Alcohol-heightened Aggression Research Articles

A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression.

A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression.

A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression.

Alcohol is associated with nearly half of all violent crimes committed in the United States; yet, a potential neural basis for this type of pathological aggression remains elusive. Alcohol may act on N-methyl-d-aspartate receptors (NMDARs) within cortical circuits to impede processing and to promote aggression. Here, male mice were characterized as alcohol-heightened (AHAs) or alcohol non-heightened aggressors (ANAs) during resident-intruder confrontations after self-administering 1.0 g/kg alcohol (6% w/v) or water. Alcohol produced a pathological-like pattern of aggression in AHAs; these mice shifted their bites to more vulnerable locations on the body of a submissive animal, including the anterior back and ventrum after consuming alcohol. In addition, through immunoblotting, we found that AHAs overexpressed the NMDAR GluN2D subunit in the prefrontal cortex (PFC) as compared to ANAs while the two phenotypes expressed similar levels of GluN1, GluN2A and GluN2B. After identifying several behavioral and molecular characteristics that distinguish AHAs from ANAs, we tested additional mice for their aggression following preferential antagonism of GluN2D-containing NMDARs. In these experiments, groups of AHAs and ANAs self-administered 1.0 g/kg alcohol (6% w/v) or water before receiving intraperitoneal (i.p.) doses of ketamine or memantine, or infusions of memantine directly into the prelimbic (PLmPFC) or infralimbic medial PFC (ILmPFC). Moderate doses of IP ketamine, IP memantine, or intra-PLmPFC memantine increased aggression in AHAs, but only in the absence of alcohol. Prior alcohol intake blocked the pro-aggressive effects of ketamine or memantine. In contrast, only memantine, administered systemically or intra-PLmPFC, interacted with prior alcohol intake to escalate aggression in ANAs. Intra-ILmPFC memantine had no effect on aggression in either AHAs or ANAs. In sum, this work illustrates a potential role of GluN2D-containing NMDARs in the PLmPFC in alcohol-heightened aggression. GluN2D-containing NMDARs are highly expressed on cortical parvalbumin-containing interneurons, suggesting that, in a subset of individuals, alcohol may functionally alter signal integration within cortical microcircuits to dysregulate threat reactivity and promote aggression. This work suggests that targeting GluN2D-NMDARs may be of use in reducing the impact of alcohol-related violence in the human population.

OPRM1 genotype interacts with serotonin system dysfunction to predict alcohol-heightened aggression in primates.

Although the notion that alcohol promotes violence is widespread, not all individuals are aggressive while intoxicated. Genetic variation could be a contributing factor to individual differences in alcohol-heightened aggression. The present study examines the effects of OPRM1C77G genotype on responses to threat in rhesus macaques under normal conditions and following alcohol administration. Prior studies have shown that a low CSF level of 5-HIAA is a trait marker for individuals prone to escalated aggression. We wanted to examine whether the predictive value for this marker on aggression was moderated by OPRM1 genotype. Animals were administered alcohol (BAC 100-200 mg%), were provoked by a human intruder, and aggressive responses were recorded. Factor analysis was performed to generate aggressive response factors, which were then used as dependent variables for ANOVA, with OPRM1 genotype and CSF 5-HIAA as independent variables. Factor analysis generated three factors ('Threatening', 'Distance Decreasing' and 'High Intensity'). We found that High Intensity aggression was increased among carriers of the OPRM1 G allele, especially among individuals with low CSF levels of 5-HIAA. Aggression in the non-intoxicated state was predicted by 5-HIAA, but not by genotype. This study demonstrates that OPRM1 genotype predicts alcohol-heightened aggression in rhesus macaques with low CSF levels of 5-HIAA. Because OPRM1 variation predicts similar effects on alcohol response and behavior in humans and macaques, this study could suggest a role for OPRM1 genotype in alcohol-heightened aggression in humans. If so, it may be that compounds that block this receptor could reduce alcohol-associated violence in selected patient populations.

