activity can enhance aggression. polymorphisms in the monoamine oxidase A and 5-HT transporter may be of particular importance. l Rodent models of aggression are not comparable to aggression in humans. l Similar molecular mechanisms are found in aggression in mice and humans. l Functional
SUMMARY POINTS l Studies
of the relation between cannabis consumption and abnormal aggression have provided contrasting results. l Cannabinoids act on a G-protein-coupled receptor presynaptically located at nerve terminals that modulate synaptic transmission, called the CB1 receptor. l There is general agreement that low doses of cannabis can slightly increase aggression and that moderate and high doses can suppress or even eliminate aggressive behavior in human beings. l Increasing evidence associates withdrawal after chronic cannabis use with an increase in aggression. l Animal studies confirm a role for the CB1 receptor in controlling aggressive behavior. l Several variables should be taken into consideration when studying cannabis and aggression, such as previous aggressive profile or stressful circumstances.
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CB1 Cannabinoid Receptors and Aggression: Relationship to Cannabis Use Marta Rodríguez-Arias, José Miñarro, M. Carmen Arenas, María A. Aguilar Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de València, Valencia, Spain
Abbreviations 2-AG 2-Arachidonoylglycerol 5-HT Serotonin AA Arachidonic acid AEA N-Arachidonoylethanolamine or anandamide AMT/AT Anandamide and 2-arachidonoylglycerol membrane transporter ASPD Antisocial personality disorder CB1-KO Mice lacking the CB1 receptor DAG Diacylglycerol DAGL Diacylglycerol lipase ECS Endogenous cannabinoid system FAAH Fatty acid amide hydrolase GABA γ-Aminobutyric acid GPR G-Protein-coupled receptor MA Monoamine MAGL Monoacylglycerol lipase MAPK Mitogen-activated protein kinase MAR Monoamine receptor NADA N-Arachidonoyldopamine NAPE N-Arachidonylphosphatidylethanolamine NAT N-Acyltransferase OA Oleic acid OEA Oleoylethanolamide PA Palmitic acid PEA Palmithylethanolamide Ph Chol Phosphatidylcholine Ph Eth Phosphatidylethanolamine PKA Protein kinase A PK−/−/TauVLW mice Parkin-null, human tau-overexpressing PK−/−/TauVLW PLC Phospholipase C PLD Phospholipase D PPAR Peroxisome proliferator-activated receptor PPARα Peroxisome proliferator-activated receptor α SUD Substance use disorder TAG Triacylglycerol
THC Δ9-Tetrahydrocannabinol TRPA1 Transient receptor potential ankyrin 1 TRPV1 Transient receptor potential channel type V1
INTRODUCTION The relationship between drug use and violent behavior has been firmly established through a great number of studies (see reviews Boles & Miotto, 2003; Chermack et al., 2010; Friedman, 1998). Substance use disorder is considered a common risk factor for perpetration of violence (Barrett, Teesson, & Mills, 2014), since it contributes more to violent behavior than any other mental health disorder (Pulay et al., 2008). Violent behavior can be necessary to gain access to drugs, to acquire the resources to purchase a drug, or to resolve disputes in the illegal and unregulated drug market. Violence and drug use can be results of the same factor, including personality traits such as high novelty seeking. Finally, drugs can increase the likelihood of aggression by exerting a direct effect on the subject (Hoake & Steward, 2003). In this line, drugs of abuse induce a state of intoxication (pharmacological effect), can provoke brain damage after prolonged use (neurotoxic effects), and induce extreme discomfort when abruptly discontinued after chronic use (withdrawal effects). Aggression can be generally defined as behavior that inflicts harm and injury or threatens to do so (Berkowitz, 1993). According to Baron’s definition (Baron & Richardson, 1994) aggression is any form of behavior whose goal is the harming or injuring of another living being who is motivated to avoid such treatment. In the literature, animal studies involving drug administration and laboratory measures tend to use the term aggression. On the other hand, research concerning individuals who have come into contact with law enforcement after drug consumption tend to use the term ‘‘violence” to denote aggression between two or more human beings involving physical harm or injury. Human aggression can be classified as defensive, premeditated, or impulsive–hostile (Vitiello & Stoff, 1997). This last type is linked to biological and environmental causes and is thus the most easily induced by consumption of drugs of abuse (Coccaro, Lee, & Kavoussi, 2010).
