Psychopharmacology (2011) 213:183–212 DOI 10.1007/s00213-010-2000-y

REVIEW

Brain serotonin receptors and transporters: initiation vs. termination of escalated aggression

Aki Takahashi & Isabel M. Quadros & Rosa M. M. de Almeida & Klaus A. Miczek

Received: 18 June 2010 /Accepted: 9 August 2010 /Published online: 3 September 2010 # Springer-Verlag 2010

Abstract MAOA) or indirectly (e.g., Y, αCaMKII, Rationale Recent findings have shown a complexly NOS, BDNF). Dysfunction in for MAOA escalates regulated 5-HT system as it is linked to different kinds pathological aggression in rodents and humans, particularly of aggression. in interaction with specific experiences. Objective We focus on (1) phasic and tonic changes of Conclusions Feedback to autoreceptors of the 5-HT1 family 5-HT and (2) state and trait of aggression, and emphasize and modulation via heteroreceptors are important in the the different subtypes, their role in specific brain expression of aggressive behavior. Tonic increase of the regions, feed-back regulation and modulation by other 5-HT2 family expression may cause escalated aggression, amines, acids and peptides. whereas the phasic increase of 5-HT2 receptors inhibits Results New pharmacological tools differentiate the first aggressive behaviors. Polymorphisms in the genes of 5-HT three 5-HT receptor families and their modulation by transporters or rate-limiting synthetic and metabolic GABA, glutamate and CRF. Activation of 5-HT1A,5-HT1B enzymes of 5-HT modulate aggression, often requiring and 5-HT2A/2C receptors in mesocorticolimbic areas, interaction with the rearing environment. reduce species-typical and other aggressive behaviors. In contrast, agonists at 5-HT1A and 5-HT1B receptors in the Keywords Aggression . Serotonin . GABA . Glutamate . medial prefrontal cortex or septal area can increase CRF. Raphe . Prefrontal cortex . . Septum . aggressive behavior under specific conditions. Activation regulation of serotonin transporters reduce mainly pathological aggression. Genetic analyses of aggressive individuals have identified several molecules that affect the 5-HT Preamble system directly (e.g., Tph2, 5-HT1B, 5-HT transporter, Pet1, Novel findings with tools from molecular genetics and receptor pharmacology in conjunction with more differen- I. M. Quadros : K. A. Miczek (*) Tufts University, tiating behavioral and clinical analysis begin to focus on the 530 Boston Ave (Bacon Hall), prominent role of brain serotonin in the predisposition to Medford, MA 02155, USA initiate impulsive aggressive behavior and the termination e-mail: [email protected] of bursts of aggressive behavior (Lesch and Merschdorf A. Takahashi 2000; Miczek et al. 2002, 2007b; Nelson and Chiavegatto National Institute of Genetics, 2001; Quadros et al. 2009b). The venerable serotonin Mishima, Shizuoka, Japan deficiency hypothesis as simplifying principle, linking low serotonin activity to the propensity to engage in aggressive R. M. M. de Almeida UFRGS, behavior, is yielding to a more differentiating interpretation Porto Alegre, RS, Brazil of the accruing data (de Boer and Koolhaas 2005; Miczek 184 Psychopharmacology (2011) 213:183–212 et al. 2007b). The current review highlights several Definition of aggression emerging themes of the past decade. First, the dimension of impulsive aggressive behavior is Most psychopharmacological research on serotonin and a heritable trait that runs in families and appears amplified aggression is motivated by gaining insights into patholog- by salient experiences during a critical postnatal develop- ical aggression, both in human and veterinary medicine mental period. The genetic architecture for synthetic and (Volavka et al. 2005). When working with laboratory metabolic enzymes, receptor and particularly transporter models of animal aggression, it is useful to consider the molecules in neurons provides ample targets ethological foundation of aggressive behavior such as its for important life events to ultimately promote increased phylogenetic and ontogenetic origins and its functional impulsive aggressive behavior (Caspi et al. 2002). significance for the individual and the species. Aggressive Second, superimposed on the serotonergic tone, plastic behavior comprises communicative signals, acts and changes in the flow in serotonin pathways to postures for the purpose of obtaining a specific goal or the forebrain are evident while an individual anticipates in defense against threatening stimuli (Miczek et al. an aggressive or defensive act (Ferrari et al. 2003). 2002). These behaviors occur in the context of competing As aggressive experiences accumulate, neuroadaptive for food and other resources that are important to an changes in serotonergic dorsal raphé cells projecting to individual’s survival and reproduction (resident-intruder terminals in the forebrain are manifested in serotonin aggression), defense of a territory or offspring (territorial impulse flow and particularly in receptor regulation. These and maternal aggression), or in response to fear or forms of neuroplasticity in serotonergic projections to the frustration (Miczek et al. 2001). In this sense, the prefrontal cortex appear important for anticipating and occurrence of aggressive behavior raises the fitness of preparing for imminent aggressive or defensive acts. the individual and enhances the survival of the species. Third, one site of regulatory influences on cellular For example, resident-intruder confrontations may repre- activity in the dorsal raphé nuclei (DRN) is the population sent male-male rivalries, establishing and maintaining a of somatodendritic autoreceptors, and stimulation of these dominance hierarchy (Fig. 1). So-called isolation-induced receptors inhibits impulse flow in serotonergic cells which, aggression captures many elements of a resident who in turn, decreases escalated aggressive behavior in rodent excludes other breeding males from the territory (Brain models. Repeated somatodendritic autoreceptor stimulation and Benton 1979;Miczeketal.2001;Table1). or antagonism have been explored in order to enhance Based on distal and proximal antecedent conditions, the clinical management of affective disorders, including behavioral topography, and the consequences, aggressive dysfunctions in social intercourse. behavior can be differentiated as offensive or defensive Fourth, excitatory and inhibitory transmitters such as (Blanchard and Blanchard 1977; Brain 1979). In rats, a set glutamate and GABA synapse with serotonergic cells in the of specific defensive behaviors occurs in response to either dorsal raphé nuclei, and the modulation of serotonergic predator or conspecific attack, and comprises escape, activity by these inputs profoundly impacts aggressive freezing, defensive postures and threats (Blanchard et al. behavior. Several members of the GABA and glutamate 2003; Pellis and Pellis 1988; Rasia-Filho et al. 2008). receptor subtypes, located on serotonergic cells, have Defensive behaviors can be a response to threatening or already been identified as key targets for several drugs fear-provoking stimuli and, usually, result in escapes (Brain such as alcohol and benzodiazepines in their escalating and 1979). For example, maternal aggressive behavior is seen in inhibiting effects on aggression. postpartum female rodents in order to protect offspring Fifth, among the many peptides that modulate seroto- against male intruders, and this type of aggression includes nin at the somata and terminals, CRF, vasopressin and both defensive and offensive elements (Lucion and de opioid peptides are noteworthy for their profound effect Almeida 1996; Parmigiani et al. 1998). on social and aggressive behavior. In rodent models, Violence in animals is a controversial term in animal CRF1 receptor antagonists effectively and selectively ethology. This term has been hypothesized to be related to reduce alcohol-heightened aggression by action on escalated, pathological and abnormal forms of aggression serotonergic neurons in the DRN, although these findings characterized by rapid attack latencies, prolonged and await translation into the clinic. frequent aggressive behavior and attack bites (Miczek et The last decade has seen also a concerted effort to al. 2002, 2003). These parameters are quantitative, in that translate more readily preclinical and clinical findings as violence is expected to show shorter attack latencies and is evident by two developments (1) an increasing focus higher frequencies and longer durations of consummatory on escalated types of aggressive behavior in animal behavior than adaptive aggression. Measures of a qualitative models and (2) by operationally and functionally defined nature have been proposed independently, where violence is aggressive behaviors in clinical assessments. considered qualitatively different from adaptive aggression. Psychopharmacology (2011) 213:183–212 185

and context independent attacks (Koolhaas 1978) aimed at the opponent regardless of its sex or state (free-living/ anaesthetized/dead) or the environment (home/neutral cage). In that sense, violence can therefore in principle refer to an escalated (hyper-) aggression (quantitative) or to an abnormal form of aggression (qualitative), or even to aggression that is both escalated and abnormal (both), which is unsurprisingly rare (for review see Natarajan and Caramaschi 2010). Aggressive behaviors in humans share commonalities with those in non-human animals, but they differ from most of them in their complexity. While social norms set the boundaries of appropriate aggressive behavior, inappropri- ate aggressive behavior in the form of interpersonal violence represents serious mental and social problems (Ferris et al. 2008). Aggressive behavior is a symptom in several psychiatric diseases, as detailed in the DSM-IV R and the updated DSM-V which is scheduled for publication in 2012, such as schizophrenia, brief reactive psychosis, anxiety disorder, adjustment disorder, impulse control disorder, antisocial personality disorder, attention deficit disorder, mania/depression, PTSD, autism, and substance abuse (Boles and Miotto 2003; Raine 2002; Rydén et al. 2009; Volavka et al. 2005). A useful scheme considers human aggression as defensive, premeditated (e.g., predatory and instrumental) or impulsive-hostile in nature (Stoff and Vitiello 1996; Vitiello and Stoff 1997). Especially the premeditated and impulsive types of aggressive behaviors are diagnosed as pathological (i.e. in need of treatment). A converging pattern of empirical data links impulsive, but not premed- itated, aggression to biological, environmental, and also to pharmacological or psychological treatment response factors (Coccaro et al. 2010). Methodologically (see Table 2), human aggressive behavior as a state is assessed using protocols according to which individuals are provoked in competitive situations with fictitious opponents and that provide opportunities to engage in measurable aggressive responses (for review see Miczek et al. 2002). The assessment of aggressive traits in human subjects are accomplished by psychometric meas- Fig. 1 Mouse agonistic behavior. Behaviors of resident and intruder ures like inventories, questionnaires and scales. These mice engaged in an aggressive confrontation: a the resident leaps and bites the intruder as the intruder attempts to escape; b the resident laboratory measures of aggressive behavior have been used (right) threatens as the intruder (left) holds a defensive upright successfully in research on the role of 5-HT (Table 2). posture; c the resident investigates the intruder’s anogenital region; d A critical challenge for this and similar experimental the resident pursues the fleeing intruder; e both resident and intruder approaches is to relate the laboratory measures of aggres- engage in a mutual upright defensive posture. Reprinted with permission from Miczek and O’Donnell (1978) sion to aggressive and violent acts outside of the laboratory. It also remains difficult to discern subtypes of human aggression with laboratory measurement techniques. Table 2 For instance, attach bites aimed at vulnerable parts of the summarizes the psychometric instruments which identify opponent’s body are considered characteristic of abnormal individuals with contrasting aggressive traits such as the aggression (Haller et al. 2005). A few additional qualitative impulsive-reactive-hostile-affective subtype versus the facets have been studied, namely lack of ritualistic behaviors controlled-proactive-instrumental-predatory subtype (Stoff as measured by Attack/Threat (A/T) ratios (Haller et al. 2005) and Vitiello 1996). 186 Psychopharmacology (2011) 213:183–212

