Social defeat stress and escalation of cocaine and alcohol consumption: Focus on CRF.

Both the ostensibly aversive effects of unpredictable episodes of social stress and the intensely rewarding effects of drugs of abuse activate the mesocorticolimbic dopamine systems. Significant neuroadaptations in interacting stress and reward neurocircuitry may underlie the striking connection between stress and substance use disorders. In rodent models, recurring intermittent exposure to social defeat stress appears to produce a distinct profile of neuroadaptations that translates most readily to the repercussions of social stress in humans. In the present review, preclinical rodent models of social defeat stress and subsequent alcohol, cocaine or opioid consumption are discussed with regard to: (1) the temporal pattern of social defeat stress, (2) male and female protocols of social stress-escalated drug consumption, and (3) the neuroplastic effects of social stress, which may contribute to escalated drug-taking. Neuroadaptations in corticotropin-releasing factor (CRF) and CRF modulation of monoamines in the ventral tegmental area and the bed nucleus of the stria terminalis are highlighted as potential mechanisms underlying stress-escalated drug consumption. However, the specific mechanisms that drive CRF-mediated increases in dopamine require additional investigation as do the stress-induced neuroadaptations that may contribute to the development of compulsive patterns of drug-taking.

Microglial Over-Activation by Social Defeat Stress Contributes to Anxiety- and Depressive-Like Behaviors.

Hyper activation of the neuroimmune system is strongly related to the development of neuropsychiatric disorders. Psychosocial stress has been postulated to play an important role in triggering anxiety and major depression. In preclinical models, there is mounting evidence that social defeat stress activates microglial cells in the central nervous system. This type of stress could be one of the major factors in the development of these psychopathologies. Here, we reviewed the most recent literature on social defeat and the associated immunological reactions. We focused our attention on microglial cells and kept the effect of social defeat over microglia separate from the effect of this stressor on other immune cells and the influence of peripheral immune components in priming central immune reactions. Furthermore, we considered how social defeat stress affects microglial cells and the consequent development of anxiety- and depressive-like states in preclinical studies. We highlighted evidence for the negative impact of the over-activation of the neuroimmune system, especially by the overproduction of pro-inflammatory mediators and cytotoxins. Overproduction of these molecules may cause cellular damage and loss or decreased function of neuronal activity by excessively pruning synaptic connections that ultimately contribute to the development of anxiety- and depressive-like states.

Corticotropin Releasing Factor in the Bed Nucleus of the Stria Terminalis in Socially Defeated and Non-stressed Mice with a History of Chronic Alcohol Intake.

Stress exposure has been identified as one risk factor for alcohol abuse that may facilitate the transition from social or regulated use to the development of alcohol dependence. Preclinical studies have shown that dysregulation of the corticotropin releasing factor (CRF) neurotransmission has been implicated in stress-related psychopathologies such as depression and anxiety, and may affect alcohol consumption. The bed nucleus of the stria terminalis (BNST) contains CRF-producing neurons which seem to be sensitive to stress. In this study, adult male C57BL/6 mice previously defeated in resident-intruder confrontations were evaluated in the elevated plus-maze and tail suspension test. Mice were also tested for sweet solution intake before and after social stress. After having had continuous access to ethanol (20% weight/volume) for 4 weeks, control and stressed mice had CRF type 1 (CRFR1) or type 2 (CRFR2) receptor antagonists infused into the BNST and then had access to ethanol for 24 h. In separate cohorts of control and stressed mice, we assessed mRNA levels of BNST CRF, CRFR1 and CRFR2. Stressed mice increased their intake of sweet solution after ten sessions of social defeat and showed reduced activity in the open arms of the elevated plus-maze. When tested for ethanol consumption, stressed mice persistently drank significantly more than controls during the 4 weeks of access. Also, social stress induced higher BNST CRF mRNA levels. The selective blockade of BNST CRFR1 with CP376,395 effectively reduced alcohol drinking in non-stressed mice, whereas the selective CRFR2 antagonist astressin2B produced a dose-dependent increase in ethanol consumption in both non-stressed controls and stressed mice. The 10-day episodic defeat stress used here elicited anxiety- but not depressive-like behaviors, and promoted an increase in ethanol drinking. CRF-CRFR1 signaling in the BNST seems to underlie ethanol intake in non-stressed mice, whereas CRFR2 modulates alcohol consumption in both socially defeated and non-stressed mice with a history of chronic intake.

