精神分裂症患者攻击行为与5-HTTLPR多态性的关联研究

目的 探讨精神分裂症患者的攻击行为与5-HTTLPR多态性的相关性.方法 采用〈修订版外显攻击行为量表〉（MOAS）对符合美国〈精神障碍统计与诊断手册第4版〉（DSM-Ⅳ）的精神分裂症患者进行评定,99例MOAS加权总分≥4分者为有攻击行为组（攻击组）,96例MOAS加权总分0分者为无攻击行为组（非攻击组）.应用聚合酶链式反应-限制性片段长度多态性（PCR-RFLP）技术检测受试者的5-HTTLPR多态性.结果 攻击组的基因型分别为SS 38例、SL 44例、LL17例,等位基因频率分布分别为S 120例、L 78例;非攻击组间的基因型分别为SS40例、SL 39例、LL 17例,等位基因频率分布分别为S 119例、L73例,两组比较差异无显著性（P＞0.05）.按性别分层后分析,两组间的基因型和基因频率分布差异亦无显著性（P＞0.05）.结论 未见5-HTTLPR多态性与精神分裂症患者的攻击行为存在关联.     

Acute effects of gabapentin on laboratory measures of aggressive and escape responses of adult parolees with and without a history of conduct disorder

Rationale The possible role of GABA in human aggression was evaluated by administering gabapentin to subjects with and without a history of conduct disorder and comparing the effects on laboratory measures of aggression and escape.Methods Eighteen male and two female subjects with a history of criminal behavior participated in experimental sessions, which measured aggressive and escape responses. Ten subjects had a history of childhood conduct disorder (CD+) and ten subjects with no history (non-CD controls). Aggression was measured using the Point Subtraction Aggression Paradigm (PSAP), which provided subjects aggressive, escape and monetary reinforced response options.Results Acute doses (200, 400 and 800 mg) of gabapentin had similar effects on aggressive responses among CD+ subjects compared to non-CD control subjects. Aggressive responses of CD+ and non-CD control subjects increased at lower gabapentin doses, and decreased at the highest 800 mg gabapentin dose. Gabapentin increased escape responses for both CD+ and non-CD controls CD– subjects at the lowest dose, but then produced dose-related decreases at the two higher doses in both groups. No changes in monetary reinforced responses were observed, indicative of no CNS stimulation or sedation.Conclusions Gabapentin produced similar bitonic effects upon aggressive and escape responses in subjects with and without a history of childhood conduct disorder. This is in marked contrast to prior differential effects of baclofen on aggressive responses between CD+ and non-CD control subjects in a previous study.     

Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter.

Inhibition of the serotonin transporter (5-HTT) is a principal initial target of many antidepressants. However, the contribution of the 5-HTT to their therapeutic efficacy is incompletely understood. We utilized a targeted gene mutation approach to examine the role of the 5-HTT in the behavioral actions of antidepressants. The 5-HTT mutation was bred onto two separate genetic backgrounds, C57BL/6J and 129S6. On a preliminary screen for gross physical, neurological and behavioral functions, all measures were normal with the exception that 5-HTT -/- mice on the C57BL/6J background showed increased body weight and poor rotarod performance, and 5-HTT -/- mice on the 129S6 background showed reduced neuromuscular strength. On the tail suspension test, 5-HTT -/- mice on the 129S6 background showed a baseline antidepressant-like reduction in immobility. In contrast, the same mice showed increased immobility in the forced swim test, possibly due to compromised neuromuscular strength. 5-HTT -/- mice on the C57BL/6J background showed no baseline antidepressant-related phenotype on either test. The behavioral effects of three antidepressants were tested in 5-HTT mutant mice (C57BL/6J background) in the tail suspension test. The anti-immobility effects of the serotonin reuptake inhibitor, fluoxetine (30 mg/kg), were abolished in 5-HTT -/- mice, confirming that the 5-HTT gene is required for the behavioral effects of fluoxetine. In contrast, 5-HTT-/- mice retained sensitivity to the anti-immobility effects of the norepinephrine reuptake inhibitor, desipramine (20 mg/kg), and the mixed serotonin/norepinephrine reuptake inhibitor, imipramine (25 mg/kg). 5-HTT knockout mice provide a valuable tool for delineating the neuropsychopharmacological actions of antidepressants.     