Table 1 Types of aggressive behavior in preclinical models

Situational or experimental variable Agonistic behavioral measurements References

A. Species-typical aggressive behavior Dominant resident, In a stable colony where dominance Frequency and duration of agonistic Mehlman et al. 1994; Higley mainly in primates hierarchy is to be established and acts, postures, and displays including et al. 1996; Fairbanks et al. and rats maintained. supplants, threat, pursue, and fight. 1999; Bennett et al. 2002; Bernstein et al. 1974; Steiniger 1950; Vandenbergh 1967 Territorial resident Requires an established territory. Frequency of attack bite, sideways Van Oortmerssen and Bakker (resident–intruder test), In the laboratory, home-cage of threat, tail-rattle, pursue, upright 1981; Eibl-Eibesfeldt 1950; mainly in mice and hamsters experimental male (resident) where posture. Miczek and O’Donnell 1978; it is pair-housed with a female. A Latency to the first bite. Crawley et al. 1975 male stimulus animal (intruder) that is group housed with other males is introduced into resident’s cage. Maternal aggression, Home-cage of lactating females Frequency of attack bite (especially Hurst 1987; Sgoifo et al. mainly in rats, mice, from postpartum day 1 to 7. Either directed at the snout and the face), 1992; Lonstein and Gammie and hamsters male or female of intruder is sideways threat, tail-rattle, pursue, 2002; Noirot et al. 1975; introduced into dam’s cage. upright posture. Haney et al. 1989 Latency to the first bite Female aggression, Dominant hierarchy among female Harrassing attacks by dominant Smuts 1986; Palanza et al. mainly in primates monkeys. In the laboratory settings, female. Frequency of attack bite, 2005; DeBold and Miczek and rodents female rodent pair-housed with a sideways threat, tail-rattle, pursue, 1981; Zitzman et al. 2005 breeding male. Sexually matured upright posture. female is introduced as an intruder. Latency to the first bite Isolation-induce d Male isolated for same time, Frequency of attack bite, sideways Malick 1979; Valzelli and aggression (similar ranging from 24 h to 8 weeks prior threat, tail-rattle, pursue, upright Bernasconi 1979; Cairns and to territorial to resident–intruder encounter. posture. Nakelski 1971; Yen et al. aggression) Latency to the first bite. 1959 B. Escalated aggressive behavior Alcohol-height Animals receive ethanol (1.0 g/kg) (These 3 methods measure aggressive Peeke and Figler 1981; ened aggression, intraperitoneally or orally before behavior in same resident–intruder Blanchard et al. 1987; mainly in rats the resident–intruder encounter. method). Frequency of attack bite, Miczek et al. 1992, 1998a; and mice sideways threat, tail-rattle, pursue, Miczek and de Almeida 2001 Social provocations A resident male pre-exposed to upright posture. Latency to the first Heiligenberg 1974; Potegal (instigations), mainly another breeding male in his bite. Targets of attack bites (head, and Tenbrink 1984; Potegal in hamsters, mice, home-cage without direct agonistic dorsal areas, ventral areas, 1991; Fish et al. 1999 and rats interaction (stimulus animals are appendages) behind protective screen), followed by resident–intruder encounter. Frustration-heightened A resident male trained to obtain Berkowitz 1993; De Almeida aggression rewards. Before the resident–intruder and Miczek 2002 encounter, reward is omitted. Aggression induced Animals are adrenalectomized and Haller et al. 2001 by low glucocorticoids implanted with a low corticosterone pellet Affective defense Electrical stimulation (0.2–0.8 mA, Hissing, arching of the back, Leyhausen 1979; Siegel (“rage”), mainly in 63 Hz, 1 ms per half cycle retraction of the ears, piloerection, et al. 1999; Hess 1954 cats duration) delivered in medial unsheathing of the claws, papillary hypothalamus or midbrain dilatation and paw striking periaqueductal gray.

Aggressive “trait” vs. “state” Lesch and Merschdorf 2000; Linnoila and Virkkunen 1992; Mann 1999; Valzelli 1977). These individuals may benefit Based on early clinical and preclinical studies, the most particularly from pharmacological treatments aimed at frequently reiterated hypothesis links a serotonin deficiency inhibiting 5-HT transporters (using SSRIs such as , to individuals presenting impulsive, hostile, and violent ), or activating 5-HT1A (buspirone) or blocking behavior (Brown and Goodwin 1986; Goldman et al. 1992; 5-HT2A receptors (risperidone). Acutely, these drugs induce Psychopharmacology (2011) 213:183–212 187

Table 2 Experimental protocols for assessing 5-HT effects on human aggressive behavior

A. Experimental manipulations Experimental manipulation Measurement Trait/state References Aggressive responses toward a competitor Activate buttons at 5–10 settings, each State Buss 1961 are measured in the form of electric shock settings corresponding to a different intensity Godlaski and Giancola 2009 or duration of electric shock A fictitious instigator or competitor is the target Setting of electric shock level on a State Taylor 1967 – of aggressive responses that are measured in the scale from 1 10 Chermack and Giancola 1997 form of electric shock deliveries The subjects are provoked by having points Number of point subtractions from a State Cherek and Heistad 1971 subtracted that are earned in a competitive task. fictitious competition Cherek and Lane 1999 The point losses are attributed to a fictitious Gowin et al. 2010 opponent, but are actually determined by a computer program according to a random schedule. Subjects responded by retaliation of point subtractions (=aggressive responses Aggression was defined as delivery of electric Use of a modified version of the Buss State Zeichner and Pihl 1979 shocks to a fictitious opponent aggression machine. Setting of shock Giancola et al. 2009 level on a scale from 1–5 B. Psychometric inventories Psychometric Assessment Instrument Trait/State References Aggression, impulsive and hostility are measured Inventory Trait McKinley et al. 1948 by Minnesota Multiphasic Personality Inventory Nagtegaal and Rassin 2004 MMPI Buss-Durkee Hostility Inventory (BDHI), a self- Inventory Trait Buss and Durkee 1957 rating scale of anger and hostility. 66 items with false/true answers; also contains 7 scales: assault, indirect aggression, irritability, negativism, resentment, suspicion and verbal aggression Anger and anxiety are measured by State–Trait Inventory State/Trait Spielberg et al. 1973 Anger Expression Inventory (STAXI) Kim et al. 2009b Aggression is measured by Beck Anxiety Inventory Trait Beck et al. 1961 Inventory and Beck Depression Inventory Lamar et al. 2009

phasic changes in 5-HT function that are associated with their AC genotype show increased aggressive acts compared to transient anti-aggressive effects. Using in vivo microdialysis those with a CC genotype when they were reared without techniques, transient changes in 5-HT extracellular levels can their mother (peer-reared). This difference disappeared when be monitored before, during, after and in anticipation of an individuals of both genotypes were reared by their mothers aggressive encounter in rats. In one study, reduced 5-HT (Chen et al. 2010). In this review, we will discuss the effects levels in the prefrontal cortex were revealed during and after of genes on aggressive behaviors with a focus on the the aggressive confrontation, while no changes in 5-HT were interaction with salient environmental events. detected in another terminal region, the nucleus accumbens In addition, gene-gene interactions are also of interest (Van Erp and Miczek 2000; Fig. 2). By contrast, chronic and need to be examined in the future. For example, treatment with these anti-aggressive compounds may promote Passamonti et al. (2008) showed interactions between 5- yet to be defined neuroadaptive changes in 5-HT function that HTT and MAOA polymorphisms, and those interactions are associated with the emergence of therapeutic effects (e.g., exerted stronger effects on the activity of the anterior autoreceptor desensitization). , one of the brain areas implicated in On the other hand, genetic studies focus on aggression as a impulsivity, including impulsive aggression. Many other “trait”. While it is clear that these aggressive traits are genes may have subtle effects on aggressive phenotypes polygenic, it is remarkable that in several cases a gene- and it is possible that those genes have complex epistatic environment interaction is required for the increased propen- interactions from which stronger effects emerge (Miczek et sity to engage in violent outbursts, as observed with TPH2, al. 2001). In rodents, most genetic studies on aggression in MAO-A and 5-HTT polymorphisms (see below). For the past 15 years make use of conventional knockout example, a single nucleotide polymorphism (SNP) in TPH2 techniques in which the expression of a gene is generally gene (A2051C) has been shown to have a link to aggressive deleted in the whole body, affecting all developmental behavior in rhesus monkeys. Individuals that have an AA/ stages and inducing compensatory changes in other genes 188 Psychopharmacology (2011) 213:183–212

involvement of 5-HT3 receptors as well (McKenzie-Quirk et al. 2005; Ricci et al. 2004; Rudissaar et al. 1999).