Neuropathology of Drug Addictions and Substance Misuse, Volume 1. http://dx.doi.org/10.1016/B978-0-12-800213-1.00077-8 Copyright © 2016 Elsevier Inc. All rights reserved.
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828 PART | IV Cannabinoids
Human and nonhuman aggressive behaviors have some common features, but animal aggression is considered less complex. Nevertheless, animal aggression is a broad category of behavior rather than a single behavioral pattern and encompasses various origins, motivations, expressions, and functions (Miczek, Faccidomo, Fish, & DeBold, 2007). In the behavioral repertoire of a given species, various acts can be classified as aggressive and have varying ethological significance depending on their functionality in the survival and reproduction of the species. Blanchard and Brain classified aggressive behavior in animals as offensive or defensive depending on the distal and proximal conditions that produce it, the topography of the behavior, and its consequences (Blanchard & Blanchard, 1977; Brain & Benton, 1979). Despite the great deal of controversy concerning the relationship between marijuana use and aggressive behavior in humans (Harris et al., 2010), relatively few studies have specifically examined the association between cannabis use and violence in humans (e.g., Dembo et al., 1987; Moore & Stuart, 2005; Myerscough & Taylor, 1985; Smith, Homish, Leonard, & Collins, 2013; Taylor et al., 1976). The acute effects of Δ9-tetrahydrocannabinol (THC) (the primary psychoactive component of cannabis) on aggressive behavior have been the most studied aspect with respect to this area, but the information obtained is controversial. Results show a biphasic effect of THC; while low doses of THC can slightly increase aggression, moderate and high doses can suppress or even eliminate this type of behavior (Myerscough & Taylor, 1985; Taylor et al., 1976). However, in all of these studies, variables that could have influenced the data obtained should be taken into consideration, such as rapid eye movement sleep deprivation, social seclusion, or pretreatment with another drug. The animal literature also largely fails to support the cannabis– violence relationship, as cannabis administration has been shown to enhance submissive behaviors and suppress attack behaviors. However, some animal studies, specifically those using Wistar rats, have associated cannabis administration with increased aggression. This chapter aims to summarize the most important results concerning the relationship between the CB1 cannabinoid type 1 receptor and aggression. First, we offer a brief review of the history and current epidemiology of cannabis consumption and an explanation of the main components and functions of the endocannabinoid system. We then review studies of the relationship between cannabis and aggression in humans and discuss the main findings regarding the effects of acute or chronic cannabis consumption or withdrawal on aggressive behavior. Finally, we focus on the effects of cannabinoids in animal models of aggression.
THE ENDOCANNABINOID SYSTEM Although cannabis has been used for thousands of years, its neurobiological mechanism of action was not discovered until 1964, when the chemical structure of its main psychoactive constituent, THC, was identified (Gaoni & Mechoulam, 1964). About 20 years later, the first cannabinoid receptor (CB1) was identified (Devane, Dysarz, Johnson, Melvin, & Howlett, 1988). In 1992, the first endogenous ligand on CB receptors—arachidonoylethanolamine (AEA; anandamide), its name originating from “ananda,” meaning “the bliss” in Sanskrit—was identified (Devane et al., 1992). These findings opened the way for research that led to the discovery of the endogenous cannabinoid system (ECS), a widely distributed modulatory system involved in multiple physiological processes (pain,
growth and development, immune function), behaviors (motor control, reproduction, sleep, eating, emotional homeostasis), learning and memory, and mental disorders (Mechoulam & Parker, 2013; Rodriguez de Fonseca, 2008; Vinod & Hungund, 2006). Endocannabinoids, together with their receptors and enzymes involved in synthesis and metabolism, constitute the ECS (see Figure 1). Endocannabinoids are signaling molecules (amides, esters, and ethers of long-chain polyunsaturated fatty acids) found in abundance in the cerebral cortex, basal ganglia, and limbic structures (Matias, Bisogno, & Di Marzo, 2006). The best known are anandamide and 2-arachidonoylglycerol (2-AG) (Mechoulam et al., 1995), but several others have been identified: N-arachidonylglycine, N-arachidonoyldopamine, 2-arachidonoylglyceryl ether (noladin ether), O-arachidonoylethanolamine (virodhamine), and 9-octadecenoamide (oleamide). The ECS centers on G-protein-coupled receptors (GPR) (Pertwee et al., 2010; Rodriguez