Social setting: influence on the physiological response to electric shock in the rat.

A significant fall in tail blood pressure occurs in paired rats after shock-induced aggression. Pressure returns to baseline levels within 4 hours after fighting. Conversely, single rats subjected to jump threshold measurements or to shocks identical to those used in the aggression paradigm show significant elevations in tail blood pressure. The size of the pressure increase in rats shocked alone appears dependent on the intensity of the shocks, while the pressure fall in rats shocked in pairs occurs over a broad range of shock intensities.

6-Hydroxydopa depletion of brain norepinephrine and the function of aggressive behavior.

A significant increase in shock-induced aggression occurs in the rat 4 days after an intraventricular injection of 90 micrograms of 6-hydroxydopa. Both fluorescent histology and biochemical assay demonstrate that brain norepinephrine is reduced by 90 micrograms of 6-hydroxydopa, while brain dopamine remains unaltered. This suggests that one form of aggressive behavior (shock-induced aggression) is modulated through a central noradrenergic system.

Rat fighting behavior: serum dopamine- -hydroxylase and hypothalamic tyrosine hydroxylase.

Male Sprague-Dawley rats were subjected to 4 weeks of daily periods of immobilization stress. One of two experimental groups was allowed 1 month of recovery. After 4 weeks of stress, there was a significant increase in shockinduced fighting, in the activity of serum dopamine-beta-hydroxylase, and in the activity of hypothalamic tyrosine hydroxylase. The concentration of hypothalamic norepinephrine was not decreased. After 4 weeks of recovery, only serum dopamine-betahydroxylase activity returned to normal; it therefore appears that longterm stress may increase central catecholamine synthesis. possibly resulting in a persistent increase in aggressive behavior.

Aggressive behavior: from laboratory to clinic. Quo vadit?

This article sets forth two theses: (1) that animal models of aggressive behavior have utility in fostering and guiding human aggression research; and (2) that clinical violence research should now focus on the severely and repetitively aggressive patients for study and therapeutic research. Animal models are reviewed in terms of typology; studies of temperament; the role of sensory cues; neuroanatomy, neurochemistry, and neuroendocrinology; studies of stress; and studies of social conditions. Examples are presented that have implications and potential utility for human research. Clinical approaches to the study of human aggressive behavior are examined and five suggestions are made to enhance the efficacy and utility of clinically relevant aggression research.

The limbic system and aggression in humans.

This paper reviews the clinical literature relevant to the association between aggressive behavior and the limbic system in humans. Specific areas of review include aggressive behavior related to: (1) naturally occurring and iatrogenic brain lesions; (2) electrical disturbances; (3) pharmacologic intervention; and (4) central neurochemical concentrations which may implicate limbic lobe involvement.

Hypnotic change in combat dreams of two veterans with posttraumatic stress disorder.

The recurrent nocturnal traumatic dreams of two veterans were dispelled with hypnosis. Dream substitutions were rehearsed in hypnotic trance and subsequently dreamed at night, and afterward the original traumatic dreams ceased.

Ethics and psychiatric research: problems and justification.

The discussion of ethics in psychiatry continues to increase. Research in psychiatry, like all medical research, is of ethical concern because it often involves risks to subjects so that others may benefit. It also involves the allocation of monetary and human resources. In recent years these concerns have been brought to the forefront of professional and public attention. The authors consider the problem of justifying resource allocations and the risks involved in psychiatry research, survey some of the special problems faced by researchers in this field, and give a brief account of present government regulations that pertain to research ethics in psychiatry.

Nicardipine protects against chronic ethanol- or haloperidol-induced supersensitivity to apomorphine-induced aggression.