Clinically, the 5-HT1A receptor partial agonist buspirone can reduce aggressive behavior in mentally retarded patients (Kavoussi et al. 1997; Ratey et al. 1991). This compound has been used for the management of aggressive outbursts associated with neuropsychiatric disorders in adults and children (Connor and Steingard 1996; Pabis and Stanislav 1996). However, clinical studies have mostly focused on patients with multiple diagnoses and clinical symptoms, undergoing treatment with various drugs simultaneously (Brahm et al. 2008;Levyetal.2005; Pabis and Stanislav 1996;RateyandO’Driscoll 1989; Ratey et al. 1989). Thus, more controlled studies for different clinical populations are necessary to assess the efficacy—and side effect profile—of

buspirone and other 5-HT1A agents as selective anti- aggressive . In preclinical investigations, systemic

administration of 5-HT1A receptor agonists promotes anti- aggressive effects in several species, including fish, amphib- ian, birds, rodents, guinea pigs and non-human primates (Bell and Hobson 1994; Blanchard et al. 1988; Clotfelter et al. 2007; de Boer and Koolhaas 2005;deBoeretal.1999, 2000; Dompertetal.1985;Haugetal.1990; Joppa et al. 1997; Fig. 2 and serotonin during aggression. Measurements of Lindgren and Kantak 1987; McMillen et al. 1988; Miczek et extracellular dopamine and serotonin via in vivo microdialysis in resident al. 1998b; Muehlenkamp et al. 1995; Nikulina et al. 1992; male rats before, during, and after a confrontation with an intruder. a In the nucleus accumbens (top panel), dopamine levels (gray circles) rise Olivier et al. 1992; Sanchez et al. 1993; Sperry et al. 2003; and remain elevated after the confrontation, while serotonin levels Ten Eyck 2008;Tompkinsetal.1980). Only one exception (black diamonds) do not significantly change. b In the prefrontal cortex was observed in fruit flies (Drosophila melanogaster), in (bottom panel), dopamine levels rise after the confrontation, while which treatment with the 5-HT1A agonist, 8-OH-DPAT, serotonin decline and remain lower after the confrontation. Samples were collected every 10 min and levels are expressed as mean percent of escalated aggressive behavior (Johnson et al. 2009). Selective baseline±SEM. Baseline was measured for 50 min before the fight. The antagonists of 5-HT1A receptors, such as WAY-100635, block vertical light gray bar indicates the occurrence of the 10-min fight. the anti-aggressive effect of 5-HT1A agonists, while having * and ** represent significant differences from baseline (dashed line)at no reliable effects on aggression per se (de Boer and the p<0.05 and p<0.01 levels, respectively. Reprinted with permission from Van Erp and Miczek (2000) Koolhaas 2005; Mendoza et al. 1999; Miczek et al. 1998b). Laboratory studies have found that the anti-aggressive

effects of 5-HT1A agonists in vertebrates are consistently (trait-like change; see Table 3). Novel tools, including accompanied by non-specific effects including sedation, conditional knockout, viral vector microinfusion, or drug- slow motor routines, stereotypic behavior or reduced social induceable knockout technique, can produce transient and interest (de Boer and Koolhaas 2005; Miczek et al. 1998b; local changes in , enabling the examination Olivier et al. 1995). However, some 5-HT1A agonists, at of more “phasic” changes in gene expression and how they least in a ferally derived rat strain, can selectively reduce affect aggressive behavior. The use of these techniques may aggressive behavior without affecting other non-aggressive reduce some discrepancies in the results from genetic and behaviors, (i.e., alnespirone and S-15535; de Boer and pharmacological studies of 5-HT function in aggression. Koolhaas 2005; de Boer et al. 1999, 2000). It is possible

that those compounds act on a subpopulation of 5-HT1A receptors to exert this anti-aggressive effect, and thereby are 5-HT receptors more behaviorally specific. Despite the absence of clinically approved drugs,

Pharmacology of 5-HT receptors and aggression preclinical work suggests that targeting 5-HT1B receptors may have more specific anti-aggressive effects than 5-HT1A So far, most evidence implicates the 5-HT1 and 5-HT2 manipulations. In mice and rats, the systemic administration families of receptors in aggressive behaviors (Miczek et al. of 5-HT1B agonists reduces aggressive behavior without 2002; Olivier 2004), with some initial evidence for the sedation, or motor or sensory impairment (de Almeida and Psychopharmacology (2011) 213:183–212 189

Table 3 Genes and aggressive behavior in mice

Gene Abb Chr Background strain Type of aggression Effects Serotonin function References (Generations of backcross)

Plasmacytoma Pet1 1 Mix C57BL/6 Isolation-induced Increased 90% reduction of Hendricks expressed transcript 1 (Fev) and 129 Sv resident aggression brain 5-HT et al. 2003 vasopressin V1bR 1 Mix C57BL/6 Isloation-induced Suppressed Wersinger receptor 1B and 129/SvJ aggression et al. 2002 Neutral cage Suppressed aggression Adenosine A1 A1AR 1 Mix C57BL Isolation-induced Increased Gimenez-Llort receptor and 129/OlaHsd resident aggression et al. 2002 Regulators of G Rgs2 1 C57BL/6 J (N5) Social dominance Suppressed Oliveira-dos- protein signaling 2 test Santos et al. 2000 v-abl Abelson murine Arg 1 Mix C57BL/6 Resident aggression Suppressed Koleske leukemia viral and 129/SvJ et al. 1998 oncogene homolog 2 (Abelson-related gene) Glutamic acid GAD65 2 Mix C57BL/6 Isolation-induced Suppressed Stork decarboxylase 2 and CBA2 resident aggression et al. 2000 Calcium channel, Cav2.2 2 Mix C57BL/6 J Isolation-induced Increased Increased Kim voltage-dependent, N and 129 S4/SvJae resident aggression hypothalamus et al. 2009a type, α1B subunit 5-HT dopamine β- Dbh 2 Mix C57BL/6 J Isolation-induced Suppressed Marino hydroxylase and 129/SvEv resident aggression et al. 2005 Brain-derived BDNF 2 C57BL/6 J Isolation-induced Increased Decreased brain Lyons neurotrophic factor (>N10) resident aggression 5-HT et al. 1999 [+/-] Β2-microglobulin β2m 2 129 S2/SvPas Resident aggression Suppressed Loconto (Mix C57BL/6 J?) et al. 2003 Oxytocin Oxt 2 Mix C57BL/6 J Isolation-induced Increased Winslow and 129SvEv resident aggression et al. 2000 Resident aggression Increased Suppressed DeVries et al. 1997 Membrane metallo NEP 3 Mix C57BL/6 J Resident aggression Increased Fischer endopeptidase and 129 Sv et al. 2000 (enkephalinase) 1 CB1 4 CD1 (N15) Isolation-induced Increaseda Martin resident aggression et al. 2002 Preproenkephalin Enk 4 Mix CD1 Isolation-induced Increaseda Konig and 129 resident aggression et al. 1996 Endothelial nitric oxide eNOS 5 Mix C57BL/6 Resident aggression Suppressed Increased 5-HT Demas synthase and 129 Sv Neutral cage Suppressed turnover et al. 1999 aggression Interleukin-6 IL-6 5 Mix C57BL/6, 129/ Isolation-induced Increasedb No difference in Alleva SvEv resident aggression brain 5-HT et al. 1998 concentration , Naα2C 5 C57BL/6 J (N7) Isolation-induced Increased Sallinen α2c resident aggression et al. 1998 Neuronal nitric oxide nNOS 5 Mix C57BL/6 J, Resident aggression Increased Reduced brain 5-HT Nelson synthase 129 Sv, DBA2 turnover et al. 1995 Maternal aggression Suppressed Gammie and Nelson 1999 Acetylcholinesterase AChE 5 129 S6/SvEvTac Home-cage Suppressed Duysen hierarchy et al. 2002 Adenylate cyclase PAC1 6 Mix C57BL/6 J Resident aggression Suppressed Nicot activating polypeptide and 129 Sv et al. 2004 1 receptor 1 190 Psychopharmacology (2011) 213:183–212

Table 3 (continued)

Gene Abb Chr Background strain Type of aggression Effects Serotonin function References (Generations of backcross)

Tachykinin receptor 1 NK-1r 6 Mix C57BL/6 Isolation-induced Suppressed De Felipe and 129 Sv resident aggression et al. 1998

A cluster of V1Ra/b 6 129/SvEv Maternal aggression Suppressed Del Punta et al. 2002 genes Oxtr 6 Mix C57BL/6 Isloation-induced Increased Takayanagi and 129 Sv aggression et al. 2005 Cage-mate injury Increased receptor H1 H1 6 Mix C57BL/6 J and Isolation-induced Suppressedb Increased 5-HT Yanai et 129 resident aggression turnover al. 1998 Amyloid β(A4) X11L 7 C57BL/6 Competitive feeding Subordinate Increased Sano et precursor protein- Hypothalamus al. 2009 binding, family A, 5-HT member 2 Transient receptor TRP2 7 Mix C57BL/6 J Resident aggression Suppressed Stowers et potential cation and 129 Sv al. 2002 channel, subfamily C, member 2 Neuropeptide Y Y1 8 Mix C57BL/6 Resident aggression Increased Reduced TPH Karl et al. receptor Y1 and 129SvJ mRNA expression 2004 in the raphe nuclei Prostaglandin E EP1 8 C57BL/6 (N5) Neutral cage Increased No difference in Matsuoka receptor 1 aggression 5-HT turnover et al. 2005 (Subtype EP1) Norepinephrine NET 8 Mix C57BL/6 J Isolation-induced Increaseda Haller et transporter and 129SvJ resident aggression al. 2002 Neural cell adhesion NCAM1 9 C57BL/6 J (>N5) Isolation-induced Increased Stork et molecule 1 resident aggression al. 1997 Aromatase (Cyp19a1) Ar 9 Mix C57BL/6 Resident aggression Suppressed Matsumoto and 129 S/SvEv et al. 2003 Aggression toward Increased female 5-Hydroxytryptamine 5-HT1B 9 129 S2/SvPas Resident aggression Increased Deleted 5-HT1B Saudou et (serotonin) receptor 1B receptor expression al. 1994 Maternal aggression Increased Brunner and Hen 1997 Estrogen Receptor-α ERα 10 Mix C57BL/6 J Resident aggression Suppressed Ogawa et and 129 al. 1998b Female aggression Increased Ogawa et al. 1998a Fyn tryrosine kinase Fyn 10 Mix C57BL/6 Isolation-induced Suppressed Miyakawa and CBA resident aggression et al. 2001 Nuclear receptor Nr2e1 10 C57BL/6 J (>N6) Resident aggression Increased Young et subfamily 2, group E, al. 2002 member 1 Adenosine A2a A2AR 10 CD1 (N4) Isolation-induced Increased Ledent et receptor resident aggression al. 1997 Tryptophan Tph2 10 FVB/N (N7) Home-cage injury Increased Reduced brain 5-HT Alenina et hydroxylase 2 al. 2009 , GluR-A 11 C57BL/6 J (N5) Isolation-induced Suppressed No difference in Vekovischeva ionotropic, AMPA1 aggression brain 5-HT level et al. 2004 α ( 1) Neutral cage Suppressed aggression 5-Hydroxytryptamine SERT 11 C57BL/6 J (N8) Isolation-induced Suppressed Increased Holmes et (serotonin) transporter resident aggression extracelluler 5-HT al. 2002 Psychopharmacology (2011) 213:183–212 191