de Fonseca, 2008). Two cannabinoid receptor subtypes have been cloned: CB1 (Matsuda, Lolait, Brownstein, Young, & Bonner, 1990), which is expressed in the brain and many peripheral tissues, and CB2 (Munro, Thomas, & Abu-Shaar, 1993), which is expressed predominantly on immune cells and damaged tissues and at low levels in the brain (Mechoulam & Parker, 2013). A yet-to-be-cloned CB3 receptor has been identified in the hippocampus. CB1 is probably the most abundant GPR to exist in the brain (Pertwee, 2010). It is presynaptically located at nerve terminals where endocannabinoids act as modulators of synaptic transmission (Howlett, 2002). These receptors are coupled negatively 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 by Gi/o proteins (Howlett, 2002). CB1 receptors are located in the cerebral cortex, basal ganglia, hippocampus, anterior cingulate cortex, and cerebellum (Herkenham, Lynn, Little, Johnson, & Melvin, 1990), where they inhibit the release of several neurotransmitters (e.g., glutamate and γ-aminobutyric acid) and stimulate dopamine release in the nucleus accumbens (Mechoulam & Parker, 2013). Synthetic CB1 receptor ligands have been developed as research tools to explore the functions of the ECS system. The hundreds of CB1 receptor agonists include WIN 55,212, HU-210, and CP 55,940. The main CB1 receptor antagonists are rimonabant (SR141716A), AM251, and AM281. Genetic knockout mice that lack CB1 receptors (or other proteins related to the ECS system, e.g., CB2, fatty acid amide hydrolase (FAAH), monoacylglycerol lipase, etc.) have also been developed with this objective in mind.
CANNABIS AND AGGRESSION IN HUMANS Cannabis was historically suspected of instigating a wide variety of aggressive behaviors, which led to it being considered a social ‘‘menace’’ and to its prohibition (Hoaken & Stewart, 2003). In 1993, after reviewing the scientific literature, the US National Research Council recognized that short-term use of cannabis inhibited aggressive behavior in humans, while long-term use could promote violence (Friedman, 1998). Today, the findings of observational research in humans are largely mixed, with studies showing positive (Arseneault, Moffitt, Caspi, Taylor, & Silva, 2000; Barrett et al., 2014; Harris et al., 2010; Moore et al., 2008; Morris, TenEyck, Barnes, & Kovandzic, 2014), negative (Arendt et al., 2007), or nonexistent (Lejoyeux et al., 2013; Macdonald, Erickson, Wells, Hathaway, & Pakula, 2008) associations between marijuana and violence.
CB1 Receptors and Aggression Chapter | 77 829
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FIGURE 1 The endocannabinoid system. The two main endocannabinoids, anandamide and 2-AG, are synthesized in the postsynaptic nerve terminal. Anandamide is produced by hydrolysis of the membrane phospholipid N-arachidonylphosphatidylethanolamine, which is catalyzed by the enzyme phospholipase D. The synthesis of N-arachidonylphosphatidylethanolamine is mediated by an uncloned enzyme—N-acyltransferase—which detaches an arachidonate moiety from phospholipids (e.g., phosphatidylcholine) and transfers it to the primary amino group of phosphatidylethanolamine. 2-AG is produced by the metabolism of diacylglycerol by specific diacylglycerol lipases. The second messenger diacylglycerol is produced by hydrolysis of phospholipids or triglycerides such as triacylglycerol by phospholipase C. Anandamide and 2-AG, as well as other endocannabinoids such as palmithylethanolamide (PEA) and oleoylethanolamide (OEA), act mainly through the CB1 and CB2 receptors, although other receptors have been identified as targets of endocannabinoids (a new uncloned CB3 receptor, the GPR119 and GPR55 orphan receptors, the vanilloid VR1 receptor, and the peroxisome proliferator-activated receptor α). Endocannabinoids function as retrograde signaling molecules that inhibit the release of classical anterograde neurotransmitters by presynaptic terminals (such as monoamines) and bind with their receptor (monoamine receptor). After the activation of presynaptic CB1 receptors (by anandamide, 2-AG, or THC), different signal transduction mechanisms are stimulated. Via G inhibitory proteins, endocannabinoids inhibit adenylyl cyclase activity and subsequently reduce cAMP, leading to reduced activity of protein kinases such as protein kinase A and mitogen-activated protein kinase (MAPK) and to the modulation of ion channels (stimulation of potassium and inhibition of calcium channels) and inhibition of neurotransmitter release. The activity of endocannabinoids is limited by a transporter that takes up AEA and 2-AG into the postsynaptic cell. AEA, PEA, and OEA are degraded by the enzyme fatty acid amidohydrolase to ethanolamide plus arachidonic, oleic, or palmitic acids. 2-AG is degraded by the enzyme monoacylglycerol lipase to arachidonic acid plus glycerol.