Affective apomorphine-induced aggression was induced in originally nonaggressive rats after withdrawal from prolonged ethanol or haloperidol treatment. If the animals were co-administered Ca(2+)-channel blockers like diltiazem or verapamil the aggressive response to apomorphine was markedly decreased. Nicardipine (2 and 5 mg/kg b.i.d.) significantly attenuated the aggression-enhancing effect of chronic ethanol or haloperidol withdrawal in nonaggressive rats. Chronic nicardipine, alone, did not enhance aggressive behavior in the nonaggressive rats. Acutely, it suppressed apomorphine-induced aggression but did not alter open field activity when injected into aggressive rats. These results demonstrate that a Ca(2+)-channel blocker of the dihydropyridine type can prevent the development of an ethanol or haloperidol-withdrawal supersensitivity to apomorphine-induced aggression. It attenuates the aggression-inducing effect of apomorphine without impairing general activity.

Binding of psychotropic drugs to isolated alpha-acid glycoprotein.

Alpha1-acid glycoprotein (alpha1-AG) was purified from human sera, and its binding properties with respect to psychotropic drugs were examined by equilibrium dialysis methods in order to clarify the specificity of binding. Radioactive imipramine, a tricyclic antidepressant, was used as the primary ligand. Other drugs, representative of different classes, were tested as potential inhibitors of the alpha1-AG-imipramine binding. The K(a) for imipramine was 2.8 x 10(5) (+/- 0.8) M(-10 (mean +/- S.D.). Chlorpromazine, fluphenazine, thioridazine, loxapine and thiothixene, which are antipsychotic drugs, were competitive inhibitors of imipramine binding, and their K(a) values were in the same range. Propranolol, haloperidol and diazepam were also competitive inhibitors but their affinities were lower. Molindone, an indolic antipsychotic, when tested at the same concentrations as the other drugs, did not affect imipramine binding. Trihexyphenidyl, an anti-Parkinson drug, was a potent but noncompetitive inhibitor. These data identify the antidepressant and major tranquilizer drugs that exhibit high affinity for alpha1-AG and indicate that alpha1-AG may account for 40 per cent of total imipramine bound in serum. Since in psychiatric clinical practice two drugs are frequently administered together, possible competitive effects are discussed as well as the potential role of alpha1-AG in psychiatric illness.

Methylxanthine-facilitated shock-induced aggression in the rat.

The methylxanthines caffeine and aminophylline, in daily doses of 100 mg/kg, facilitated shock-induced aggression in the rat. Under the limited parameters of this study, there was no induction of mouse-killing behavior or alteration of jump thresholds. Additional studies showed the optimal dose and time course for the facilitation of shock-induced aggression by caffeine to be 50 mg/kg administered i.p. 4 h prior to testing. Facilitation of a central adrenergic system may be the mechanism of action.

Facilitation of shock-induced fighting following intraventricular 5,7-dihydroxytryptamine and 6-hydroxydopa.

Using a 15-s intershock interval, an increase in shock-induced fighting was observed following intraventricular 96 microgram 5,7-dihydroxytryptamine (5,7-DHT) and 90 microgram 6-hydroxydopa (6-OHdopa). The incidence of predatory mouse killing was enhanced by 5,7-DHT, but was not affected by 6-OHdopa. Pain sensitivity was increased by 6-OHdopa, but both neurotoxins produced hyperreactivity to footshock. Specific serotonin depletion was produced by 5,7-DHT and norepinephrine depletion by 6-OHdopa. The increase in shock-induced fighting could not be predicted on the basis of monoamine depletion alone, since a long intershock interval was necessary to observe this increase.

Diltiazem suppresses quinpirole-induced oral stereotypies in haloperidol withdrawn rats.