Table 3 (continued)

Gene Abb Chr Background strain Type of aggression Effects Serotonin function References (Generations of backcross)

Estrogen Receptor-β ERβ 12 Mix C57BL/6 J Resident aggression Increaseda Ogawa et and 129 al. 1999 Dopamine transporter DAT 13 Mix C57BL/6 J Dyadic encounter Increased Rodriguiz and 129SvJ aggression et al. 2004

5-Hydroxytryptamine 5-HT1A 13 129 S1/Sv Resident aggression Suppressed Deleted 5-HT1A Zhuang et (serotonin) receptor 1A receptor expression al. 1999 Catechol-O- COMT 16 Mix C57BL/6 J Neutral cage Increased No difference in Gogos et methyltransferase 1 and 129SvJ aggression brain 5-HT level al. 1998 [+/-] Calcium/calmodulin- αCaMKII 18 Mix C57BL/6, Defensive Increased Reduced 5-HT Chen et dependent protein 129/OU, BALB/c aggression release in the al. 1994 kinase II alpha [+/−] dorsal raphe nucleus Melanocortin-5 MC5R 18 C57BL/6 (>N7) Neutral cage Suppressed Morgan et receptor aggression al. 2004 Monoamine oxidase A MAOA X C3H/HeJ Resident aggression Increased Increased brain Cases et Cage-mate injury Increased 5-HT up to 9 fold al. 1995 Cyclic nucleotide– Cnga2 X Mix C57BL/6 J Resident aggression Suppressed Mandiyan gated channel a2 and 129SvEv et al. 2005 Guanosine diphosphate Gdi1 X C57BL/6 J (N5) Isolation-induced Suppressed D’Adamo (GDP) dissociation resident aggression et al. 2002 inhibitor 1 Androgen receptorc AR X C57BL/6 and Isolation-induced Suppressedb Raskin et 129SvEv resident aggression al. 2009

[+/−]: Data obtained from heterozygote of knockout mouse a Behavioral change only at the first encounter b Behavior change after repeated exposure c Nestine-Cre-LoxP conditional knockout mice that selectively lack AR expression in the nervous system

Miczek 2002; de Almeida et al. 2001; de Boer and Koolhaas interactions (Bannai et al. 2007; Faccidomo et al. 2008;Mos

2005;Fishetal.1999;Miczeketal.2002, 2004;Olivier et al. 1993; Van Der Vegt et al. 2003). Infusion of a 5-HT1A 2004;Olivier et al. 1990 Fig. 3). These effects were agonist into the median raphé nucleus (MRN) also reduced antagonized by the 5-HT1B/1D antagonist GR-127935, further aggressive behavior of lactating female rats (de Almeida and confirming the involvement of 5-HT1B in mediating the anti- Lucion 1997). aggressive effects (de Boer and Koolhaas 2005). However, The overall relevance of presynaptic mechanisms for the differences in the binding domain of 5-HT1B receptors of anti-aggressive effects of these manipulations is challenged humans and rodents may yield different pharmacological by several reports that lesions or depletion of 5-HT neurons selectivity and specificity of 5-HT1B agonists (Olivier 2004). (e.g., using tryptophan hydroxylase inhibitor PCPA, or the Determination of the critical brain regions and specific neurotoxin 5,7-dihydroxytryptamine (5,7-DHT)) do not mechanisms underlying the anti-aggressive effects of 5-HT1A affect the anti-aggressive effects of 5-HT1A and 5-HT1B and 5-HT1B receptor agonists still remains to be resolved agonists (de Almeida et al. 2001; Miczek et al. 1998b; (Table 4). Neurobiological studies have associated the effects Sanchez and Hyttel 1994; Sijbesma et al. 1991). While of 5-HT1A and 5-HT1B agonists with reduced 5-HT neuronal these data suggest postsynaptic 5-HT1 receptors as critical firing and release in projection sites (Adell et al. 2001; sites of action, these pharmacological depletions spared a Bonvento et al. 1992; Sprouse and Aghajanian 1987), subpopulation of receptors. suggestive of presynaptic mechanisms mediating the anti- In projection sites of 5-HT neurons, 5-HT1B receptors aggressive effects of these drugs. Activation of 5-HT1A and likely modulate 5-HT release from synaptic terminals as 5-HT1B inhibitory autoreceptors in the dorsal raphé nucleus autoreceptors, whereas both 5-HT1A and 5-HT1B receptors (DRN) with microinfusion of selective receptor agonists modulate postsynaptic neurons (Olivier et al. 1992). In consistently reduced aggressive behavior in rats and mice, most studies, local activation of 5-HT1A and 5-HT1B in but with concomitant reduction of motor activity and social projection regions (e.g., medial preoptic area, lateral 192 Psychopharmacology (2011) 213:183–212

Tyrer et al. 2008). The placebo treatment group showed the greatest recovery from aggressive challenges compared to antipsychotic drug groups in people with intellectual disability (Tyrer et al. 2008). In animal models, risperidone

and other drugs with more selective action as 5-HT2A antagonists (e.g., ketanserin, ritanserin and MDL 100907) reduce aggressive behaviors in a behaviorally non-specific manner (Rodriguez-Arias et al. 1998; Sakaue et al. 2002; Shih et al. 1999; White et al. 1991).

Activation of 5-HT2A and 5-HT2C receptors by DOI and other substituted phenylisopropylamines also reduce aggressive behavior in several species including flies, amphibians, mice and rats (Bonson et al. 1994; de Almeida and Lucion 1994; Johnson et al. 2009; Muehlenkamp et al. 1995; Olivier et al. 1995; Sanchez et al. 1993; Ten Eyck

2008). However, the effects of 5-HT2 ligands are accom- panied by sedative effects in the same dose range as the

anti-aggressive effects. Local infusion of 5-HT2A/2C agonist into the PAG reduces maternal aggression in rats (de Almeida et al. 2005), whereas microinjections into the medial hypothalamus and into the PAG increased defensive Fig. 3 a Effects of social instigation on aggressive behavior by a resident aggression in cats (Hassanain et al. 2003; Shaikh et al. mousetowardamaleintruder.Bars represent the mean frequency±SEM 1997; see Table 4). This latter effect is likely linked to the (vertical lines) of attack bites under control (light gray) and instigated role of 5-HT2A/2C receptors in anxiety-like behavior (Lucki (dark gray) conditions. Asterisks denote statistical significance from and Wieland 1990; Nogueira and Graeff 1995). The control (**P<0.01). b Preferential reduction of instigated aggressive behavior by the 5-HT1B agonist anpirtoline (left panel, filled circles) development of more selectively acting pharmacological and CP-94,253 (right panel, filled squares). Symbols represent the mean tools will allow a more adequate differentiation of 5-HT2 frequency of attack bites, expressed as a percentage of vehicle (V) receptor subtypes, and promises to dissociate the anti- baseline, ±SEM. Light gray symbols represent non-instigated fighting aggressive and sedative effects. and dark gray symbols represent instigated levels of fighting. Asterisks denote significance from vehicle baseline (P<0.05). Adapted from Fish et al. (1999) and de Almeida and Miczek (2002) Genetics of 5-HT receptors and aggression

The 5-HT1B receptor is the first molecule that has been septum, , anterior hypothalamus, medial linked to aggression by using the genetic knockout hypothalamus, periacqueductal gray) promote reduction of technique. Male mice with disrupted 5-HT1B receptor aggressive behavior under different procedures and species expression (Htr1b−/−) increased aggressive behavior in the (see Table 4). Interestingly, under conditions that may resident-intruder test relative to wild-type residents after a promote escalated aggression, such as consumption of month of isolation (Saudou et al. 1994; Table 3; but see moderate doses of alcohol or maternal aggression, a Bouwknecht et al. 2001). However, due to very low, close

5-HT1B or 5-HT1A agonist further increased levels of to zero, aggressive behavior in the wild-type mice (129/Sv- aggressive behavior when infused into the medial prefrontal ter), the number of attacks in Htr1b−/−was very low and the cortex (Faccidomo et al. 2008) or the medial septal area (de latency to initiate was very long compared to other strains Almeida and Lucion 1997), respectively. Further studies are of mice. These mice displayed behavioral disinhibition in required to delineate the mechanisms for such pro-aggressive other behavioral tests including hyperlocomotor activity effects. (Brunner et al. 1999; Ramboz et al. 1995), drug intake agents (e.g., risperidone) with (Crabbe et al. 1996; Rocha et al. 1998), measures of anxiety- significant antagonist action at 5-HT2A receptors have been like behavior (Brunner et al. 1999;Malleretetal.1999), and successfully used to reduce aggressive outbursts in patients autonomic hyperreactivity to novelty (Bouwknecht et al. diagnosed with various neuropsychiatric disorders (Buckley 2001). Females of Htr1b−/−also show increased aggressive et al. 1997; Buitelaar et al. 2001; Czobor et al. 1995;De behavior during the postpartum period (Brunner and Hen Deyn et al. 1999; Fava 1997; Keck, Jr. et al. 2000; Zarcone 1997). These results have been interpreted to suggest a role et al. 2001). On the contrary, some reports cast doubt on for 5-HT1B receptors in the inhibition of aggressive and these routine uses of antipsychotics (Swanson et al. 2008; impulsive behaviors. Psychopharmacology (2011) 213:183–212 193

Table 4 Modulation of aggressive behaviors after local infusion of drugs targeting 5-HT receptors in selected brain regions

Brain region Type of aggression, Target; drugs and doses Pharmacological effects References species

DRN Resident aggression, 5-HT1A: 8-OH-DPAT, 1–10 μg ↓ aggressive behavior, with Mos et al. 1993 male rats 5-HT1A/5-HT1B: Eltopronazine, inactivity and decreased social 1–30 μg (agonists) interaction

Resident aggression, 5-HT1A: Alnespirone, 25 μg ↓ aggression; no side effects Van der Vegt et al. male rats (agonist) 2003