The main reason for these discrepant results is the heterogeneity of the studies performed. First, as previously stated, human aggression is a multidimensional construct that hinders a simple definition. We have found research demonstrating an association between marijuana and delinquent behavior based on reports of marijuana consumers committing violent crimes (Arseneault et al., 2000) and exhibiting a significantly higher level of delinquent behaviors (Dembo et al., 1987) than subjects testing negative for marijuana. Conversely, White, Loeber, Stouthamer-Loeber, and Farrington (1999) found that the association between marijuana use and aggression was nonsignificant after controlling for history of aggression and alcohol use in a longitudinal study of substance use and aggression. Other studies evaluating the relation between marijuana use and violence have distinguished between nonintimate interpersonal and intimate partner violence (see review by Moore & Stuart, 2005). While mixed results were documented when nonintimate interpersonal
violence was evaluated (Moore & Stuart, 2005), studies examining the relationship between drug abuse and aggression between intimate partners revealed a significant association with marijuana, considering it an important factor in the incidence of partner aggression (Moore et al., 2008). Another reason for these relatively inconsistent findings could be the heterogeneity of the subjects assessed, which have included college students (Taylor et al., 1976), delinquents in a detention center (Dembo et al., 1987), and psychiatric patients (Arseneault et al., 2000; Barrett et al., 2014; Becker et al., 2012; Lejoyeux et al., 2013). Serious aggression in first-episode psychosis was associated with regular cannabis use (Harris et al., 2010), and posttraumatic stress disorder violence and trait aggression were associated with higher levels of cannabis use (Barrett et al., 2014). However, a lack of association between cannabis use and aggressive behavior was reported in a population of schizophrenics (Lejoyeux et al., 2013).
830 PART | IV Cannabinoids
Correlational studies support a link between cannabis use and violent behavior, but their results do not offer insight into potential causal relationships. Although cannabis use has been shown to be an independent predictor of violence at a community level (Arseneault et al., 2000), it is unclear whether it is a direct cause of violence; whether people who use cannabis are violent as a result of a third factor, such as a personality type; or whether cannabis dependence is an indirect cause of violence as a result of criminal association or crime to obtain money for the drug (Harris et al., 2010). This review principally examines studies based on psychopharmacological explanations. Multiple researchers have considered that cannabis in moderate-to-high doses reduces aggressive behavior (Hoaken & Stewart, 2003; Myerscough & Taylor, 1985). In this way, cannabis-intoxicated subjects are less likely to react aggressively (Hoaken & Stewart, 2003). This indicates that cannabis is used as a means of self-medication; indeed, in one study subjects that reported having problems controlling their violent behavior were much more likely to use cannabis to decrease aggression, as the drug helped them to relax and to decrease suspiciousness (Arendt et al., 2007). In favor of this hypothesis, a longitudinal study to assess the longterm predictive validity of antisocial personality disorder (ASPD) on criminal behavior in samples of substance abusers over a 30-year period reported a lower propensity for crime in cannabis users than in users of other stimulant drugs. Moreover, violence in ASPD patients was predicted by the absence of cannabis addiction (Fridell, Hesse, Jæger, & Kühlhorn, 2008). Marijuana use has also been related to decreased likelihood of violence with injury in interpersonal conflict incidents among men and women in substance use disorder treatment (Chermack et al., 2010). Moreover, Becker et al. (2012) observed that delinquent behavior predicted subsequent marijuana use, whereas marijuana use did not predict subsequent delinquent behavior.