Prevention of alcohol-heightened aggression by CRF-R1 antagonists in mice: critical role for DRN-PFC serotonin pathway.

Alcohol can escalate aggressive behavior in a significant subgroup of rodents, humans, and nonhuman primates. The present study investigated whether blockade of corticotropin-releasing factor receptor type 1 (CRF-R1) could prevent the emergence of alcohol-heightened aggression in mice. The serotonin (5-HT) pathway from the dorsal raphe nucleus (DRN) to the medial prefrontal cortex (mPFC) by CRF-R1 was investigated as a possible target for the prevention of alcohol-heightened aggressive behavior. Male CFW mice that reliably exhibited aggressive behaviors after consuming 1 g/kg of alcohol received systemic or intra-DRN administration of CRF-R1 antagonists, CP-154,526 or MTIP, before a confrontation with a male conspecific. Blockade of DRN CRF-R1 receptors with both antagonists significantly reduced only alcohol-heightened aggression, whereas systemic administration reduced both alcohol-heightened and species-typical aggression. Next, a 5-HT1A agonist, 8-OH-DPAT, was coadministered with CP-154,526 into the DRN to temporarily disrupt 5-HT activity. This manipulation abolished the antiaggressive effects of intra-DRN CP-154,526. In the mPFC, in vivo microdialysis revealed that extracellular 5-HT levels were increased in mice that consumed alcohol and were then injected with CP-154,526, both systemically or intra-DRN. Neither alcohol nor CP-154,526 alone affected 5-HT release in the mPFC. The present results suggest the DRN as a critical site for CRF-R1 to modulate alcohol-heightened aggression via action on the serotonergic DRN-PFC pathway.

GABA(A) receptors in the dorsal raphé nucleus of mice: escalation of aggression after alcohol consumption.

The dorsal raphé nucleus (DRN), the origin for serotonin (5-HT) in forebrain areas, has been implicated in the neural control of escalated aggression. Gamma aminobutyric acid type-A (GABA(A)) and type-B (GABA(B)) receptors are expressed in the DRN and modulate 5-HT neuronal activity, and both play a role in the behavioral effect of alcohol. The purpose of this study is to examine the interaction between drugs acting on GABA receptors in the DRN and alcohol in their effects on aggressive behaviors. Male CFW mice, housed with a female, were trained to self-administer ethanol (1.0 g/kg) or water via an operant conditioning panel in their home cage. Immediately after they drank either ethanol or water, the animals were microinfused with a GABAergic drug into the DRN, and their aggressive behaviors were assessed 10 min later. Muscimol (0.006 nmol), a GABA(A) receptor agonist, escalated alcohol-heightened aggression but had no effect in the absence of ethanol. This effect of muscimol was prominent in the animals that showed alcohol-heightened aggression, but not the animals that reduced or did not change aggressive behavior after ethanol infusion compared to water. On the other hand, the GABA(B) agonist baclofen (0.06 nmol) increased aggressive behavior similarly in both water and ethanol conditions. Antagonists of the GABA(A) and GABA(B) receptors, bicuculline (0.006 nmol) and phaclofen (0.3 nmol) respectively, did not suppress heightened-aggressive behavior induced by ethanol self-administration. GABA(A) receptors in the DRN are one of the neurobiological targets of alcohol-heightened aggression. Activation of the GABA(B) receptors in the DRN also produced escalated aggression, but that is independent of the effect of alcohol.