Alcohol-escalated 5-HT1A: 8-OH-DPAT, 1.0 μg 8-OH-DPAT and CP-94253: ↓ Faccidomo et al. aggression, male 5-HT1B: CP-94253, 1.0 μg baseline aggression, with reduced 2008 mice (agonists) motor activity; no effects on alcohol-related aggression Schedule-heightened 5-HT1B: CP-93129, ↓ escalated aggression; reduced Bannai et al. 2007 aggression, male 0.1–1.0 μg (agonist) walking behavior mice Alcohol-escalated 5-HT1B: CP-93129, ↓ baseline and alcohol-related Faccidomo et al. aggression, male 0.1–1.0 μg (agonist) aggression (0.5–1.0 μg); submitted mice concomitant reduction in motor activity Maternal aggression, 5-HT1A: 8-OH-DPAT, ↑ maternal aggression (0.56 μg); Veiga et al. 2010 rats 0.56 μg (agonist) no motor effects DPAT-escalated aggression prevented by infusion of CP-93129 (1.0 μg) into the orbitofrontal cortex

MRN Maternal aggression, 5-HT1A: 8-OH-DPAT, ↓ maternal aggression; no side De Almeida and rats 0.2–2.0 μg (agonist) effects Lucion 1997 PAG Maternal aggression, Dorsal PAG ↓ maternal aggression (0.2–2.0 μg); de Almeida rats 5-HT1A: 8-OH-DPAT, no side effects and Lucion 1997 0.2–2.0 μg (agonist) Maternal aggression, Dorsal PAG Α-methyl-5-HT maleate: ↓ maternal de Almeida et al. rats 5-HT2A/2C: α-methyl-5-HT aggression; no motor effects 2005 maleate, 0.2–1.0 μg (agonist)

5-HT2A/2C: ketanserin, 1.0 μg Ketanserin: no effects on (antagonist) aggression, decreased motor activity Hypothalamic- PAG 8-OH-DPAT: ↓ defensive hissing Shaikh et al. 1997 a stimulated defensive 5-HT1A: 8-OH-DPAT, (0.66–1.0 μg), effect prevented by aggression, cats 0.016 ng–1.0 μg antagonist p-MPPI. No motor effect a 5-HT2C: DOI, 3.57 ng–0.54 μg DOI: facilitation of defensive (agonists) hissing (0.54 μg) Septal nuclei Maternal aggression, Medial septal nucleus ↑ maternal aggression (0.2–0.5 μg); de Almeida and rats 5-HT1A: 8-OH-DPAT, reduced activity only with highest Lucion 1997 0.2–2.0 μg (agonist) dose (2.0 μg) Maternal aggression, Medial septal nucleus No effects on aggressive or non- de Almeida et al. rats 5-HT2A/2C: alpha-methyl-5-HT aggressive behaviors (agonist) 2005 maleate, 0.2–1.0 μg (agonist)

5-HT2A/2C: ketanserin, 1.0 μg Ketanserin: no effects on (antagonist) aggression, but decreased motor activity Resident aggression, Lateral septal nucleus 8-OH-DPAT: no behavioral effects Cologer-Clifford et a male mice (castrated 5-HT1A: 8-OH-DPAT, 0.33 ng al. 1997 males with hormonal a 5-HT1B: CGS12066, 18.0 ng CGS: ↓ aggression with CGS, only replacement) (agonists) in androgen-replacement condition; no side effects Alcohol-escalated Lateral septal nucleus No effects on alcohol-related or Faccidomo et al. aggression, male 5-HT1B: CP-94253, 1.0 μg baseline aggression 2008 mice (agonist) Hypothalamus Resident aggression, Medial pre-optic area 8-OH-DPAT: ↓ aggression in Cologer-Clifford et a male mice (castrated 5-HT1A: 8-OH-DPAT, 0.16 ng androgen- and estrogen-replacement al. 1997 194 Psychopharmacology (2011) 213:183–212

Table 4 (continued)

Brain region Type of aggression, Target; drugs and doses Pharmacological effects References species

males with hormonal conditions; no motor effects a replacement) 5-HT1B: CGS12066, 9.0 ng CGS: ↓ aggression in androgen- (agonists) and estrogen-replacement conditions; no motor effects Vasopressin- Anterior hypothalamus 8-OH-DPAT: ↓ escalated Ferris et al. 1999 a escalated aggression, 5-HT1A: 8-OH-DPAT, aggression (0.33,3.28 ng); no male hamsters 0.03–3.28 ng apparent motor effects a 5-HT1B: CGS12066, 5-HT1B: no effects on aggression 4.5–45.0 ng (agonists) (trends toward inhibition) PAG-stimulated Medial hypothalamus 8-OH-DPAT: ↓ defensive hissing Hassanain et al. 2003 a defensive aggression, 5-HT1A: 8-OH-DPAT, 0.03– (0.33–1.0 μg); effect prevented by cats 1.0 μg antagonist p-MPPI a 5-HT2C: DOI, 0.036–0.36 μg DOI: facilitates defensive hissing (agonists) (0.36 μg); effect prevented by antagonist LY-53,857 Amygdala Maternal aggression, Corticomedial amygdaloid nucleus ↓ maternal aggression (0.5–2.0 μg); De Almeida and rats 5-HT1A: 8-OH-DPAT, 0.2–2.0 μg no side effects Lucion 1997 (agonist)

Prefrontal cortex Resident aggression, 5-HT1B: CP-94253, 1.0 μg No effects on aggressive or non- de Almeida et al. male mice (agonist) aggressive behaviors 2006

Alcohol-escalated 5-HT1B: CP-94253, 0.5–1.0 μg ↑ alcohol-related aggression Faccidomo et al. aggression, male (agonist) (1.0 μg); mild increases in activity; 2008 mice no effects on baseline aggression Alcohol-escalated 5-HT1B: CP-93129, 0.1–1.0 μg ↓ baseline and alcohol-related Faccidomo et al. aggression, male (agonist) aggression (0.1–1.0 μg); no submitted mice motor effects Orbitofrontal cortex Resident aggression, 5-HT1B: CP-94253, 0.1–1.0 μg ↓ aggression (0.56–1.0 μg); no De Almeida et al. male mice (agonist) side effects. 2006 CP-94253 effects prevented by 1B antagonist, GR-127935.

Maternal aggression, 5-HT1B: CP-93129, 1.0 μg CP-93129: ↓ maternal aggression Veiga et al. 2007 rats (1.0 ug); no side effects 5-HT1B: CP-94253, 0.56–1.0 μg CP-94253: no behavioral effect (agonists) Alcohol-escalated 5-HT1B: CP-94253, 0.5–1.0 μg No effects on alcohol-related or Faccidomo et al. aggression, male (agonist) baseline levels of aggression 2008 mice Social instigation- 5-HT1A: 8-OH-DPAT, 0.1–1.0 μg 8-OH-DPAT: ↓ instigated Centenaro et al. 2008 escalated aggression, aggression (0.56–1.0 μg); no side male mice effects 5-HT1B: CP-93129, 0.1–1.0 μg CP-93129: ↓ instigated aggression (agonists) (only 0.1 μg); no side effects a Doses calculated based on the following molecular weights (MW) of the compounds (as available at Sigma-Aldrich): 8-OH-DPAT hydrobromide, MW=328.29; CGS-12066 maleate salt, MW=450.41; DOI hydrochloride, MW=357.62 DRN dorsal raphé nucleus; MRN median raphé nucleus; PAG periaqueductal gray area

Linkage analysis on a SNP in the 5’UTR region of the to lifetime aggression in suicidal victims. By contrast, other

5-HT1B gene, A161T, found a significant correlation SNPs in the 5-HT1B showed an opposite pattern. A linkage between this SNP and the history of aggression in subjects study of 5-HT1B with alcoholism and antisocial personality who completed violent suicides (Zouk et al. 2007). disorder showed that the G861C polymorphism had Individuals with the T161 locus had higher lifetime significant linkage with antisocial alcoholism in two groups aggressive behaviors. T161 polymorphism had reduced (Lappalainen et al. 1998). Specifically, C861, the SNP with transcriptional activity of 5-HT1B receptor (Sun et al. 2002), higher 5-HT1B receptor expression (Huang et al. 1999), was and thus lower 5-HT1B receptor expression may be related related to antisocial behavior in alcoholics. However, these Psychopharmacology (2011) 213:183–212 195

associations between the 5-HT1B polymorphisms (G861C, 5-HT transporter (5-HTT) G261T, or C129T) and aggression/antisocial behavior are not seen in other studies (Huang et al. 1999; Kranzler et al. Pharmacology of 5-HTT and aggressive behavior 2002; Sinha et al. 2003; Van den Berg et al. 2008). Therefore, findings from pharmacological manipulation, Blocking serotonin transporter molecules is effective in genetic deletion and polymorphism studies of the 5-HT1B reducing and preventing aggressive behavior in humans and receptor do not follow a simple and consistent scheme. This non-human animals, presumably due to increased brain suggests that the role of 5-HT1B receptors may depend on 5-HT levels. Clinically, blocking 5-HT transporters with the the types of aggressive behaviors or tonic and phasic level administration of selective serotonin reuptake inhibitors of aggression. (SSRIs), reduces aggressive outbursts and violent behavior