Other studies reported no correlation with violent crime when marijuana was the only drug consumed (for review see Friedman, 1998). However, other studies have reported that marijuana use predicts later delinquent behavior, while delinquency did not predict later marijuana use in a longitudinal study of high-school students (Becker et al., 2012). Additionally, consistent marijuana use during adolescence has been related to an increase in the likelihood of being involved in intimate partner violence in young adulthood and consistent marijuana use has been associated with an increase in the odds of being the perpetrator of intimate partner violence, independent of whether there is alcohol use (Morris et al., 2014). As previously highlighted, researchers in general agree that low doses of cannabis can slightly increase aggression, but that moderate and high doses can suppress or even eliminate aggressive behavior, since marijuana use has been found to depress mental activity (Boles & Miotto, 2003; Myerscough & Taylor, 1985; Taylor et al., 1976). It is likely that cannabis temporarily inhibits aggression in the general population, whereas it increases aggression in some individuals (Smith et al., 2013). In some cases, when consumed in high doses or in an extremely potent form, marijuana can have psychoactive effects that are difficult to differentiate from those of hallucinogens such as LSD (Boles & Miotto, 2003). Additionally, other factors are likely to account for associations between marijuana use and violence, such as personality, expectancies about drug effects, and/or social contextual factors associated with general marijuana use (Chermack et al., 2010). While cannabis intoxication seems to reduce the likelihood of violence, mounting evidence associates withdrawal with an increase of aggression (Budney & Hughes, 2006; Hoaken & Stewart, 2003; Kouri, Pope, & Lukas, 1999; Moore & Stuart, 2005; Smith et al., 2013) (see Figure 2). Anger, aggression, and
CANNABIS Acute intoxicaon
Chronic consumpon
Personality trait
Depresses mental acvity (depresser of CNS)
Suppresses aggressive behavior
(impulsivity, noveltyseeking, etc.)
Cannabis withdrawal
Mental health problems (post-
traumac stress disorder, psychosis, etc.)
Criminal environment / Legal problems
Increases aggressive behavior:
inmate partner aggression, interpersonal violence, suicide
FIGURE 2 Different effects of cannabis use on aggressive behavior in humans. Depending on the pattern of cannabis consumption, increases or decreases in aggression can be observed. Depressed mental activity observed after acute consumption is associated with decreased aggression. Conversely, chronic cannabis consumption interacts with genetic and environmental factors and can increase aggression. These increases are observed particularly during withdrawal syndrome.
CB1 Receptors and Aggression Chapter | 77 831
irritability are common symptoms observed during cannabis withdrawal (Ramesh, Schlosburg, Wiebelhaus, & Lichtman, 2011; Vandrey, Budney, Hughes, & Liguori, 2008), and can persist for weeks (Budney, Moore, Vandrey, & Hughes, 2003; Kouri et al., 1999). The greatest risk of violence seems to be within the first week of abstinence and is associated with different variables. In highly controlled experimental settings, it has been observed that heavy chronic THC users are significantly more aggressive than controls and with respect to their preabstinence aggression levels at 3 and 7, but not at 28 days, of abstinence (Kouri et al., 1999). In a laboratory experiment with dependent cannabis users, withdrawalrelated angry outbursts were associated with high levels of distress (Allsop, Norberg, Copeland, Fu, & Budney, 2011). Finally, in one observational study, marijuana withdrawal symptoms were linked with current relationship aggression (but not with general aggression) among users with a history of aggression, but not among those without such a history (Smith et al., 2013). According to the authors, one explanation for the differential findings between relationship and general aggression stems from the transitive nature of marijuana withdrawal. Withdrawal symptoms peak after 2–6 days of abstinence and may last for up to 2 weeks, during which time users tend to interact more frequently with their partner than others. Moreover, as the authors of the study in question stated, these results do not exclude marijuana withdrawal as a contributing factor to general aggression in particular individuals. Chronic marijuana users may run an increased risk of aggression during periods of abstinence. Moreover, individuals who have a tendency to be aggressive are more likely to act aggressively during periods of marijuana withdrawal than other periods. This needs to be confirmed by research employing alternative approaches, such as longitudinal studies. Finally, it has been hypothesized that sensitization of CB1receptor-mediated G-protein signaling in the prefrontal cortex is one of the etiological or neuroadaptive factors in the pathophysiology of suicide, a less common form of aggression that is selfdirected (Vinod & Hungund, 2006).