Individual vulnerability to escalated aggressive behavior by a low dose of alcohol: decreased serotonin receptor mRNA in the prefrontal cortex of male mice

Low to moderate doses of alcohol consumption induce heightened aggressive behavior in some, but not all individuals. Individual vulnerability for this nonadaptive behavior may be determined by an interaction of genetic and environmental factors with the sensitivity of alcohol's effects on brain and behavior. We used a previously established protocol for alcohol oral self-administration and characterized alcohol-heightened aggressive (AHA) mice as compared with alcohol non-heightened (ANA) counterparts. A week later, we quantified mRNA steady state levels of several candidate genes in the serotonin [5-hydroxytryptamine (5-HT)] system in different brain areas. We report a regionally selective and significant reduction of all 5-HT receptor subtype transcripts, except for 5-HT(3), in the prefrontal cortex of AHA mice. Comparable gene expression profile was previously observed in aggressive mice induced by social isolation or by an anabolic androgenic steroid. Additional change in the 5-HT(1B) receptor transcripts was seen in the amygdala and hypothalamus of AHA mice. In both these areas, 5-HT(1B) mRNA was elevated when compared with ANA mice. In the hypothalamus, AHA mice also showed increased transcripts for 5-HT(2A) receptor. In the midbrain, 5-HT synthetic enzyme, 5-HT transporter and 5-HT receptors mRNA levels were similar between groups. Our results emphasize a role for postsynaptic over presynaptic 5-HT receptors in mice which showed escalated aggression after the consumption of a moderate dose of alcohol. This gene expression profile of 5-HT neurotransmission components in the brain of mice may suggest a vulnerability trait for alcohol-heightened aggression.

5-HT1B receptor inhibition of alcohol-heightened aggression in mice: comparison to drinking and running

Serotonin 5-HT(1B) receptors are promising targets for the management of several mood and impulse disorders. These experiments examine a 5-HT(1B) agonist, CP-94,253, and attempt to distinguish between its effects on seeking to perform three rewarding behaviors: aggression, drinking, and wheel running. Male CFW mice perform nose-poke responses that are maintained by a fixed interval schedules of 10-min (FI10) schedule to gain access to one of three rewarding activities. The first experiment studies mice reinforced by the opportunity to confront an intruder mouse after drinking water or alcohol; the second studies mice reinforced by the presentation of alcoholic or non-alcoholic solutions (i.e., 6% ethanol, 0.05% saccharin vs 0.05% saccharin); the third studies mice reinforced by access to a running wheel. CP-94,253 (1.0-10 mg/kg i.p.) dose-dependently reduces aggression, drinking, and wheel running. Of these behaviors, alcohol-heightened aggression is the most sensitive to the 5-HT(1B) receptor agonist (ED50 = 4.8 mg/kg). Responding for the opportunity to drink or engage in alcohol-heightened aggression is suppressed by the highest dose of CP-94,253, whereas CP-94,253 does not affect responding that is reinforced by wheel running or species-typical aggression. These results confirm the inhibitory effects of 5-HT(1B) receptor stimulation on aggressive performance and drinking. They also reveal an inhibition of voluntary wheel running, contrary to the stimulation of running in a novel, open arena. 5-HT(1B) receptor agonists may be particularly useful for the treatment of aggressive behavioral disorders, but their efficacy and potency appear to be sensitive to the intensity and context of the behavior.

Long-term citalopram maintenance in mice: selective reduction of alcohol-heightened aggression

Selective serotonin reuptake inhibitors (SSRIs) alleviate many affective disturbances in human clinical populations and are used in animal models to study the influence of serotonin (5-HT) on aggressive behavior and impulsivity. We hypothesized that long-term SSRI treatment may reduce aggressive behavior escalated by alcohol consumption in mice. Therefore, aggression was tested in male CFW mice to determine whether repeated citalopram (CIT) administration reduces alcohol-heightened aggression. Resident male mice self-administered alcohol by performing an operant response on a panel placed in their home cage that delivered a 6% alcohol solution. Mice repeatedly confronted an intruder 15 min after self-administration of either 1 g/kg alcohol (EtOH) or water (H(2)O). Aggressive behaviors were higher in most mice when tests occurred after EtOH intake relative to H(2)O. Once baseline aggression was established, animals were injected (i.p.) twice daily with 10 mg/kg CIT or saline (SAL) for 32 days. Every 4 days throughout the CIT treatment period, aggressive encounters occurred 6 h after CIT injections, with testing conditions alternating between EtOH and H(2)O intake. Aggression was only modestly affected by CIT in the first 2 weeks of treatment. However, by day 17 of CIT treatment, alcohol-heightened aggressive behavior was abolished, while baseline aggression remained stable. These data lend support for the role of the 5-HT transporter in the control of alcohol-related aggressive behavior, and the time course of effects suggests that a change in density of 5HT(1A) autoreceptors is necessary before antidepressant drugs produce beneficial outcomes.