In contrast to the important role of 5-HT1A receptors in in psychiatric patients (Barkan et al. 2006; Blader 2006; the neural control of aggressive behavior based on Bond 2005; Coccaro and Kavoussi 1997; New et al. 2004; pharmacological evidence, no prominent linkage has been Reist et al. 2003; Walsh and Dinan 2001), with therapeutic reported with polymorphisms in the 5-HT1A gene and effects being usually observed after chronic treatment aggression so far. However, there is evidence for a (>3 weeks). However, there are occasional reports that correlation between 5-HT1A receptor expression and aggres- SSRIs may facilitate aggressivity and suicidal behavior, and sion. A human PET study found a higher 5-HT1A receptor the causes for these unusual outcomes remain to be distribution in prefrontal cortex of subjects with higher determined (Spigset 1999; Troisi et al. 1995). aggression scores based on a self-report questionnaire (Witte In animal models, both acute and chronic treatment with et al. 2009). Also, rats selected for higher defensive reactions SSRIs can dose-dependently reduce aggressive behavior showed reduced 5-HT1A receptor expression in several brain (Carrillo et al. 2009; Delville et al. 1996; Olivier et al. areas (Popova et al. 1998). It is possible that the poly- 1989; Pinna et al. 2003). Acute administration of several morphisms which directly or indirectly affect 5-HT1A SSRIs (e.g., fluoxetine, , ) reduced receptor transcription may be associated with either aggres- aggression in different contexts and species, including sive or defensive responses. 5-HT1A receptor knockout mice rodents and non-human primates (Carrillo et al. 2009; engaged in less aggressive behavior relative to wild-type Cutler et al. 1997; Delville et al. 1996; Fairbanks et al. controls, which also implicates the possible involvement of 2001; Ferris et al. 1997; Fuller 1996; Ho et al. 2001; the 5-HT1A gene in aggressive behavior (Zhuang et al. 1999; Sanchez and Meier 1997). Chronically, daily treatment with Table 3). Given the consistent pharmacological data on anti- the SSRI citalopram abolished the escalated levels of aggressive effects of 5-HT1A agonists in clinical and aggression induced by a moderate dose of alcohol over preclinical studies, lack of complementary genetic data the course of three weeks, with modest reductions in remains disconcerting. baseline levels of aggression in mice (Caldwell and Miczek

Platelet 5-HT2A receptor binding is increased in patients 2008; Fig. 4). On the other hand, chronic SSRI treatment with personality disorders and in a psychiatric population may restore competent agonistic behavior in placid, non- with greater lifetime aggression scores (Coccaro et al. 1997; aggressive laboratory rats (Mitchell 2005; Mitchell and McBride et al. 1994). In postmortem brains, lifetime Redfern 1992, 1997; Mitchell et al. 1991). Thus, the anti- aggression was positively correlated with prefrontal 5-HT2A aggressive effects of SSRIs are more prominent in receptor binding in suicide victims (Oquendo et al. 2006). conditions of escalated aggressive behavior such as those Therefore, it is possible that polymorphisms that affect the promoted by alcohol (Caldwell and Miczek 2008). level of expression of 5-HT2A receptors can be associated Mechanistically, acute or chronic administration of with self-directed aggression. In some samples, significant citalopram (or the more potent isomer ) both linkage was found between polymorphisms in the 5-HT2A elevate extracellular levels of 5-HT in the prefrontal cortex receptor, T102C, A1438G and His452Tyr, and aggressive- of rats, suggesting increased cortical 5-HT as a putative impulsive trait or adolescent-onset antisocial behavior in therapeutic mechanism for SSRIs’ effects on aggression humans (Assal et al. 2004; Bjork et al. 2002;Burtand and other mood disorders (Ceglia et al. 2004). However, the Mikolaiewski 2008;Nomuraetal.2006). But others have anti-aggressive effects of another SSRI, fluoxetine, might reported no such link between aggression and 5-HT2A be primarily mediated by actions on neurosteroids and polymorphisms (Khait et al. 2005; Van den Berg et al. GABA transmission, and only secondarily via 5-HT (Pinna 2008). Again, the success with pharmacotherapeutic man- et al. 2003, 2006). Furthermore, long-term effects of SSRIs agement of aggressive patients using compounds with likely recruit pre- and post-synaptic mechanisms and affinity for 5-HT2A receptors would suggest that violence- neuroplastic events that contribute to their therapeutic prone individuals may be characterized by distinctive 5-HT effects (Benmansour et al. 1999; Blier and de Montigny polymorphisms. 1998; Ceglia et al. 2004; Pineyro et al. 1994). 196 Psychopharmacology (2011) 213:183–212

lower 5-hydroxyindoleacetic acid (5HIAA) in CSF than l/l individuals when they were reared without their mother (peer-reared). This difference disappeared when both were reared by their mothers (Bennett et al. 2002). Peer-reared monkeys showed increased aggression-related behavior as well as altered CSF 5HIAA levels (Higley et al. 1991; Kraemer et al. 1989). In humans, higher suicide ideations or attempts were observed in individuals carrying the s allele than in l/l homozygotes when they encountered a number of stressful life events, but not in less stressful situations (Caspi et al. 2003). Therefore, it is possible that animals with the s allele are more vulnerable to the stressful challenges, and subsequently escalate their aggressive behaviors towards others and themselves. However, the effect of the s allele on aggression differed among sexes (Cadoret et al. 2003)and even cultures (Baca-Garcia et al. 2004). Fig. 4 Effects of repeated, twice daily administration of the SSRI Seemingly contrary results were observed in mice with a citalopram (10 mg/kg, i.p.) on aggressive behavior in mice after deletion of the 5-HTT gene (Slc6a4). Homozygote and drinking 1.0 g/kg alcohol in operant self-administration panels. Frequency of aggressive acts (±SEM) is defined as sum of attack heterozygote 5-HTT knockout mice on a C57BL/6 J bites, threats, pursuits and tail rattles, and was analyzed in 5 min background showed fewer attack bites and longer latencies confrontations against a male intruder, during the course of 4 weeks of to start fighting relative to wild-type mice in the resident- citalopram (or saline control) treatment. + symbols represent differ- intruder test (Holmes et al. 2002; Table 3). 5-HTT knockout ences from baseline (++ p<0.01; +++ p<0.001); * symbols represent group (citalopram vs. saline-controls) differences (**p<0.01; ***p< mice have lower 5-HT uptake and higher extracellular 5-HT 0.001). Adapted from Caldwell and Miczek (2008) concentrations in the forebrain compared to wild-type (Mathews 2004). 5-HTT knockout mice underwent changes Genetics of 5-HTT and aggressive behavior in more than 50 phenotypes including morphological, physiological, sensory, and behavioral functions (Murphy A variation in the length of 5’-flanking transcriptional and Lesch 2008), and thus those pleiotropic changes of control region (promoter) of the 5-HTT gene (the serotonin- other phenotypes may contribute to the reduction of transporter-gene-linked polymorphic region; 5-HTTLPR) aggressive behaviors in these mice. Comparable findings has been identified in humans (Heils et al. 1996), great apes on 5-HTT and aggression were reported in the rat. 5-HTT and rhesus monkeys (Lesch et al. 1997). This variation knockout rats on a Wistar/Crl background also showed affects the transcriptional activity of the 5-HTT gene, and reduced offensive behaviors and longer attack latencies the short length (s) allele reduces 5-HTT expression in vitro compared to wild-type rats (Homberg et al. 2007). and lowers the prolactin response to in Therefore, genetic ablation of 5-HTT consistently reduced human, which reflects reduced 5-HT function, compared aggressive behaviors in rodents. to the homozygote of long length allele (l/l) (Heils et al. 1995; Lesch et al. 1996; Whale et al. 2000). An association study in humans showed that individuals with one or two Monoamine oxidase A (MAOA) copies of the s allele (s/s, s/l) were characterized by higher anxiety, depression, hostility and aggression, and lower Pharmacology of MAOA and aggression agreeableness than individuals of the l/l homozygote in both sexes (Lesch and Merschdorf 2000). Higher frequency Inhibition of MAOA reduces the oxidative metabolism of of the s allele was observed in alcoholics accompanied with monoamines, thus presumably increasing the availability of high impulsivity and antisocial behaviors (type 2 alcohol- 5-HT and other monoamines in the brain. Despite the early ism) compared to alcoholics without antisocial behavior recognized importance of MAO inhibitors as , (type 1) or healthy controls (Hallikainen et al. 1999). there are only a few preclinical studies that systematically Consistent with the human polymorphism, rhesus monkeys evaluated the effects of MAO inhibitors on aggression that possess the s allele engaged in higher rates of (Miczek 1987). For the most part, non-selective inhibitors aggressive behaviors compared to l/l individuals (Jarrell et of both MAOA and MAOB (e.g. , isocarboxazid, al. 2008; Lesch and Merschdorf 2000). ) show acute anti-aggressive effects in doses A genotype-environment interaction can be found in 5- that also alter motor and other non-aggressive behaviors HTT polymorphism. Rhesus monkeys with the s allele had (DaVanzo et al. 1966; Sofia 1969; Valzelli et al. 1967; Welch Psychopharmacology (2011) 213:183–212 197 and Welch 1968). Clinically, non-selective MAO inhibitors or selective MAOB inhibitors can be useful in the pharmacological management of personality disorders that include impulsive aggression and suicidal tendencies as important symptoms, but are accompanied by an unfavorable profile of side effects (Hollander 1999;Raj2004).

Genetics of MAOA and aggression

The gene for MAOA was the first candidate identified as a determinant in the susceptibility for aggression in humans, and it has remained the focus of most genetic and Fig. 5 Means on the composite index of antisocial behavior as a function epigenetic studies. Brunner and colleagues (Brunner et al. of MAOA activity and a childhood history of maltreatment. MAOA 1993b) identified a large Dutch kindred with a syndrome of activity is the gene expression level associated with allelic variants of the borderline mental retardation and dysregulated impulsive functional promoter polymorphism, grouped into low and high activity; aggression. All affected males showed aggressive outbursts, childhood maltreatment is grouped into 3 categories of increasing severity. The antisocial behavior composite is standardized (z score) to and some exhibited sexually aberrant behavior, attempted a M=0 and SD=1; group differences are interpretable in SD unit murder and arson. Linkage and sequence analyses showed differences (d). Reprinted with permission from Caspi et al. (2002) that all affected males in this family possessed one missense mutation in the MAOA gene on the X , so that arrests and a violent history, adolescent conduct disorder, MAOA function was completely disturbed (Brunner et al. and also higher aggressive disposition in self-report ques- 1993a). The affected males had higher serotonin and lower tionnaire compared to individuals with higher MAOA metabolites of norepinephrine (NE), dopamine (DA), and expression (MAOA-H) allele or MAOA-L individuals 5-HT in the urine (Brunner et al. 1993a). MAOA also is of without abuse (Caspi et al. 2002; Foley et al. 2004; Frazzetto significance in the probability of fighting in animals. Male et al. 2007; Kim-Cohen et al. 2006; Weder et al. 2009; mice with disrupted MAOA gene on either C3H/He or Widom and Brzustowicz 2006). If rearing environments 129 Sv background showed escalated aggressive behaviors were lumped together, the effect of MAOA genotype compared to wild-types, as is evident by skin wounds among disappeared (Fresan et al. 2007) or sometimes MAOA-H the cage-mates and a short latency to initiate attacks in the individuals reported higher aggression using data from resident-intruder test (Cases et al. 1995; Scott et al. 2008). interviews and questionnaires (Manuck et al. 2000, 2002). MAOA-deficient mice also showed a large increase in 5-HT Therefore, individuals with MAOA-L allele are vulnerable to and NE, and a subtle DA elevation, in the brain and liver environmental factors and show a high propensity to engage (Cases et al. 1995; Kim et al. 1997; Table 3). It is likely that in aggressive behaviors only when they are in a stressful the change of 5-HT function is the cause of the behavioral environment. These findings are consistent in males, but not changes in the MAOA-deficient mice. Ketanserin and in females (Sjoberg et al. 2007). Similarly, rhesus monkeys