Administration of a Histone Deacetylase Inhibitor into the Basolateral Amygdala Enhances Memory Consolidation, Delays Extinction, and Increases Hippocampal BDNF Levels.

Gene expression related to the formation and modification of memories is regulated epigenetically by chromatin remodeling through histone acetylation. Memory formation and extinction can be enhanced by treatment with inhibitors of histone deacetylases (HDACs). The basolateral amygdala (BLA) is a brain area critically involved in regulating memory for inhibitory avoidance (IA). However, previous studies have not examined the effects of HDAC inhibition in the amygdala on memory for IA. Here we show that infusion of an HDAC inhibitor (HDACi), trichostatin A (TSA), into the BLA, enhanced consolidation of IA memory in rats when given at 1.5, 3, or 6 h posttraining, but not when the drug was infused immediately after training. In addition, intra-BLA administration of TSA immediately after retrieval delayed extinction learning. Moreover, we show that intra-BLA TSA in rats given IA training increased the levels of brain-derived neurotrophic factor in the dorsal hippocampus, but not in the BLA itself. These findings reveal novel aspects of the regulation of fear memory by epigenetic mechanisms in the amygdala.

Glucocorticoid receptor gene modulates severity of depression in women with crack cocaine addiction.

Crack cocaine addicted inpatients that present more severe withdrawal symptoms also exhibit higher rates of depressive symptoms. There is strong evidence that the identification of genetic variants in depression is potentialized when reducing phenotypic heterogeneity by studying selected groups. Since depression has been associated to dysregulation of the hypothalamic-pituitary-adrenal axis, this study evaluated the effects of SNPs in stress-related genes on depressive symptoms of crack cocaine addicts at early abstinence and over the detoxification treatment (4th, 11th and 18th day post admission). Also, the role of these SNPs on the re-hospitalization rates after 2.5 years of follow-up was studied. One hundred eight-two women were enrolled and eight SNPs in four genes (NR3C2, NR3C1, FKBP5 and CRHR1) were genotyped. A significant main effect of NR3C1-rs41423247 was found, where the C minor allele increased depressive symptoms at early abstinence. This effect remained significant after 10,000 permutations to account for multiple SNPs tested (P=0.0077). There was no effect of rs41423247 on the course of detoxification treatment, but a slight effect of rs41423247 at late abstinence was detected (P=0.0463). This analysis suggests that the presence of at least one C allele is worse at early abstinence, while only CC genotype appears to increase depressive symptoms at late abstinence. Also, a slight effect of rs41423247 C minor allele increasing the number of re-hospitalizations after 2.5 years was found (P=0.0413). These findings are in agreement with previous studies reporting an influence of rs41423247 on sensitivity to glucocorticoids and further elucidate its resulting effects on depressive-related traits.

Alcohol and violence: neuropeptidergic modulation of monoamine systems.

Neurobiological processes underlying the epidemiologically established link between alcohol and several types of social, aggressive, and violent behavior remain poorly understood. Acute low doses of alcohol, as well as withdrawal from long-term alcohol use, may lead to escalated aggressive behavior in a subset of individuals. An urgent task will be to disentangle the host of interacting genetic and environmental risk factors in individuals who are predisposed to engage in escalated aggressive behavior. The modulation of 5-hydroxytryptamine impulse flow by gamma-aminobutyric acid (GABA) and glutamate, acting via distinct ionotropic and metabotropic receptor subtypes in the dorsal raphe nucleus during alcohol consumption, is of critical significance in the suppression and escalation of aggressive behavior. In anticipation and reaction to aggressive behavior, neuropeptides such as corticotropin-releasing factor, neuropeptide Y, opioid peptides, and vasopressin interact with monoamines, GABA, and glutamate to attenuate and amplify aggressive behavior in alcohol-consuming individuals. These neuromodulators represent novel molecular targets for intervention that await clinical validation. Intermittent episodes of brief social defeat during aggressive confrontations are sufficient to cause long-lasting neuroadaptations that can lead to the escalation of alcohol consumption.