5-HT3 receptors, alcohol and aggressive behavior in mice

Alcohol is a positive modulator at the 5-HT(3) receptor, which has been implicated in alcohol drinking, anxiety and aggression. The reported experiments explored the role of the 5-HT(3) receptor in aggressive behavior and alcohol-heightened aggression. Male, CFW mice were trained to self-administer 1.0 g/kg of alcohol, after which they confronted an intruder. Half of the CFW mice exhibited consistently increased aggressive behavior after alcohol and were designated as showing alcohol-heightened aggression, the others showed no increase and were designated as showing alcohol non-heightened aggression. The 5-HT(3) antagonist, ondansetron (0.01-1.0 mg/kg), significantly reduced aggression in both groups of CFW mice without affecting non-aggressive behaviors. Zacopride also reduced aggression effectively in both groups of mice, but at high doses began to affect walking. Male B6SJL/F2 transgenic 5-HT(3) over-expressing mice (TG) and wild-type mice (WT) were tested for aggressive behavior in their home cage. In those individuals that fought in tests of resident-intruder aggression, no differences were found in aggression after alcohol intake. In tests of aggression without alcohol intake, zacopride reduced aggression in both TG and WT mice at a dose of 56 mg/kg. Antagonism of 5-HT(3) receptors shows promising anti-aggressive effects, although these effects depend on the genetic background of the mice.

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.

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.

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

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. 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. 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. 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. 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.

Neurosteroids, GABA A receptors, and escalated aggressive behavior

Aggressive behavior can serve important adaptive functions in social species. However, if it exceeds the species-typical pattern, it may become maladaptive. Very high or escalated levels of aggressive behavior can be induced in laboratory rodents by pharmacological (alcohol-heightened aggression), environmental (social instigation), or behavioral (frustration-induced aggression) means. These various forms of escalated aggressive behavior may be useful in further elucidating the neurochemical control over aggression and violence. One neurochemical system most consistently linked with escalated aggression is the GABAergic system, in conjunction with other amines and peptides. Although direct stimulation of GABA receptors generally suppresses aggression, a number of studies have found that positive allosteric modulators of GABA A receptors can cause increases in aggressive behavior. For example, alcohol, benzodiazepines, and many neurosteroids are all positive modulators of the GABA A receptor and all can cause increased levels of aggressive behavior. These effects are dose-dependent and higher doses of these compounds generally shift from heightening aggressive behavior to being sedative and anti-aggressive. In addition, these modulators interact with each other and can have additive effects on the GABA A receptor and on behavior, including aggression. The GABA A receptor is a heteropentameric protein that can be constituted from various subunits. It has been shown that subunit composition can affect sensitivity of the receptor to some modulators and that subunit composition differentially affects the sedative vs anxiolytic actions of benzodiazepines. Initial studies targeting α subunits of the GABA A receptor point to their significant role in the aggression-heightening effects of alcohol, benzodiazepines, and neurosteroids.

Oral drug self-administration in the home cage of mice: alcohol-heightened aggression and inhibition by the 5-HT1B agonist anpirtoline.