Studies on the involvement of GABA in the aggression directed by groups of intact or gonadectomized male and female mice towards lactating intruders

The aims of the present studies were (a)_to determine the effects of pharmacological elevation of GABA by treatment with DPA (competitive inhibitor of GABA transaminase) on a form of aggression displayed by grouped female mice towards lactating and non-lactating intruders; (b) to estimate GABA levels in six different brain areas of intact and gonadectomized male and female mice. The results revealed that DPA treatment considerably reduced this form of aggression. Increased GABA levels, modulated by the hormonal state of the animals, were observed in most brain areas studied.     

The effects of benzodiazepines on aggression: Reduced or increased?

The effects of various benzodiazepines on animal models of aggression are presented. The differences in response noted after single dose or after chronic drug administrations are stressed. The implications for predicting responses to these drugs in humans are discussed.     

Reduced anxiety and depression-like behaviors in mice lacking GABA transporter subtype 1.

Gamma-aminobutyric acid (GABA) transporter subtype 1 (GAT1), which transports extracellular GABA into presynaptic neurons, plays an important regulatory role in the function of GABAergic systems. However, the contributions of the GAT1 in regulating mental status are not fully understood. In this paper, we observed the behavioral alterations of GAT1 knockout (GAT1(-/-)) mice using several depression- and anxiety-related models (eg, the forced-swimming test and the tail-suspension test for testing depression-related behaviors; the open-field test, the dark-light exploration test, the emergence test, and the elevated plus maze (EPM) test for anxiety-related behaviors). Here we found that GAT1(-/-) mice showed a lower level of depression- and anxiety-like behaviors in comparison to wild-type mice. Furthermore, GAT1(-/-) mice exhibited measurable insensitivity to selected antidepressants and anxiolytics such as fluoxetine, amitriptyline, buspirone, diazepam, and tiagabine in the tail-suspension test and/or the EPM test. Moreover, the basal level of corticosterone was found to be significantly lower in GAT1(-/-) mice. These results showed that the absence of GAT1 affects mental status through enhancing the GABAergic system, as well as modifying the serotonergic system and the hypothalamic-pituitary-adrenal (HPA) activity in mice.     

Altered serotonin synthesis, turnover and dynamic regulation in multiple brain regions of mice lacking the serotonin transporter

To evaluate the consequences of inactivation of the serotonin transporter (SERT) gene on 5-HT homeostasis and function, 5-HT synthesis and turnover rates were measured using the decarboxylase inhibition method in multiple brain regions (frontal cortex, striatum, brainstem, hippocampus and hypothalamus) from mice with a genetic disruption of SERT. 5-HT synthesis rates were increased 30-60% in the different brain regions of SERT -/- mice compared to littermate +/+ control mice despite 55-70% reductions in tissue 5-HT concentrations. Brain regions that possessed a greater capacity to increase synthesis and turnover (frontal cortex, striatum) demonstrated lesser reductions in tissue 5-HT. Female SERT -/- mice had greater increases (79%) in brain 5-HT synthesis than male -/- mice did (25%), a finding associated with higher brain tryptophan concentrations in females. Despite increased 5-HT synthesis, there was no change in either TPH2 or TPH1 mRNA levels or in maximal in vitro TPH activity in the brainstem of SERT -/- mice. Catecholamine homeostasis as reflected in brain tissue concentrations and in synthesis and turnover of dopamine and norepinephrine was unchanged in SERT -/- mice. Taken together, the results demonstrate a markedly altered homeostatic situation in SERT -/- mice that lack 5-HT reuptake, resulting in markedly depleted tissue stores that are inadequately compensated for by increased 5-HT synthesis, with brain region and gender specificity observed.     