MDL100907, antagonists that preferentially bind to 5-HT2A have a repeat length variation polymorphism (rhMAOA- receptors, blocked the escalated aggression in the MAOA LPR) in the MAOA gene, and this polymorphism is also mutant mice (Shih et al. 1999). Depletion of 5-HT by PCPA linked to aggression. Monkeys with a low-activity allele during the early developmental stage improved some exhibited higher aggressive behavior and tend to attain behavioral and brain structural abnormality in the MAOA- higher dominance rank when they were reared by their deficient mice (Cases et al. 1995, 1996). mother. In contrast, when they were reared separately from Variable-number tandem repeat (VNTR) polymorphism, their parents (peer-reared), monkeys with the low-activity which exists on the upstream region of the MAOA gene, allele engaged in less aggressive behavior (Newman et al. regulates MAOA expression depending on the number of 2005). This inhibition of aggression has been attributed to repeats: Alleles with 3.5 or 4 repeats have 2-10 times higher increased fear and anxiety in peer-reared monkeys (Higley transcription than 3 or 5 repeat alleles in vitro (Denney et al. and Suomi 1986). 1999; Sabol et al. 1998). A prominent interaction between Neuroimaging studies have indicated pronounced differ- MAOA genotype and environment on aggressive behavior ences in volume and activity of limbic system and neocortical hasbeenreported(Caspietal.2002;Fig.5). Under stressful areas between individuals with MAOA-L and MAOA-H (see rearing conditions, such as abuse or neglect, or exposure to Buckholtz and Meyer-Lindenberg 2008 for a review). fMRI traumatic life events in the first 15 years of their lives, analysis in healthy human volunteers showed that MAOA-L individuals with low MAOA expression (MAOA-L) poly- males had smaller limbic and orbitofrontal volumes, and morphisms showed higher propensity to have criminal higher activity in amygdala and hippocampus during 198 Psychopharmacology (2011) 213:183–212 aversive recall (Meyer-Lindenberg et al. 2006), that may GABA receptors are involved in escalated forms of be related to violent behavior in MAOA-L individuals. aggressive behavior via different mechanisms. In vivo

Alia-Klein et al. (2008) reported that lower MAOA activity microdialysis showed that GABAB activation in the DRN in cortical and subcortical brain areas is associated with high increased extracellular 5-HT level in the medial prefrontal aggression measured by self-report questionnaire, indepen- cortex (Takahashi et al. 2010b; Fig. 6). This result suggests dent from MAOA polymorphism. These data show that the that the phasic activation of 5-HT system may be able to MAOA activity is one of the determinants for the vulnera- promote certain types of escalated aggressive behaviors in bility to aggression, especially the interaction between mice. MAOA polymorphism and salient social experiences can escalate the aggression and also change relevant brain Glutamate structures. The DRN receives prominent glutamate input by the descending projections from the lateral habenula, periaque- Modulation of serotonergic activity by other systems ductal gray, lateral hypothalamus, interpeduncular nucleus and medial prefrontal cortex (Aghajanian and Wang 1977; The 5-HT neurons in the raphé nuclei are modulated by Behzadi et al. 1990; Kalen et al. 1986; Maciewicz et al. other amines, acids, peptides and steroids (Adell et al. 1981). Both the N-metyl-D-aspartate (NMDA) and α- 2002). Recently, several efforts were undertaken to uncover amino-3-hydroxy-5-methyl-4-isoxazolaproprionate/kainate the nature of the neural systems that modulate 5-HT (AMPA/kainate) are localized on serotonergic neurons and neurons to promote escalated aggressive behaviors. Here increase the 5-HT release in the DRN and its projection we will focus briefly on inhibitory and excitatory neuro- areas (Celada et al. 2001; Pallotta et al. 1998; Tao and transmitters and some in terms of their Auerbach 2000; Tao et al. 1996; Vandermaelen et al. 1986). interaction with 5-HT system. The more general role of Systemic administrations of classic antagonists of NMDA those molecules on aggressive behavior was reviewed receptors, including phencyclidine (PCP) and dizocilpine recently (Miczek et al. 2007b). (MK-801), can increase aggressive behavior (Burkhalter and Balster 1979; Krsiak 1974; McAllister 1990; Musty GABA and Consroe 1982; Rewerski et al. 1971; Wilmot et al. 1987), while other studies find that these compounds are The inhibitory γ-aminobutyric acid suppressive and sedative due to their strong side-effects (GABA) plays a crucial role in the modulation of the (Belozertseva and Bespalov 1999; Lang et al. 1995; Miczek dorsal raphé nuclei (DRN). Large number of GABA and Haney 1994; Tyler and Miczek 1982). Anatomically interneurons and distal GABAergic afferents can be found discrete analysis is required to identify the sites of action in the DRN (Belin et al. 1983; Gervasoni et al. 2000; for NMDA receptors that produce enhanced aggressive Nanopoulos et al. 1982; Wang et al. 1992), and both behavior. The 5-HT system is one of the candidates,

GABAA and GABAB receptors are expressed in the DRN especially the descending projection from (Bowery et al. 1987). In vitro electrophysiology studies the medial prefrontal cortex (mPFC) to the DRN will be have shown that the activation of the GABAA and GABAB interesting to investigate. The prefrontal cortex (PFC) has receptors on the 5-HT neurons both inhibit 5-HT cell firings been implicated in the emotion regulation including (Colmers and Williams 1988; Gallager and Aghajanian aggression (Davidson et al. 2000; Miczek et al. 2007a). 1976; Innis and Aghajanian 1987; Judge et al. 2004). On This PFC-DRN glutamatergic projections are involved in the other hand, in vivo microdialysis studies have shown the controllability or emotion regulation (Amat et al. 2005) that the GABAA and GABAB receptors in the DRN and further study will be required to address the role of this differentially modulate 5-HT release depending on the PFC-DRN glutamatergic neurons on aggressive behaviors. projection sites (Tao et al. 1996). We recently found that the pharmacological activation of GABAB receptors in the CRF DRN escalated aggressive behaviors in mice (Takahashi et al. 2010b). Interestingly, only under the influence of The DRN is innervated by Corticotropin-Releasing Factor alcohol, local administration of GABAA receptor agonist (CRF) immunoreactive fibers, and presents both subtypes muscimol also heightened aggressive behaviors (Takahashi of CRF receptors, CRF1 and CRF2 (Chalmers et al. 1995; et al. 2010a). By contrast, intra-DRN muscimol inhibited Potter et al. 1994; Swanson et al. 1983). Evidence suggests aggressive behaviors in rats (Van Der Vegt et al. 2003)or that CRF, CRF receptors and other peptides of the CRF was without effect on aggression in the absence of alcohol family (Urocortins), play key modulatory roles on DRN (Takahashi et al. 2010b). Therefore, both subtypes of serotonin neurons (see Valentino and Commons 2005). Psychopharmacology (2011) 213:183–212 199

Fig. 6 Extracellular 5-HT concentration in the medial prefrontal cortex 7). *p<.05 compared to the baseline. (b) The effect of 0.06 nmol (mPFC) of mice after GABAB receptor activation in the dorsal raphe baclofen on attack bites after the different interval (10, 40 and 100 min, nucleus (DRN). (a) Baclofen microinjected into the DRN increased the corresponding to the time period of fraction 9, 11, and 14 in the 5-HT level in the mPFC whereas saline injection did not change the 5- microdialysis, respectively). Escalated attack bites were observed both HT level. Twenty minutes samples were collected 5 samples for 10 and 40 min after the intra-DRN baclofen injection. *p<.05 compared baseline, 3 samples after saline injection, and 6 samples after baclofen to corresponding vehicle control (0.06 nmol) injection. Data are expressed as percentage of baseline (n=

Electrophysiological and microdialysis studies consistently such anti-aggressive effects of CRF1 antagonists can be report that i.c.v. or intra-DRN microinjections of CRF, or abolished with the infusion of 8-OH-DPAT into the DRN, drugs targeting CRF receptors, exert potent modulatory which transiently slows 5-HT impulse flow. On the other control over 5-HT neural firing (Kirby et al. 2000; Lowry et hand, microinfusion of a CRF2 antagonist (Astressin-2B) al. 2000), and 5-HT output to limbic, striatal and prefrontal into the DRN escalates aggressive behavior (Quadros et al. cortical regions (Amat et al. 2004, 2005; Forster et al. 2008; 2009a). Lukkes et al. 2008; Meloni et al. 2008; Price and Lucki Thus, the modulation of aggressive behaviors by CRF 2001; Price et al. 1998). systems depends on the species (mice, rats) and type of

A role for CRF, CRF1 and CRF2 receptors in aggressive aggression (species-typical, maternal or escalated aggres- behavior has been indicated by studies on maternal- and sion). Initial evidence suggests the 5-HT cells in the DRN inter-male aggression in mice and hamsters (D’Anna et al. as one of the critical sites for such modulation in the 2005; Farrokhi et al. 2004; Gammie and Stevenson 2006; escalated aggression promoted by alcohol, with presumably

Gammie et al. 2004, 2005, 2007). In rats, there is evidence opposing roles for CRF1 and CRF2 receptors. that low doses of CRF themselves may facilitate or induce pro-aggressive effects after i.c.v. or intra-amygdala infusions Vasopressin (Elkabir et al. 1990;Tazietal.1987). Under conditions of escalated aggression promoted by moderate doses of alcohol Arginine vasopressin (AVP) is a neuropeptide that modulates in male mice, CRF1 receptors are a promising target for a variety of social behaviors including pair-bonding, social pharmacological intervention. Systemically, antagonists of recognition, maternal behavior, and aggression (Albers and