In order to model heightened aggression after alcohol consumption and to study the inhibitory influence of 5-HT1B receptors on drinking and fighting, an experimental procedure should enable self-administration of precise amounts of alcohol in a limited period of time before an aggressive confrontation. To design a new device that can reinforce operant responding by the delivery of sweet alcohol in the resident mouse home cage, where aggressive behavior toward an intruder can subsequently be examined, and to demonstrate inhibition of alcohol-heightened aggression by 5-HT1B receptor agonist treatment. Within one experimental session, all singly housed CFW male mice (n=26) performed a nose-poke response that was reinforced by 0.05 ml sucrose. Using the sucrose fading technique, eventually the mice consumed a 6% ethanol/4% sucrose solution after each fifth nose poke during daily 15-min experimental sessions. The number of ethanol reinforcements was adjusted so that 0.6, 1.0, 1.7, and 3.0-g/kg doses were consumed in 15 min or less. Assays confirmed blood alcohol levels at 68.1 mg/dl for intake of 1.0 g/kg. After consuming a specific dose of ethanol in the form of a fixed number of response-dependent deliveries, the response panel was removed from the home cage and, 15 min later, the resident confronted a male intruder. Anpirtoline was administered either before alcohol self-administration or before the aggressive confrontation. After being reinforced with 1.0 g/kg or 1.7 g/kg sweet ethanol, the mice significantly increased attack and threat behavior relative to their aggressive behavior following sucrose or water consumption only. Treatment with the 5-HT1B receptor agonist anpirtoline (0.125, 0.25, 0.5 mg/kg, i.p.) before the confrontation decreased alcohol-heightened aggression and species-typical aggression in the absence of changes in other elements of the behavioral repertoire. Anpirtoline affected ethanol-reinforced behavior only at doses that were 5-10 times higher than those producing anti-aggressive effects. Self-administration of alcohol in the home cage of mice is readily accomplished with the aid of a simple, removable panel. The effective inhibition of high levels of aggressive behavior due to alcohol consumption after anpirtoline treatment confirm the 5-HT1B receptor as a critical site in the termination of aggression.

Zolmitriptan - a 5-HT 1B/D agonist, alcohol, and aggression in mice

Zolmitriptan is an anti-migraine agent with action at 5-HT1B/D receptors. It penetrates into the central nervous system and, like other 5-HT1B/D agonists, its pharmacotherapeutic profile may include significant anti-aggressive effects. To examine whether zolmitriptan has potential anti-aggressive effects by studying two kinds of aggressive behavior in mice--species-typical and aggression under the influence of alcohol. A second objective was to study whether pre- or post-synaptic receptors mediate these anti-aggressive effects. Initially, the anti-aggressive effects of zolmitriptan were studied in male CFW mice during 5-min resident-intruder confrontations. To confirm the 5-HT1B receptor as a critical site of action for the anti-aggressive effects, the zolmitriptan dose-effect determinations were repeated after pretreatment with GR 127935 (10 mg/kg, i.p.). In further experiments, mice were treated concurrently with alcohol (1.0 g/kg, p.o.) and zolmitriptan (1-30 mg/kg, i.p.) in order to compare the effects of this agonist on species-typical and alcohol-heightened aggression. Finally, mice were infused with the neurotoxin 5,7-DHT (10 microg) into the raphé area to eliminate somatodendritic and presynaptic autoreceptors. The anti-aggressive effects of zolmitriptan (17 mg/kg, i.p.) or CP-94,253 (10 mg/kg, i.p.) were assessed 10 days after the lesion, and levels of 5-HT and 5-HIAA were measured in the hippocampus and prefrontal cortex. Zolmitriptan exerted behaviorally specific anti-aggressive effects. The reduction in aggression was antagonized by GR 127935, indicated by a rightward shift in the dose-effect curves of zolmitriptan, showing the specificity for the 5-HT1B receptors. Zolmitriptan also decreased alcohol-heightened aggression with equal efficacy. The anti-aggressive effects of CP-94,253 and zolmitriptan remained unaltered by 5,7-DHT lesions that depleted cortical and hippocampal 5-HT by 60-80%. Zolmitriptan proved to be an effective and behaviorally specific anti-aggressive agent in situations that engender moderate and alcohol-heightened levels of aggression. These effects are potentially due to activation of post-synaptic 5-HT1BD receptors.

Alcohol, allopregnanolone and aggression in mice.