The effect of nitrites on isolation-induced aggression in mice

Chronic administration of sodium nitrite (1 g/1) in drinking water of pregnant mice and their offspring caused a significant increase in the isolation-induced aggression of the male young. The cessation of administration of sodium nitrite reduced the aggressive behavior of the experimental group to the control level.     

Reduced serotonin transporter binding in binge eating women

RATIONALE: There is evidence that abnormalities in brain dopamine, norepinephrine and serotonin metabolism may play an important role in binge eating. Serotonin-active antidepressant drugs have also been found to decrease binge eating. OBJECTIVE: We investigated serotonin transporter binding in obese binge-eating women. Eleven obese binge-eating and seven obese control women participated in the study. The subjects were not taking any medication known to affect serotonin (5-HT) transporters. METHODS: We used single-photon emission tomography (SPECT) with the radioligand 123I-labelled nor-beta-CIT, which specifically labels 5-HT transporters. RESULTS: Obese binge-eating women showed significantly decreased 5-HT transporter binding in the mid-brain compared with obese controls (2.1 +/- 0.5 versus 2.9 +/- 0.5, respectively). CONCLUSIONS: SPECT imaging with a ligand specific for 5-HT transporters can be used to assess altered serotonin transporter binding in the living human brain. The results tentatively suggest that 5-HT transporter binding is decreased in binge-eating women.     

Repeated alcohol: behavioral sensitization and alcohol-heightened aggression in mice

RATIONALE: Repeated administration of psychomotor stimulants or opiates can induce behavioral sensitization, typically detected as progressive and long-lasting increases in the motor-activating effects of these drugs. This phenomenon may be relevant to seizure susceptibility, drug self-administration, and sexual behavior. Repeated administration of alcohol can also induce behavioral sensitization and may have consequences on how alcohol affects aggressive behavior. OBJECTIVES: To (1) determine the enduring nature of locomotor sensitization to alcohol; (2) examine subsequent changes to morphine and amphetamine effects on locomotor behavior; and (3) test whether behavioral sensitization to alcohol or morphine is relevant to alcohol-heightened aggression. METHODS AND RESULTS: In the first experiment, male CFW mice were given ten injections of alcohol (2.4 g/kg/day), morphine (30.0 mg/kg/day), or saline. Video tracking confirmed locomotor sensitization--an approximate 200% increase in the motor-stimulating effects of these drugs. Challenges with 2.0 g/kg alcohol revealed that locomotor sensitization to alcohol persisted for at least 2 months. Alcohol-sensitized mice showed evidence of cross-tolerance to the sedative effects of morphine (5 mg/kg) but showed no evidence of cross-sensitization to the stimulant effects of 30.0 mg/kg morphine or 1.0 mg/kg amphetamine. In the second experiment, under conditions resulting in species-typical aggressive behavior against a male intruder, there were no differences in the aggressive behavior relative to saline control mice following alcohol or morphine sensitization. However, in the mice sensitized to alcohol, but not to morphine, there was a vertical shift in the dose-effect curve for moderate doses of alcohol (0.6-1.7 g/kg, p.o.). In addition, twice as many alcohol-sensitized mice consistently showed alcohol-heightened aggression when compared with the saline control mice (74% vs 37%, respectively). CONCLUSIONS: Repeated administration of alcohol can sensitize locomotor stimulation and may also render mice more vulnerable to increased aggression after alcohol. Moreover, the results suggest that at least some of the neuroadaptations caused by repeated administration of alcohol are relevant to alcohol-heightened aggression.     