1. Tardive dyskinesia (TD) is one of the most serious untoward effects of chronic neuroleptic therapy. Dopaminergic receptor sensitization is assumed to be involved in its pathogenesis. 2. Male Wistar rats were administered (b.i.d.) intragastrically haloperidol (2 mg/kg), diltiazem (5 mg/kg), diltiazem plus haloperidol, and water (controls), for 21 days. 3. Forty eight hours after withdrawal the rats were injected ip with 0.3 mg/kg of quinpirole and observed for stereotypic behaviors (rearing, grooming, licking, and tongue protrusions). 4. There was a significant overall between-group difference in the duration of grooming and the number of tongue protrusions. The haloperidol withdrawn rats scored markedly higher than control and diltiazem alone treated rats. 5. Conjoint treatment with diltiazem and haloperidol prevented the increase of tongue protrusion episodes. 6. We conclude that concurrent diltiazem and haloperidol administration can prevent the occurrence of some behavioral manifestations of dopaminergic receptor supersensitivity, including a lingual dyskinesia.

Regional changes in monoamines and metabolites following defensive aggression in the rat.

Pharmacological studies have demonstrated that shock-induced defensive fighting is modulated by manipulations of the serotonergic, noradrenergic and dopaminergic neurotransmitter systems. In the present study, regional changes in 5- hydroxytryptamine , norepinephrine, dopamine and their metabolites 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylethylene glycol and 3,4-dihydroxyphenylacetic acid were measured following shock-induced fighting using high performance liquid chromatography coupled with electrochemical detection. Fighting produced reductions in the serotonergic, noradrenergic and dopaminergic systems and elevations in the noradrenergic and dopaminergic systems within the brain stem, hypothalamus, hippocampus, caudate and amygdala relative to shocked or non-shocked controls. These data demonstrate that the activities of these neurotransmitters are involved in defensive aggression in rats. The changes in catecholamines may indicate adaptive responses to stress, while the changes in serotonin may indicate a permissive function for serotonin depletion in defensive fighting.

Decreased hyperthermic effect of MK-801 in selectively bred hypercholinergic rats.

The Flinders Sensitive Line (FSL) of rats has been selectively bred to have increased sensitivity to cholinergic agonists. However, these rats exhibit altered responsiveness to a number of noncholinergic agents, such as apomorphine, buspirone and ethanol. This study compared the FSL and control Flinders Resistant Line (FRL) rats in terms of their hyperthermic response to the phencyclidine (PCP) receptor agonist, MK-801 (0.2 mg/kg SC) and their MK-801 binding characteristics. We have found that FSL rats react with a delayed hyperthermia, having a significantly lower hyperthermia for the first 120 min of observation. Thereafter the response does not differ in FSL and FRL rats. Both groups had similar affinities and numbers of [3H]MK-801 binding sites in the hippocampus/cerebral cortex. Pretreatment with scopolamine (1 mg/kg SC) failed to affect MK-801-induced hyperthermia in either line of rats. These findings suggest that selective breeding of FSL rats attenuated the secondary mechanisms involved in the PCP receptor-mediated hyperthermic response. However, by itself cholinergic supersensitivity does not appear to be a major factor in the blunted responsiveness of FSL rats to MK-801.

Facilitated shock-induced aggression following antidepressive medication in the rat.

Rats were tested for changes in shock-induced fighting following treatment with antidepressants of both the dibenzazepine and monoamine oxidase inhibitor classes of drug. Rats were retested for shock-induced fighting 3, 4, and 5 days after initial injections of imipramine (10 mg/kg IP bid), or saline. All three dibenzazepine groups showed increased levels of shock-induced fighting (p less than 0-01). In addition, rats were retested for shock-induced fighting 6, 30. 54, and 78 hours following the initiation of treatment with daily injections of saline, or the monoamine oxidase inhibitors: nialamide (100 mg/kg/day), iproniazid (150 mg/kg/day), and pargyline (20 mg/kg/day). All three monoamine oxidase inhibitor groups showed increased levels of shock-induced fighting after 30 hr (p less than 0.001). There was no difference in the jump threshold of rats treated with pargyline or saline.

Increased shock-induced fighting with supersensitive beta-adrenergic receptors.