Escalated Aggression in Animal Models: Shedding New Light on Mesocorticolimbic Circuits.

Recent developments promise to significantly advance the understudied behavioral and neurobiology of aggression: (1) Animal models that capture essential features of human violence and callousness have been developed. These models range from mice that have been selectively bred for short attack latencies, monogamous prairie voles, and glucocorticoid-compromised rats to rodents and non-human primates that escalate their aggression after consuming or when withdrawing from alcohol. (2) Optogenetic stimulation and viral vector-based approaches have begun to identify overlapping and distinctive neural microcircuits and intracellular molecules for adaptive vs. excessive, maladaptive aggressive behavior in several rodent models. Projections from hypothalamic and mesencephalic neurons to the medial prefrontal cortex contain microcircuits that appear pivotal for the escalation of aggression.

Behavioral and pharmacogenetics of aggressive behavior.

Serotonin (5-HT) has long been considered as a key transmitter in the neurocircuitry controlling aggression. Impaired regulation of each subtype of 5-HT receptor, 5-HT transporter, synthetic and metabolic enzymes has been linked particularly to impulsive aggression. The current summary focuses mostly on recent findings from pharmacological and genetic studies. The pharmacological treatments and genetic manipulations or polymorphisms of aspecific target (e.g., 5-HT1A receptor) can often result in inconsistent results on aggression, due to "phasic" effects of pharmacological agents versus "trait"-like effects of genetic manipulations. Also, the local administration of a drug using the intracranial microinjection technique has shown that activation of specific subtypes of 5-HT receptors (5-HT1A and 5-HT1B) in mesocorticolimbic areas can reduce species-typical and other aggressive behaviors, but the same receptors in the medial prefrontal cortex or septal area promote escalated forms of aggression. Thus, there are receptor populations in specific brain regions that preferentially modulate specific types of aggression. Genetic studies have shown important gene-environment interactions; it is likely that the polymorphisms in the genes of 5-HT transporters or rate-limiting synthetic and metabolic enzymes of 5-HT (e.g., MAOA) determine the vulnerability to adverse environmental factors that escalate aggression. We also discuss the interaction between the 5-HT system and other systems. Modulation of 5-HT neurons in the dorsalraphe nucleus by GABA, glutamate and CRF profoundly regulate aggressive behaviors. Also, interactions of the 5-HT system with other neuropeptides(arginine vasopressin, oxytocin, neuropeptide Y, opioid) have emerged as important neurobiological determinants of aggression. Studies of aggression in genetically modified mice identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT1B, 5-HT transporter, Pet1, MAOA) or indirectly[e.g., BDNF, neuronal nitric oxide (nNOS), aCaMKII, Neuropeptide Y].The future agenda delineates specific receptor subpopulations for GABA, glutamate and neuropeptides as they modulate the canonical aminergic neurotransmitters in brainstem, limbic and cortical regions with the ultimate outcome of attenuating or escalating aggressive behavior.

Gene expression in aminergic and peptidergic cells during aggression and defeat: relevance to violence, depression and drug abuse.

In this review, we examine how experiences in social confrontations alter gene expression in mesocorticolimbic cells. The focus is on the target of attack and threat due to the prominent role of social defeat stress in the study of coping mechanisms and victimization. The initial operational definition of the socially defeated mouse by Ginsburg and Allee (1942) enabled the characterization of key endocrine, cardiovascular, and metabolic events during the initial response to an aggressive opponent and during the ensuing adaptations. Brief episodes of social defeat stress induce an augmented response to stimulant challenge as reflected by increased locomotion and increased extracellular dopamine (DA) in the nucleus accumbens (NAC). Cells in the ventral tegmental area (VTA) that project to the NAC were more active as indicated by increased expression of c-fos and Fos-immunoreactivity and BDNF. Intermittent episodes of social defeat stress result in increased mRNA for MOR in brainstem and limbic structures. These behavioral and neurobiological indices of sensitization persist for several months after the stress experience. The episodically defeated rats also self-administered intravenous cocaine during continuous access for 24 h ("binge"). By contrast, continuous social stress, particularly in the form of social subordination stress, leads to reduced appetite, compromised endocrine activities, and cardiovascular and metabolic abnormalities, and prefer sweets less as index of anhedonia. Cocaine challenges in subordinate rats result in a blunted psychomotor stimulant response and a reduced DA release in NAC. Subordinate rats self-administer cocaine less during continuous access conditions. These contrasting patterns of social stress result from continuous vs. intermittent exposure to social stress, suggesting divergent neuroadaptations for increased vulnerability to cocaine self-administration vs. deteriorated reward mechanisms characteristic of depressive-like profiles.