Shock-induced aggression in mice is modified by lithium

Aggression is associated with numerous psychiatric disorders. Evidence suggests that lithium decreases aggression in humans and rats. The effects of lithium on aggression related behavior, and in particular shock-induced aggression, has not been as thoroughly explored in mice. Male mice were treated with lithium and tested in the shock-induced aggression and dominance tube tests. Mice treated with lithium were also assessed for thermal pain and shock sensitivity in the hot plate and jump-flinch tests. In the shock-induced aggression paradigm chronic lithium significantly decreased both the frequency and duration of attacks, without affecting social interaction or behavior in the dominance tube. Acute lithium significantly decreased the total duration of attacks and social interaction but did not affect behavior in the dominance tube test. Neither treatment regimen had an effect on temperature sensitivity in the hot plate test or on activity levels in the open field. However, chronic lithium modified the response of mice to shock in the jump-flinch test, but not at the shock level used in the aggression test. The results of this study indicate that lithium decreases shock-induced aggression in mice, but effects on baseline response to shock confound interpretation of this behavioral effect of lithium.     

5-Hydroxytryptamine correlates of isolation-induced aggression in mice

Drug regimens designed to enhance or impair serotonergic functioning were found to differentially affect isolation-induced fighting in mice. Male albino mice were isolated for at least 4 weeks. Number of fights, attack latencies, and average fight durations were recorded for 15 min every other day. On intervening days, the locomotor activity of each mouse was measured in stabilimeters. After the baseline for aggression and activity stabilized, drug procedures were instituted. While motility remained unaffected, mice injected with D,L-5-hydroxytryptophan in combination with a peripheral decarboxylase inhibitors (seryltrihydroxybenzine) engaged in fewer fights of shorter average duration which were precede by longer attack latencies. Biochemical analyses indicated that although serotonin levels were increased, catecholamine levels were reduced. A putative inhibitor of tryptophan hydroxylase, p-chloro-N-methylamphetamine (PCMA), was found to increase fighting frequency; attack latencies, average fight durations, and motility measurements did not differe significantly from non-injection performance. At time periods in which fighting was increased, levels of brain serotonin were reduced while catecholamine levels remained unaltered. Although PCMA did not affect motility at time intervals when fighting was increased, locomotor activity was increased for the first 8 hr after administration. Notwithstanding contributions by other putative neurotransmitters, these results suggest that serotonergic mechanisms are involved in the control of isolation-induced aggression in mice.     

Catecholamine correlates of isolation-induced aggression in mice.

Drugs differentially affecting catecholaminergic neurotransmission mechanisms were injected into isolated mice to assess effects on aggression. L-DOPA in combination with a peripheral decarboxylase inhibitor produced a dose-dependent decrease in the number of fights and average fight durations accompanied by an increase in attack latencies. Central dopamine levels were increased whilst brain noradrenaline and 5-hydroxytryptamine were reduced. Virtually identical effects on aggression were observed after apomorphine. Pimozide decreased fighting, but neither attack latencies nor average fight durations were effected. All doses of disulfiram virtually abolished all components of aggressive responses. The effect of D-amphetamine on number of fights was biphasic; lower doses potentiated aggression, but higher doses reduced fighting accompanied by increased attack latencies and reduced average fight durations. We conclude that catecholamines may be intimately involved in mediating certain components of aggressive responses but that balance relationships among various putative neurotransmitters may be a more meaningful correlate of this behavior.     

Benzodiazepine-receptor mediated inhibition of isolation-induced aggression in mice

The effects of a benzodiazepine receptor agonist (diazepam), antagonist (Ro 15-1788), and an "active" antagonist [inverse agonist] (3-carboethoxy-beta-carboline) were examined in an isolation-induced model of aggression. Diazepam (4 mg/kg) and 3-carboethoxy-beta-carboline (10 mg/kg), but not Ro 15-1788, significantly inhibited aggressive behavior in this model. Ro 15-1788 (10 mg/kg) reduced the anti-aggressive actions of both diazepam and 3-carboethoxy-beta-carboline, while mice treated with a combination of diazepam and 3-carboethoxy-beta-carboline had aggression scores increased to values not significantly different from vehicle treated mice. These findings suggest that both diazepam and 3-carboethoxy-beta-carboline have anti-aggressive properties in the isolation-induced model of aggression which are mediated through CNS benzodiazepine receptors.     