CRF1 receptors reduce alcohol-heightened aggression, but Bamshad 1998; Coccaro et al. 1998; Ferris 1992;Goodson also reduce baseline levels of aggressive behavior (Quadros 2008;Koolhaasetal.1990; Neumann et al. 2010; Winslow et al. 2009a). When locally administered into the DRN, et al. 1993). Selective antagonist of vasopressin V1a

CRF1 antagonists (e.g., CP-154526 or MTIP) prevent the receptors (SRX251, [d(CH2)5Tyr(Me)AVP]) inhibited inter- escalated levels of aggression observed after consumption of male aggression (Ferris and Potegal 1988; Ferris et al. 2006), alcohol, with no side effects on other behaviors. Remarkably, indicating the involvement of V1a receptors in aggressive 200 Psychopharmacology (2011) 213:183–212 behaviors. The interaction between AVP and 5-HT has been maternal and anxiety-like behaviors (Hendricks et al. 2003; shown to be critical for certain types of aggressive behaviors. Lerch-Haner et al. 2008), and it is possible that those other In humans, a positive correlation has been observed between behavioral changes promote indirectly aggressive behaviors. AVP concentrations in the CSF and the life history of aggression, a composite measure of trait aggression. Also, Brain-derived neurotrophic factor (BDNF) there was a positive correlation between AVP concentrations and prolactin responses to a challenge with d-fenfluramine BDNF has several important roles in the neuron including (Coccaro et al. 1998). This result indicates that individuals neuronal survival, development, differentiation and plasticity. that have higher aggression ratings tend to have a high AVP Mice with decreased BDNF expression including knockout concentration in the CSF and a hyporesponsive 5-HT system. (BDNF+/−) and conditional knockout (BDNF2L/1LNes-cre Neuronal interactions between AVP containing neurons and and BDNF2L/2LCk-Cre) all showed increased inter-male 5-HT neurons are found in the anterior hypothalamus (Ferris aggression (Chan et al. 2006; Lyons et al. 1999). Higher et al. 1997, 1999), and this AVP-5-HT link is implicated in hippocampal extracellular levels of 5-HT were observed in aggression. Microinjection of AVP into the anterior hypo- BDNF+/− mice compared to wild-type (Deltheil et al. 2008), thalamus increased aggressive behavior in hamsters, and but fluoxetine reduced their heightened aggressive behavior systemic fluoxetine (5-HTT inhibitor) treatment blocked the (Lyons et al. 1999). All mutants changed 5-HT2A receptor +/− pro-aggressive effect of AVP (Delville et al. 1996;Ferrisetal. expression, however BDNF showed increased 5-HT2A 1997). Therefore, 5-HT may have an inhibitory function on expression in the lateral frontal cortex and hypothalamus the AVP induced heightened aggression. In contrast, mice (Lyons et al. 1999) whereas BDNF2L/1LNes-Cre and -/- 2L/2LCk-Cre with disrupted Ca2+ channel expression (Cav2.2 )showed BDNF exhibit reduced 5-HT2A receptor expression escalated level of aggressive behavior and also higher AVP in the prefrontal cortex (Chan et al. 2006;Riosetal.2006). concentration in the CSF. However, these animals showed A SNP in the BDNF gene, Val66Met, has attracted strong overactivation of the dorsal raphe 5-HT neurons and interest because of its association with mood disorders and increased 5-HT concentration in the hypothalamus (Kim et hippocampal function in humans (Egan et al. 2003;Neves- al. 2009a). Further investigation is anticipated to uncover Pereira et al. 2002). Knock-in mice with this human Met how AVP and 5-HT interact and whether there are specific allele also showed an increased aggressive behavior and types of aggression that require the activity of either 5-HT or changed the response to SSRI treatment (Chen et al. 2006). AVP systems independently. In contrast to the consistent results on aggressive behavior among BDNF mutant mice, studies on polymorphisms of the BDNF gene in aggressive behavior in humans remain to be Other molecules that directly or indirectly affect 5-HT resolved. No association was observed between Val66Met pathways and aggression polymorphism and proneness to violence in a Chinese male sample (Tsai et al. 2005). Other SNPs in the BDNF gene Here we will briefly discuss selected molecules that directly may be associated with high impulsivity in children with or indirectly affect serotonergic pathways and modulate ADHD (Oades et al. 2008). aggressive behaviors based mainly on findings from gene knockout mouse studies, as summarized in Table 3. For Neuronal nitric oxide (nNOS) more reviews on genes and aggressive behavior, see Maxson and Canastar (2007), Miczek et al. (2001) and Nitric oxide, a free radical gas which diffuses across Nelson and Chiavegatto (2001). membranes, is involved in several cellular functions (for review see Calabrese et al. 2007). Mice lacking neuronal Pet-1 (also known as Fev) nitric oxide synthase (nNOS−/−) show various deficits in their physiological development and also behavior (Huang Pet-1, one of the transcription factors, is specifically expressed et al. 1993). nNOS−/− males, but not females, showed in the serotonergic raphé neurons, and has a critical role in 5- higher duration of aggressive behavior and also displayed HT neural development. Deletion of Pet-1 expression reduced much fewer submissive postures compared to wild-types 5-HT level in the forebrain, and also depleted expression of (Nelson et al. 1995). Serotonergic dysfunction was ob- TPH, 5-HTT, and the vesicular monoamine transporter 2 served in the nNOS−/− mice, specifically reduced 5-HT

(Vmat2). In the resident-intruder test, Pet-1 knockout mice turnover in the brain and deficient 5-HT1A and 5-HT1B (Pet-1−/−) engaged in higher frequency and intensity of receptor function (Chiavegatto et al. 2001). Escalated attacks toward a conspecific male (Hendricks et al. 2003). aggression in the nNOS−/− was rescued by 5-HTP These increases in aggressive behavior in Pet-1−/−mice are treatment which increased 5-HT level and turnover. These embedded in broad behavioral disruptions that extended to findings point to an important role of nitric oxide for the Psychopharmacology (2011) 213:183–212 201 normal 5-HT function, and thus increased aggression ing (1) the type of aggressive behavior, its topography and nNOS−/− may be induced by changing 5-HT activity. function, (2) the genetic background of the individual and the typical phenotype for this background, (3) the trait character- Neuropeptide Y (NPY) istics of the human subject or the mouse (i.e., Mus musculus are a pugnacious species and many inbred strains are quite NPY controls primarily food intake, energy balance, and placid), and (4) the situational conditions under which metabolic regulation (Herzog 2003). This molecule which is aggressive behaviors has been engendered. From a clinical critical for energy homeostasis is also implicated in aggressive perspective, the impulsive, hostile, explosive type of aggres- behavior (Emeson and Morabito 2005). Male mice with sive behavior is part of a more broadly defined trait that deleted expression of the Y1-receptor (Y1−/−) showed obesity has been linked to profound changes in the expression of and reduced energy homeostasis (Kushi et al. 1998), and also MAO-A, 5-HTT, and 5-HT receptors. A growing number of exhibited increased aggressive behaviors in the resident- studies that suggest important gene-environment interactions intruder test (Karl et al. 2004). However, this escalated involving genes that regulate 5-HT transmission (e.g., aggression in Y1−/− was observed only in the home cage, monoamine oxidase and serotonin transporters) and stressful not in the novel environment. This result suggests a specific life events are of particular interest. When associated, these increase in territorial aggression which may be related to conditions are critical in determining an increased vulnera- altered 5-HT function of Y1−/− (Karl et al. 2004). TPH bility to initiate violent acts and aggressive outbursts (e.g., mRNA expression in the raphé nuclei was reduced in the Bennett et al. 2002; Caspi et al. 2002, 2003). By associating −/− Y1 mice. In addition, 5-HT1A agonist treatment reduced the specific characteristics of the individual, the environment escalated aggression in Y1−/− mice. and the type of social interaction, the serotonin-aggression link can be further explored, providing new pharmacological α-Calcium-Calmodulin Kinase II (α-CaMKII) and molecular targets for interventions. From a therapeutic perspective, it seems clear that α-CaMKII is a neural specific enzyme and has been shown manipulations of 5-HT transmission are effective for the to be involved in long-term potentiation (LTP; Silva et al. management of aggressive behavior, despite the common 1992). Heterozygotes of α-CaMKII knockout mice showed observation of side effects. Traditionally, pharmacological escalated defensive aggression but not offensive aggression manipulations that increase 5-HT function are effective in (Chen et al. 1994). In the resident-intruder test, resident α- reducing aggression in clinical and preclinical settings. CaMKII heterozygotes showed aggressive behavior similar However, whether such increases in 5-HT transmission are to wild-type mice. In contrast, when the mutant was tested the main relevant mechanism for the anti-aggressive effects as an intruder, they exhibited high defensive reactions remains in dispute. For example, agonists of the 5-HT1 family toward the resident. Reduced 5-HT release was observed in of receptors and citalopram (SSRI) promote opposite the dorsal raphé of α-CaMKII mutants in vitro, and thus the changes in extracellular concentrations of 5-HT in terminal changed 5-HT function may be associated with defensive regions, despite both having anti-aggressive effects. Such aggression in this mouse. observations suggest that drugs acting at different 5-HT Gene targeting techniques in mice have identified a number molecular targets may recruit different neuropharmacological of genes involved in aggressive behaviors (Table 3) and these mechanisms in order to promote their anti-aggressive effects, animals offer insights into the simple serotonin-aggression likely involving actions on specific receptor subpopulations link. The direction of the change in the 5-HT system is not and downstream signaling pathways. Of particular clinical always the same (Table 3); some knockout mice that showed interest, the development of neuroplastic changes seems to escalated aggressive behaviors also showed a reduction in accompany the emergence of anti-aggressive effects after 5-HT tone (e.g. Pet1, nNOS, NPY, α-CaMKII) but others chronic treatment with SSRIs. More recently, the identifica- showed a clear increase of 5-HT release in the brain (e.g. tion of pharmacological targets that directly or indirectly

MAOA, BDNF, Cav2.2). Further examination of 5-HT modulate 5-HT function, such as receptors for glutamate, changes in dissected brain regions and also of changes in GABA and neuropeptides, show promising results for more specific 5-HT receptor subtypes in these knockout mice will selective anti- and pro-aggressive effects. clarify more details of the serotonin-aggression link.

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