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

RATIONALE: Recent findings have shown a complexly regulated 5-HT system as it is linked to different kinds of aggression. OBJECTIVE: We focus on (1) phasic and tonic changes of 5-HT and (2) state and trait of aggression, and emphasize the different receptor subtypes, their role in specific brain regions, feed-back regulation and modulation by other amines, acids and peptides. RESULTS: New pharmacological tools differentiate the first three 5-HT receptor families and their modulation by GABA, glutamate and CRF. Activation of 5-HT(1A), 5-HT(1B) and 5-HT(2A/2C) receptors in mesocorticolimbic areas, reduce species-typical and other aggressive behaviors. In contrast, agonists at 5-HT(1A) and 5-HT(1B) receptors in the medial prefrontal cortex or septal area can increase aggressive behavior under specific conditions. Activation of serotonin transporters reduce mainly pathological aggression. Genetic analyses of aggressive individuals have identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT(1B), 5-HT transporter, Pet1, MAOA) or indirectly (e.g., Neuropeptide Y, αCaMKII, NOS, BDNF). Dysfunction in genes for MAOA escalates pathological aggression in rodents and humans, particularly in interaction with specific experiences. CONCLUSIONS: Feedback to autoreceptors of the 5-HT(1) family and modulation via heteroreceptors are important in the expression of aggressive behavior. Tonic increase of the 5-HT(2) family expression may cause escalated aggression, whereas the phasic increase of 5-HT(2) receptors inhibits aggressive behaviors. Polymorphisms in the genes of 5-HT transporters or rate-limiting synthetic and metabolic enzymes of 5-HT modulate aggression, often requiring interaction with the rearing environment.

Drugs and aggression.

Aggression is conceived as a social behavior that, in conjunct with motor and visceral displays, is related with acts for obtaining a specific goal or is directed against threatening stimuli with the intention of causing harm, either for attack or defense. Here it is reviewed basic concepts and aspects for the classification of aggression, the behavioral displays regarded as aggressive in animal models, the basic neural circuits that are involved to them and the pharmacological approaches involving some neurotransmitters (5-HT, dopamine and GABA) and drugs that can be used to identify the neural basis of aggression and to modulate its expression. Drug patents are referred in the text. Data are based on experiments developed mainly with rodents; however, some research hypotheses that may well give some insights for the clinical sciences in men were also included.

Neurobiology of escalated aggression and violence.

Psychopathological violence in criminals and intense aggression in fruit flies and rodents are studied with novel behavioral, neurobiological, and genetic approaches that characterize the escalation from adaptive aggression to violence. One goal is to delineate the type of aggressive behavior and its escalation with greater precision; second, the prefrontal cortex (PFC) and brainstem structures emerge as pivotal nodes in the limbic circuitry mediating escalated aggressive behavior. The neurochemical and molecular work focuses on the genes that enable invertebrate aggression in males and females and genes that are expressed or suppressed as a result of aggressive experiences in mammals. The fruitless gene, immediate early genes in discrete serotonin neurons, or sex chromosome genes identify sexually differentiated mechanisms for escalated aggression. Male, but not female, fruit flies establish hierarchical relationships in fights and learn from previous fighting experiences. By manipulating either the fruitless or transformer genes in the brains of male or female flies, patterns of aggression can be switched with males using female patterns and vice versa. Work with Sts or Sry genes suggests so far that other genes on the X chromosomes may have a more critical role in female mouse aggression. New data from feral rats point to the regulatory influences on mesocortical serotonin circuits in highly aggressive animals via feedback to autoreceptors and via GABAergic and glutamatergic inputs. Imaging data lead to the hypothesis that antisocial, violent, and psychopathic behavior may in part be attributable to impairments in some of the brain structures (dorsal and ventral PFC, amygdala, and angular gyrus) subserving moral cognition and emotion.