RELATION BETWEEN AGGRESSION AND CB1 RECEPTOR IN ANIMAL STUDIES Numerous experimental studies have highlighted the involvement of the endocannabinoid system in the control of emotional behavior (for review see Valverde & Torrens, 2012). However, few studies have used animal models to specifically address the relationship between CB1 receptors and aggression. Most of those that have done so have shown that stimulation of this receptor decreases aggression, although blockade or absence of the CB1 receptor can also decrease aggression in several circumstances. In a series of studies performed in the 1970s, Miczek and coworkers studied the effects of acute or chronic THC administration in mice and rats. Acute THC administration decreased offensive aggression in dominant animals, but also altered the submissive reaction of subordinate subjects (Miczek, 1978; Miczek & Barry, 1977). However, after chronic administration of THC for 5–8 weeks, 25–70% of previously “nonkiller” rats presented mouse-killing (Miczek, 1976). Sativex®, a mixture of THC (a stimulant of both CB1 and CB2 receptors) and cannabidiol, has been approved for the treatment of spasticity in multiple sclerosis. In comparison with vehicle-treated
PK−/−/TauVLW mice (parkin-null, human tau-overexpressing PK−/−/TauVLW, a model of complex frontotemporal dementia, parkinsonism, and lower motor neuron disease), Sativex®-treated animals show a significant improvement in abnormal behaviors related to stress, such as auto- and heteroaggressive behavior and stereotypes (Casarejos et al., 2013). In the study in question, there was a significant reduction in self-injury facial masks, which was very severe in vehicle-treated PK−/−/TauVLW mice and very mild in Sativex®-treated littermates. Repeated administration of psychostimulants and cannabinoids can elicit so-called behavioral sensitization, a gradually increased behavioral response to a drug. Landa, Slais, and Sulcova (2006) demonstrated that the CB1 receptor was involved in the development of sensitization to the antiaggressive effects of methamphetamine. Pretreatment with the CB1 agonist methanandamide resulted in cross-sensitization to this methamphetamine antiaggressive effect, whereas pretreatment with a CB2 agonist, JWH015, did not. Combined pretreatment with methamphetamine plus a CB1 antagonist (AM251) suppressed this sensitization. Among the countless consequences of stress in animals and in humans, evidence suggests that endocannabinoid transmission in the brain is altered. Indeed, stress has been shown to alter endocannabinoid content in several brain areas, including the amygdala, striatum, and prefrontal cortex (Rademacher et al., 2008). Activation of the endocannabinoid system during stress modulates complex responses such as stress-induced analgesia, escaping behavior, suppression of reproductive behavior, and sensitivity to natural reward. A social defeat stress paradigm was shown to cause a dramatic rearrangement of the CB1 receptor in the striatum (Rossi et al., 2008). However, Moise Eisenstein, Astarita, Piomelli, and Hohmann (2008) observed that neither unconditioned nor conditioned social defeat in the Syrian hamster depended on CB1 receptor activation, blockade of CB1, or inhibition of FAAH-altered conditioned defeat behavior. In line with this, Griebel, Stemmelin, and Scatton (2005) observed that the CB1 antagonist rimonabant did not affect flight or risk assessment when mice were able to escape from the oncoming rat. In contrast, when escape was not possible, the CB1 antagonist decreased defensive threat and attack reactions. The forced-contact test is thought to be particularly stressful for animals because of the impossibility of escape and unavoidable confrontation with the threat stimulus. Similar to the acute blockade of CB1 receptors by rimonabant, permanent deletion of the CB1 receptor gene (CB1−/−) in mice led to a profile of reduced defensiveness, suggesting that said receptor plays an important role in the expression of this particular set of behaviors. Genetically modified mice lacking the CB1 receptor behave normally under basal conditions, but can display altered behavior under adverse environmental conditions (for review see Valverde & Torrens, 2012). Experiments with CB1-knockout (CB1-KO) mice have revealed anxiogenic- and depressive-like phenotypes. To date, only two studies have evaluated the social and aggressive profile of CB1-KO mice. Martin, Ledent, Parmentier, Maldonado, and Valverde (2002) used the resident–intruder paradigm, in which aggressive behavior by a resident toward an intruder represents the species-typical repertoire of offensive aggressive acts and postures. In this paradigm, males living in a pair with a female or isolated for several weeks attack an intruder/opponent that is placed in their home cage (Rodriguez-Arias, Aguilar, & Simon, 2005). In Martin’s study, resident CB1-KO mice were significantly more
832 PART | IV Cannabinoids
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FIGURE 3 Aggressive behavior displayed by mice lacking the CB1 receptor in a social interaction test. Means ± SEM of accumulated times (in seconds) for threat (blue) and attack (pink) behaviors of group- or singly housed CB1-KO and WT adult mice during the social interaction test (n = 10–15 mice per group). Differences with respect to group-housed WT mice, *p < 0.05, **p < 0.01, ***p < 0.001. Modified with permission from Rodriguez-Arias et al. (2013).