Effect of isolation induced aggression in mice on serum creatine kinase

It is known that the serum creatine kinase increases as a result of different conditions and that isolation in male mice induces aggressive behaviour after regrouping. The levels of serum creatine kinase were studied in isolated and in regrouped male albino mice. A considerable increase of creatine kinase was found in regrouped male mice fighting for different hours. Further studies are needed to prove whether these results are due to isolation, aggression or motor activity.     

Acute and chronic effects of cocaine on isolation-induced aggression in mice

The purpose of the present study was to investigate the effects of acute and chronic cocaine administration on aggressive behaviour in mice. The animals were made more aggressive by individual housing for a period of 6 weeks. Group-housed anosmic conspecifics which were not aggressive were used as intruder controls. In acute studies, cocaine induced no significant change in aggressive behaviour at low doses (0.5–5 mg/kg) but significantly decreased aggressive behaviour after doses of 10 and 20 mg/kg. Cocaine increased the isolation-induced aggressive behaviour in mice when they were injected twice daily for a week with low doses of 0.5 or 1 mg/kg. In particular, the latency to first attack was significantly decreased by the drug and the frequency of attack towards the non-aggressive intruder was dramatically increased. Higher cocaine doses (10 or 20 mg/kg) under the described treatment regimen decreased these agonistic repertories. Tolerance did not develop to the anti-aggressive effects of high doses of cocaine on continued treatment.     

Effects of GABAergic modulators on food and cocaine self-administration in baboons

Drugs that indirectly alter dopaminergic systems may alter the reinforcing effects of cocaine. The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has extensive neural connections in mesolimbic regions that appear to modulate dopamine. The current study evaluated the effects of GABA_B receptor agonists baclofen and CGP44532, the benzodiazepine agonist alprazolam, and the GABA reuptake inhibitor tiagabine on lever responding maintained by low dose cocaine injections (0.032 mg/kg) or by food pellet (1 g) delivery in baboons. The benzodiazepine antagonist flumazenil was tested as a negative control. Cocaine or food was available under a fixed ratio (FR 10) schedule of reinforcement during daily 2-h sessions. During baseline conditions, cocaine and pellets maintained similar numbers of reinforcers per session. Baclofen, CGP44532 and tiagabine dose-dependently reduced the number of cocaine injections, where as the benzodiazepine antagonist flumazenil did not. Baclofen, CGP44532 and tiagabine also produced dose-related decreases in food-maintained behavior. In contrast, the benzodiazepine agonist alprazolam, which positively modulates GABA_A receptors via the benzodiazepine site, produced decreases in cocaine self-injection, but not food-maintained behavior. Thus, the effects of alprazolam were specific for cocaine-maintained behavior, where as the effects of baclofen and CGP44532 were not.     

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

Background 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. Objective 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. Materials and methods 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 (H₂O). Aggressive behaviors were higher in most mice when tests occurred after EtOH intake relative to H₂O. 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 H₂O intake. Results 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.     

Morphine effects on maternal aggression,pup care and analgesia in mice

In order to assess the respective contribution of opioid receptors to the behavioral and physiological characteristics of lactating animals, we challenged mice with morphine at different phases of the lactation period. Sensitivity to morphine's effects on aggressive behavior, pup care, pain response and body temperature were measured. Lactating mice were assigned to 1 of the 3 weeks of lactation and to 1 of 5 doses of morphine sulfate (0, 1, 3, 6, 10 mg/kg IP). After morphine administration, rectal temperature and tail flick were assessed. Behavior towards three pups was observed for 5 min, followed by an aggression test with a female intruder. Morphine significantly increased the latency to retrieve pups and decreased aggressive behavior at doses that do not decrease motoric activity. Compared to virgin mice, lactating females are less sensitive to the analgesic actions of morphine but similarly sensitive to its hypothermic properties. The fact that virgin and lactating females can be distinguished on the basis of their sensitivity to morphine-induced analgesia suggests that lactating animals undergo functionally relevant changes in opioid regulation of pain sensitivity. Furthermore, morphine's specific and potent inhibition of pup retrieval supports the hypothesis that decreased opioid peptide activity is important for the expression of certain postpartum behaviors.