Adult male rats were treated chronically with haloperidol (1 mg/kg) daily or propranolol (10 mg/kg bid) and evaluated for changes in shock-induced fighting. Haloperidol suppressed fighting. Chronic propranolol facilitated fighting when rats were tested eight hours after injection. Acutely, either 5 or 10 mg/kg of d,1-propranolol suppressed shock-induced fighting. Chronic pindolol (10 mg/kg bid) and chronic 1-propranolol (5 mg/kg bid) administration increased fighting. Chronic d,1-propranolol, 1-propranolol or pindolol administration was associated with an increase in Bmax for beta-adrenergic receptors. No change in fighting or Bmax was observed with the chronic administration of d-propranolol (5 mg/kg bid) or metoprolol (10 mg/kg bid). This increase in shock-induced fighting appears to be a behavioral response developing as a consequence of increased beta-adrenergic receptors responding to endogenously released norepinephrine.

Alkali metal cations: effects on isolation-induced aggression in the mouse.

Alkali metal cations were given in varying doses over 14 days to CF-1, male mice, isolated for 4 weeks prior to testing for isolation-induced fighting. Lithium and cesium in doses of 4.5 and 6.0 meq/kg reduced the duration of isolation-induced aggression in a 15 min test period when compared with controls. Toxicity was evident in the cesium-treated, but not the lithium-treated mice. No enhancement of aggression was seen in the rubidium-treated group.

Dietary tryptophan modulation and aggressive behavior in mice.

The effects of a tryptophan-free diet on isolation-induced fighting and predatory cricket killing in mice were examined. The results demonstrated that consumption of a tryptophan-free diet for 18-20 days decreased both the number of fighters and duration of isolation-induced fighting; increased the number of cricket-killing mice and decreased the latencies to attack and the latencies to kill crickets; reduced brain serotonin 27%; increased water intake 38%; and decreased body weight 27% without affecting food intake. To determine if these effects were due specifically to the lack of dietary tryptophan, other groups of mice were fed a 5% tryptophan load in the standard chow; a 0.15% tryptophan supplement in the tryptophan-free diet; or a 3 grams/day restricted chow diet. The lack of tryptophan in the diet produced the marked inhibition in isolation-induced fighting, the reduction in brain serotonin, and the large decrease in body weight. The other non-specific effects appeared to be related to general factors such as dietary need for the cricket killing or diet composition (other than the lack of tryptophan) for the water intake.

Dietary tryptophan reversal of septal lesion and 5,7-DHT lesion elicited shock-induced fighting.

Using two procedures known to enhance shock-induced defensive fighting (SIF) and mouse-killing--septal lesions and 5,7-DHT lesions--we determined if a 5% tryptophan-loaded diet could reverse the lesion effects. The results indicated that SIF, but not mouse-killing, could be maintained at normal levels following dietary tryptophan loading in both septally lesioned and 5,7-DHT lesioned rats. This behavioral reversal was independent of pain sensitivity, feeding, drinking and body weight levels. Regional brain analysis of monoamines and metabolites indicated that the lesions produced substantial depletions in 5-HT and 5-HIAA with minimal reduction or no change in catecholamines. Dietary tryptophan loading elevated 5-HT and 5-HIAA in unlesioned animals and partially restored 5-HT and 5-HIAA levels in lesioned animals. These patterns of depletion and repletion were confined to the hippocampus following septal lesions and distributed throughout the brain following 5,7-DHT lesions. The results are discussed in terms of a possible hippocampal mediation of the dietary tryptophan reversal in shock-induced defensive fighting following lesioning.

Taming effects of p-chlorophenylalanine on the aggressive behavior of septal rats.

Septal irritability and shock-induced aggression were suppressed by the administration of p-chlorophenylalanine (PCPA) to septal rats. The levels of septal irritability and shock-induced fighting were significantly lower in septal, PCPC-treated rats than in nontreated septal rats. Since both parameters of septal aggression were reduced by PCPA, and while PCPA has no effect on shock-induced fighting of unlesioned rats under similar parameters, it appears that both forms of aggression may function through a common neural mechanism.