Escalated aggressive behavior: dopamine, serotonin and GABA.

The ethical dilemma in aggression research is how to reconcile two divergent objectives, namely to avoid harm and injury as much as possible and, at the same time, how to study behavioral phenomena that validly represent the essence of the neurobiology of aggression. Clinical and preclinical aggression research focuses on different types of aggression. Preclinical studies are usually stimulated by an ethological approach and focus on the phylogeny, ontogeny, survival value and neural mechanisms of ritualized displays and signals. On the other hand, clinical studies focus on violent individuals and pathologically excessive forms of aggressive behavior. This review emphasizes research on escalated forms of aggression in animals and humans and their pharmacotherapy. The current experimental models to generate escalated levels of aggressive behavior in laboratory rely on social instigation, frustrative non-reward and alcohol drinking. These types of aggression are modulated by canonical neurotransmitters like dopamine, serotonin (5-HT) and GABA. It continues to be a main goal of much neurobiological research to find potential targets of pharmacological agents that interact with dopaminergic, GABAergic and serotonergic systems and have high efficacy and selectivity to reduce excessive levels of aggressive and violent behaviors without side-effects. While the mesocorticolimbic dopamine system is implicated in the initiation, execution, termination and consequences of aggressive behavior, drugs with a high affinity for dopamine D2 receptors lack specificity for reducing aggressive behavior. Current investigations point to 5-HT(1B) receptor subtypes as particularly relevant. First, they are differentially expressed in aggression-prone individuals relative to those who are not excessively aggressive. Second, these and also other 5-HT receptor subtypes emerge to be significant targets for anti-aggressive interventions. Positive modulators of GABA(A) receptors with specific subunit configuration may be relevant for heightening aggression, and these sites may be targets for intervention. A prerequisite for rational pharmacotherapies will be adequate characterization of serotonergic and GABAergic receptor regulation in individuals exhibiting escalated aggression.

Serotonin and aggressive behavior in rodents and nonhuman primates: predispositions and plasticity.

This review analyzes psychosocial and genetic determinants of aggressive behavior in rodents and nonhuman primates and the role of the serotonin (5-HT) system on aggressive behaviors in order to trace possible evolutionary common origins between psychopathological and adaptive forms of aggression. Studies in primates suggest that deficit in serotonin activity, as indicated by the levels of the cerebrospinal fluid (CSF) serotonin major metabolite 5-hydroxyindoleacetic acid (5-HIAA) correlates with impulsive and aggressive behavior. It is possible that CSF 5-HIAA reflects the prevailing serotonergic tone and may be related to an aggressive trait. Superimposed on this tone are phasic serotonin changes that may be related to the inhibition of aggressive acts. Genetic factors determine aggressive behaviors as demonstrated by classic selection and strain comparison studies. Manipulations of genes targeting 5-HT receptors, transporters and enzymes can influence aggression. Some of these genes related to the serotonin transporter (5-HTT) and the monoamine oxidase A (MAO-A) show a polymorphism that may predispose, under specific environmental conditions, certain individuals to display pathological forms of aggression.

GABAA/alpha1 receptor agonists and antagonists: effects on species-typical and heightened aggressive behavior after alcohol self-administration in mice.