Aggressive behavior of certain individual animals can be greatly increased when under the influence of low doses of alcohol. One of alcohol's neurochemical actions that may be relevant to alcohol-heightened aggression (AHA) is its positive modulation of the GABA(A) receptor complex. The objective of this study was to investigate whether alcohol interacts with an endogenous modulator of the GABA(A) receptor complex, the neurosteroid allopregnanolone, in stimulating/heightening aggressive behavior. The first experiment was designed to test the hypothesis that neurosteroid modulators of the GABA(A) receptor complex will increase aggression and to compare these effects with alcohol. Male CFW mice were injected with allopregnanolone, alphaxalone (3-30 mg/kg, i.p.), or alcohol (1.0 g/kg, p.o.) 15 min prior to a 5-min confrontation with an intruder. Moderate doses of alcohol and the neurosteroids increased aggression by ca. 50% above baseline; impaired locomotion was seen only at the highest doses. A second experiment compared AHA and ANA (i.e. alcohol-non-heightened aggression) mice by giving allopregnanolone (1-10 mg/kg) with a simultaneous oral injection of alcohol (0.6 or 1.0 g/kg) or water. When administered with water and the 0.6 g/kg dose of alcohol, allopregnanolone increased the aggression of AHA and ANA mice. Administration of the 1.0 g/kg dose of alcohol in ANA mice prevented allopregnanolone-heightened aggression. In AHA mice, addition of allopregnanolone to 1.0 g/kg alcohol dose-dependently reduced alcohol-heightened aggression, suggesting potentiation of alcohol's suppressive effects on aggression. The neuroactive steroid allopregnanolone appears to play an important role in alcohol-heightened aggression. Moreover, the upward shift of the aggression-heightening effects of alcohol and the downward shift at the maximally effective alcohol dose by allopregnanolone point to a shared mechanism for both positive modulators of the GABA(A) receptor complex.

Alcohol-heightened aggression in mice: attenuation by 5-HT1A receptor agonists.

One of the critical mechanisms by which alcohol heightens aggression involves forebrain serotonin (5-HT) systems, possibly via actions on 5-HT1A receptors. The present experiments tested the hypothesis that activating 5-HT1A receptors by selective agonists will block the aggression-heightening effects of ethanol. Initially, the selective antagonist WAY 100635 was used to assess whether or not the changes in aggressive behavior after treatment with 8-OH-DPAT and flesinoxan result from action at the 5-HT1A receptors. Resident male CFW mice engaged in aggressive behavior (i.e. attack bites, sideways threats, tail rattle) during 5-min confrontations with a group-housed intruder male. Quantitative analysis of the behavioral repertoire revealed systematic reductions in all salient elements of aggressive behavior after treatment with 8-OH-DPAT (0.1-0.3 mg/kg, i.p.) or flesinoxan (0.1-1.0 mg/kg, i.p.). The 5-HT1A agonists also reduced motor activities such as walking, rearing and grooming, although to a lesser degree. Pretreatment with the antagonist WAY 100635 (0.1 mg/kg, i.p.) shifted the agonist dose-effect curves for behavioral effects to the right. In a further experiment, oral ethanol (1.0 g/kg, p.o.) increased the frequency of attacks in excess of 2 SD from their mean vehicle level of attacks in 19 out of 76 resident mice. Low doses of 8-OH-DPAT (0.03-0.3 mg/kg) and flesinoxan (0.1, 0.3, 0.6 mg/kg), given before the ethanol treatment, attenuated the alcohol-heightened aggression in a dose-dependent fashion. By contrast, these low 5-HT1A agonist doses affected motor activity in ethanol-treated resident mice to a lesser degree, suggesting behavioral specificity of these anti-aggressive effects. The current results support the hypothesized significant role of 5-HT1A receptors in the aggression-heightening effects of alcohol. If these effects are in fact due to action at somatodendritic 5-HT1A autoreceptors, then the anti-aggressive effects would be associated with decreased 5-HT neurotransmission.