aggressive toward intruders than wild-type animals, although this difference disappeared after successive encounters. In a more recent study performed in our laboratory we studied the aggressive behavior of CB1-KO mice by means of another paradigm, namely, intermale aggression (Rodriguez-Arias et al., 2013). We employed an ethological model of intermale aggression in which an experimental adult mouse is group housed or isolated for 28 days and is then confronted with a conspecific that has been housed in groups and rendered anosmic with zinc sulfate 1 day before the test. This opponent mouse induces an attack reaction in its opponent but does not outwardly provoke or defend itself, since it cannot perceive a pheromone that is present in the urine of the experimental animals. However, the opponent mouse elicits aggressive behavior in mice with a normal sense of smell. The agonistic encounter takes place in a neutral area, and both offensive and defensive behaviors are evaluated. Our results suggested that the CB1 receptor played a relevant role in the regulation of aggressive behavior. First, we observed that grouped CB1-KO mice showed more aggression than their wild-type (WT) counterparts, spending more time in threat and attack, needing less time to perform the first aggressive behavior, and showing longer aggressive interactions during the social interaction test (see Figure 3). However, when WT or CB1-KO mice were housed in isolation, a procedure that has been shown to facilitate the display of aggression in laboratory mice (Rodriguez-Arias et al., 2005), no differences were observed. These KO mice presented differences in serotonin (5-HT), a key neurotransmitter system involved in aggression control. 5-HT in the mammalian central nervous system is derived mainly from dorsal and medial raphe. Inhibition of the metabolism of monoamines renders 5-HT and other monoamines more available in the brain. However, CB1-KO mice seem to better metabolize 5-HT, as they show higher levels of catechol-O-methyltransferase (COMT) in the raphe nucleus and amygdala. Gene expression of
monoamine oxidase A was also increased in the amygdala. This may have reduced 5-HT levels, which could have been related with the elevated concentration of 5-HT1Br observed in these mice. In the same study, we tested the antiaggressive effect of the CB1 agonist Arachidonyl-2’-chloroethylamide (ACEA), and observed how it significantly decreased aggressive behaviors in isolated, highly aggressive mice (see Figure 4).
CONCLUSIONS The relationship between cannabis use and aggressive behavior, although widely studied in humans and in animal models, is a subject that requires clarification, as there are many confounding variables that need to be taken into consideration. As a general conclusion, we can affirm that acute cannabis use does not lead to increases in aggressive behavior, but rather has the opposite effect. However, under different circumstances, such as high stress, contrasting effects can be seen; for example, withdrawal syndrome after discontinuation of chronic cannabis use is one of the most strongly associated with heightened aggression. Pharmacological studies in animal models do not generally support the hypothesis that cannabis induces aggression. Studies performed in mice lacking the CB1 receptor confirm this lack of a relation.
APPLICATIONS TO OTHER ADDICTIONS AND SUBSTANCE MISUSE l Alcohol
is a drug that has been associated with heightened aggression and is often consumed with cannabis among adolescents and young people. l The increase in aggression observed after cannabis withdrawal must be considered when seeking to abstain from multiple drugs simultaneously (e.g., tobacco or opioids).