RATIONALE: The positive modulation of gamma-aminobutyric acid type-A (GABAA) receptors is a putative mechanism via which alcohol escalates aggressive behavior. Broad-spectrum benzodiazepine antagonists block alcohol-heightened aggression in rats and monkeys. However, the degree to which GABAA subunit composition plays a role in heightened aggressive behavior induced by self-administration of a moderate alcohol dose remains unresolved. OBJECTIVE: Beta-carboline-3-carboxylate-t-butyl ester (beta-CCt) and zolpidem act preferentially at GABAA receptors containing the alpha1 subunit as antagonist and agonist, respectively, and serve as useful tools to evaluate the role of GABAA receptor subtypes in self-administered alcohol on aggression. METHODS: Male resident mice, housed in breeding pairs, were conditioned to nose-poke in a removable panel in their home cage, with each fifth poke being reinforced by the delivery of 0.05 ml of 6% ethanol (EtOH). After consuming EtOH, the resident mice were given the antagonists beta-CCt and flumazenil or agonists zolpidem and triazolam, and then confronted an intruder male in their home cage for a 5-min period. RESULTS: Following self-administration of EtOH (1.0 g/kg, 1.7 g/kg), 14 of 37 resident mice displayed unusually large increases in the frequency of attack bites and sideways threats. Flumazenil or beta-CCt decreased alcohol-heightened and non-heightened aggression in a dose-dependent manner. Administration of 3 mg/kg beta-CCt lowered the aggression-heightening effects of 1 g/kg and 1.7 g/kg EtOH, but did not antagonize the sedative effects of 3.0 g/kg EtOH. Triazolam and zolpidem decreased alcohol-heightened and non-heightened aggressive behavior, and these antiaggressive effects were accompanied by reduced motor activity, indicating sedation. CONCLUSIONS: Benzodiazepine antagonists, particularly those acting preferentially at GABAA/alpha1 subunit-containing receptors, decrease alcohol-heightened and species-typical aggressive behavior, but are ineffective in attenuating the sedative effects of alcohol.

Role of alcohol consumption in escalation to violence.

No other drug has been associated with aggressive and violent behavior more than alcohol has. A major characteristic of the link between alcohol and social interactions is the very large variation in who becomes more aggressive while drinking and who does not. Tracing the origins of these individual differences has led to a focus on predispositions, such as the antisocial behavior of Type 2 alcoholics. Successful development of an experimental procedure to model heightened aggressive behavior after voluntary consumption of alcohol has facilitated the neurobiologic analysis of the link between alcohol and aggression. From a pharmacologic perspective, consumption of low to moderate doses of alcohol engenders heightened aggressive behavior in a significant minority of individuals before the circulation of appreciable amounts of the aldehyde metabolite. Ionophoric receptors such as NMDA, 5-HT(3) and GABA(A) have been identified in the brain as major sites of action for alcohol in the dose range that is relevant for engendering heightened aggression. Actions at the GABA(A) receptor complex that depend on particular GABA(A) subunits appear to be necessary for alcohol-heightened aggression. Genes that encode the synthesis of these alpha and gamma subunits are potentially significant markers for those individuals that are prone to engage in heightened aggressive behavior after the consumption of alcohol. Of particular importance are the reciprocal interactions between GABA and serotonin. Activating specific serotonin receptor subtypes such as 5-HT(1B) receptors reduces alcohol-heightened aggressive behavior. How these GABAergic and serotonergic corticolimbic mechanisms for alcohol-heightened aggression develop during the adolescent period remains an area of urgent study.

Escalated aggressive behavior: new pharmacotherapeutic approaches and opportunities.

Psychopharmacologic studies of aggressive behavior in animals under controlled laboratory conditions have been instrumental in developing and evaluating specific and effective novel drug treatments that reduce aggressive behavior. An initial contribution of this research is to create experimental conditions that enable the display of aggressive and defensive acts and postures in species that engage in either dominance or territorial or maternal aggression. Quantitative ethological analyses allow the precise delineation of the sequential organization of aggressive bursts, providing a benchmark for assessing excessive or pathological forms of aggressive behavior. A second contribution of preclinical research is the development of experimental models of escalated forms of aggressive behavior, such as focusing on genetic predispositions or social provocations and frustrative experiences. A critical role of preclinical research is in the pharmacological and neurochemical analysis of aggressive behavior; for example, a host of undesirable side effects prompted a shift from classic dopaminergic neuroleptic compounds to the more recently developed atypical neuroleptics with effective and more specific anti-aggressive effects. The long-established role of brain serotonin in impulsive and escalated forms of aggressive behavior continues to be a focus of preclinical studies. New evidence differentiates dynamic state changes in corticolimbic serotonergic neurons during the termination of aggressive behavior from the deficient-serotonin trait in violence-prone individuals. It can be anticipated that currently developed tools for targeting the genes that code for specific subtypes of serotonin receptors will offer new therapeutic options for reducing aggressive behavior, and the 5-HT(1B) receptor appears to be a promising target. The modulation of GABA and GABA(A) receptors by 5-HT in corticolimbic neurons promises to be particularly relevant for specific forms of escalated aggressive behavior such as alcohol-heightened aggression.