CB1 Receptors and Aggression Chapter | 77 833
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FIGURE 4 Effect of a single dose of the CB1 agonist ACEA. Means ± SEM of accumulated times (in seconds) for threat (blue) and attack (pink) behaviors during the social interaction test in highly aggressive isolated adult OF1 mice treated with saline or the CB1 agonist ACEA (1 or 2 mg/kg) (n = 9–12 mice per group). Differences with respect to saline-treated group-housed mice, *p < 0.05. Modified with permission from Rodriguez-Arias et al. (2013).
l The
CB1 receptors are involved in feeding behavior and mood change. l Among adolescents, cannabis use may be a means of forming relationships. l Cannabis consumption is closely associated with psychiatric illness (dual pathology). Knowledge of the relation between cannabis and aggression could be of relevance for treatment of this comorbidity.
DEFINITION OF TERMS Aggression This refers to any form of behavior directed toward the goal of harming or injuring another living being that is motivated to avoid such treatment. Animal models of aggression An animal model allows for the study of one or several aspects of a human condition. Its purpose is the study of a given phenomenon found in humans. Animal models are essential because they have a heuristic, hypothesis-generating function and provide important parallels to human aggression. CB1 receptor This is the most abundant G-protein-coupled receptor presynaptically located at nerve terminals, where endocannabinoids act as modulators of synaptic transmission. CB1 receptor agonists These are compounds that induce a change in the configuration of the CB1 receptor, producing a biological response. As example is WIN 55,212. CB1 receptor antagonists These are compounds that induce a change in the configuration of the CB1 receptor, without inducing any biological response. Examples are rimonabant and SR141716A. Correlational study This is a scientific study in which researchers investigate associations between variables. It allows us to determine which variables are related. However, the fact that two variables are related or correlated does not mean there is a causal relationship. Endocannabinoid system This is the retrograde neurotransmitter system formed by the cannabinoid receptors, endogenously produced compounds displaying significant affinity for these receptors (endocannabinoids), and enzymes involved in the synthesis and metabolism of endocannabinoids.
Longitudinal study This is a study in which researchers conduct several observations of the same subjects over a period of time, sometimes lasting many years. It is an observational study, as researchers do not interfere with their subjects. Offensive and defensive aggression The distinction between offensive and defensive aggression is based upon the distal and proximal antecedent conditions that precipitate aggression, the topography of the behavior, and its consequences. Offensive aggressive behavior between conspecifics is ritually organized, and the attack is usually directed toward less vulnerable body areas such as the back and flanks of the opponent. Defensive aggression involves attack in defense of the self in response to threatening or fear-inducing stimuli and is often accompanied by escape. Sensitization In the context of the use of drugs, sensitization refers to the increased effectiveness of a given drug with repeated administration. Substance use disorder The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), defines a substance use disorder as a cluster of cognitive, behavioral, and physiological symptoms indicating that the individual continues using the substance despite significant substance-related problems. An important characteristic of substance use disorders is an underlying change in brain circuits that may persist beyond detoxification, particularly in individuals with severe disorders Withdrawal syndrome The DSM-5 defines this as a syndrome that occurs when blood or tissue concentrations of a substance decline in an individual who has maintained prolonged heavy use of the substance. After developing withdrawal symptoms, the individual is likely to consume the substance to relieve the symptoms.
KEY FACTS OF AGGRESSION l Aggressive
behavior is influenced by genetic and environmental factors. l The amygdala, anterior cingulate cortex, and regions of the prefrontal cortex are associated with aggression control. l Aggression is elicited by excessive reactivity in the amygdala plus inadequate prefrontal regulation.
834 PART | IV Cannabinoids
l Insufficient
serotonergic activity can enhance aggression. polymorphisms in the monoamine oxidase A and 5-HT transporter may be of particular importance. l Rodent models of aggression are not comparable to aggression in humans. l Similar molecular mechanisms are found in aggression in mice and humans. l Functional
SUMMARY POINTS l Studies
of the relation between cannabis consumption and abnormal aggression have provided contrasting results. l Cannabinoids act on a G-protein-coupled receptor presynaptically located at nerve terminals that modulate synaptic transmission, called the CB1 receptor. l There is general agreement that low doses of cannabis can slightly increase aggression and that moderate and high doses can suppress or even eliminate aggressive behavior in human beings. l Increasing evidence associates withdrawal after chronic cannabis use with an increase in aggression. l Animal studies confirm a role for the CB1 receptor in controlling aggressive behavior. l Several variables should be taken into consideration when studying cannabis and aggression, such as previous aggressive profile or stressful circumstances.
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