Social and neural determinants of aggressive behavior: pharmacotherapeutic targets at serotonin, dopamine and gamma-aminobutyric acid systems.

BACKGROUND AND RATIONALE: Aggressive outbursts that result in harm and injury present a major problem for the public health and criminal justice systems, but there are no adequate treatment options. Obstacles at the level of social policy, institutional regulation, and scientific strategy in developing animal models continue to impede the development of specific anti-aggressive agents for emergency and long-term treatments. OBJECTIVE: To be more relevant to the clinical situation, preclinical aggression research has begun to focus on the neurobiological determinants of escalated aggressive behavior that exceeds species-typical patterns. It is the goal of this review to examine novel pharmacological and molecular tools that target the neural mechanisms for different kinds of aggressive behavior more selectively than previously possible and to outline potential pharmacotherapeutic options. RESULTS AND CONCLUSIONS: (1) The preclinical focus on the behavioral characteristics and determinants of intense aggression promises to be most relevant to the clinical distinction between the proposed impulsive-reactive-hostile-affective subtypes of human aggression and the controlled-proactive-instrumental-predatory subtypes of aggression. The neural circuits for many types of human and animal aggression critically involve serotonin, dopamine and gamma-aminobutyric acid (GABA) and specific receptor subtypes. (2) The dynamic changes in frontal cortical serotonin that are triggered by engaging in aggressive behavior imply that serotonergic drug effects are largely determined by the functional state of the receptors at the time of drug treatment. Of the numerous 5-HT receptors currently identified, the 5-HT(1B) receptors offer a promising target for reducing impulsive aggressive behavior, particularly if the action can be limited to sites in the central nervous system. (3) Aggressive confrontations are salient stressors, both for the aggressor as well as the victim of aggression, that are accompanied by activation of the mesocorticolimbic but not the striatal dopamine system. Dopaminergic manipulations, particularly targeting the D(2) receptor family, can influence aggressive behavior in animals and human patients, suggesting that mesocorticolimbic dopamine may have important enabling or permissive functions. (4) GABA is critical in the neurochemical control of aggressive behavior as evidenced by studies that directly modify GABAergic neurotransmission and neurochemical studies that correlate GABA measurements with aggressive behavioral responses in several animal species. The GABA(A) receptor complex is a mechanism through which certain benzodiazepines and alcohol enhance and inhibit aggressive behaviors. Social and pharmacological experiences decisively determine the effects of GABAergic positive modulators on aggression.

Aggression escalated by social instigation or by discontinuation of reinforcement ("frustration") in mice: inhibition by anpirtoline: a 5-HT1B receptor agonist.

Experiments with social instigation or the omission of scheduled reinforcement show that serotonergic mechanisms may be involved in escalated aggression in animals. 5-HT1B receptor agonists have anti-aggressive effects in individuals who show moderate as well as high levels of aggression. The present study compared the effects of the 5-HT1B agonist anpirtoline (0.125-1.5 mg/kg) on (1) species-typical aggressive behavior in male mice, (2) aggression "instigated" or primed by prior exposure to the opponent, and (3) aggression heightened by "frustration" caused by omission of scheduled reinforcement. The effects of anpirtoline on species-typical behavior were also assessed after pretreatment with the 5-HT1B/1D receptor antagonist GR127935 (10 mg/kg). Anpirtoline, like other 5-HT1B agonists (CP-94,253, zolmitriptan), decreased both instigated and frustration-heightened aggression, while motor behavior was unaffected. The aggression-inhibiting effects of anpirtoline were blocked by pretreatment with GR127935. The current results indicate that the 5-HT(1B) receptor is critically involved in the modulation of escalated aggression.