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A post-2000 literature search reviewed prevalence of health consequences associated with zolpidem, plus two salient case reports. Common zolpidem-related harms encompassed accidents, falls, overdoses, delirium, and infections. Risks to others included assaults, vehicular accidents, various crimes, and civil actions that occurred during zolpidem-induced delirium, withdrawal, and other impediments. Remarkably, much harm occurred while patients were taking therapeutic doses of licitly prescribed zolpidem (10-30 mg). Zolpidem-associated health, behavioral, and social problems comprise an international pandemic of preventable heath misfortunes.

Objective: To examine the safety and efficacy of liquid risperidone to reduce duration of rages in children with severe mood dysregulation (SMD) or possible bipolar disorder (BP)., Method: The sample included 151 consecutive admissions of 5-12 year old children to a psychiatric inpatient unit. Diagnostic information and history of prior rage outbursts were obtained at admission. In hospital, a first rage was treated with seclusion. If a second rage occurred, the child was offered liquid risperidone to help him/her regain control. Durations of unmedicated and last medicated rage were compared. Rage frequency in children with SMD and several definitions of BP were compared., Results: Although 82 of 151 admissions were prompted by rages, rages occurred during only 49 hospitalizations and occurred more than once in only 24. In 16 multiply medicated children, duration of rages dropped from a baseline of 44.4 +/- 20.2 min to 25.6 +/- 12.5 min at the child's last dose. Neither SMD nor any definition of BP influenced rage response in this small sample. The average liquid risperidone dose was 0.02 mg/kg. All but two children also took atypical antipsychotics daily. In the evaluation of medicated rage episodes with standard rating scales, no extrapyramidal side effects, akathisia, or abnormal involuntary movements were observed, and the rate of sedation/sleepiness (7/67 = 10.4%) was similar and not significantly different from that observed during nonmedicated episodes (8/46 = 17.4%)., Conclusions: Liquid risperidone may be a safe and effective way to shorten the duration of rage episodes regardless of diagnosis. However, definitive conclusions cannot be drawn in the absence of a placebo control as children were also receiving other behavioral and psychopharmacologic treatments.

Based upon recent findings in our laboratory that cytokines microinjected into the medial hypothalamus or periaqueductal gray (PAG) powerfully modulate defensive rage behavior in cat, the present study determined the effects of peripherally released cytokines following lipopolysaccharide (LPS) challenge upon defensive rage. The study involved initial identification of the effects of peripheral administration of LPS upon defensive rage by electrical stimulation from PAG and subsequent determination of the peripheral and central mechanisms governing this process. The results revealed significant elevation in response latencies for defensive rage from 60 to 300 min, post LPS injection, with no detectable signs of sickness behavior present at 60 min. In contrast, head turning behavior elicited by stimulation of adjoining midbrain sites was not affected by LPS administration, suggesting a specificity of the effects of LPS upon defensive rage. Direct administration of LPS into the medial hypothalamus had no effect on defensive rage, suggesting that the effects of LPS were mediated by peripheral cytokines rather than by any direct actions upon hypothalamic neurons. Complete blockade of the suppressive effects of LPS by peripheral pretreatment with an Anti-tumor necrosis factor-alpha (TNFalpha) antibody but not with an anti- interleukin-1 (IL-1) antibody demonstrated that the effects of LPS were mediated through TNF-alpha rather than through an IL-1 mechanism. A determination of the central mechanisms governing LPS suppression revealed that pretreatment of the medial hypothalamus with PGE(2) or 5-HT(1A) receptor antagonists each completely blocked the suppressive effects of LPS, while microinjections of a TNF-alpha antibody into the medial hypothalamus were ineffective. Microinjections of -Iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) benzamide monohydrochloride (p-MPPI) into lateral hypothalamus (to test for anatomical specificity) had no effect upon LPS induced suppression of defensive rage. The results demonstrate that LPS suppresses defensive rage by acting through peripheral TNF-alpha in periphery and that central effects of LPS suppression of defensive rage are mediated through PGE(2) and 5-HT(1A) receptors in the medial hypothalamus.

Aggression is a complex social behavior that involves a similarly complex neurochemical background. The involvement of substance P (SP) and its potent tachykinin receptor (NK1) in the induction of both defensive rage and predatory attack appears to be a consistent finding. However, an overall understanding of the nature of the SP involvement in the induction of aggressive behavior has not yet been fully achieved. The aim of this review is to summarize and present the current knowledge with regards to the role of SP in the induction of aggressive behavior and to synopsize: (a) its biochemical profile, and (b) the exact anatomical circuits through which it mediates all types of aggressive behavior. Future studies should seriously consider the potential use of this knowledge in their quest for the treatment of mood and anxiety disorders.

Context: Observations suggest that the use of anabolic androgenic steroids (AAS) may trigger uncontrolled, violent rage. Other observations indicate that certain groups of criminals may use AAS with the intention of being capable of committing crime more efficiently., Objective: To examine the proposed association between the use of AAS and criminality., Design: A controlled retrospective cohort study of registered criminal activity among individuals tested for AAS use during the period of January 1, 1995, to December 31, 2001., Setting: All individuals in Sweden who were tested for AAS use during this period. These individuals were referred for testing from both inpatient and outpatient clinics as well as from centers for treatment of substance abuse., Participants: Individuals testing positive for AAS (n=241), with those testing negative for AAS during the same period (n=1199) serving as the control group., Main Outcome Measures: The ratios (expressed as relative risk [RR]) of the incidences of several categories of crime in the 2 study groups., Results: The risk of having been convicted for a weapons offense or fraud was higher among individuals testing positive for AAS than among those testing negative (RR, 2.090 and 1.511, respectively; 95% confidence interval [CI], 1.589-2.749 and 1.208-1.891, respectively) whereas there were no significant differences with respect to violent crimes (RR, 1.116; 95% CI, 0.981-1.269) or crimes against property (RR, 0.942; 95% CI, 0.850-1.044). When patients referred from substance abuse centers were excluded, a lower risk for crimes against property was observed for the individuals who tested positive for AAS (RR, 0.761; 95% CI, 0.649-0.893) and the risk for fraud in the 2 groups was equalized (RR, 1.117; 95% CI, 0.764-1.635). The increased risk for a weapons offense among the individuals testing positive for AAS remained virtually unchanged., Conclusions: In addition to the impulsive violent behavior previously shown to be related to AAS use, such use might also be associated with an antisocial lifestyle involving various types of criminality. However, the existence and nature of this possible association remain unclear and call for further investigation.

Wilson disease is an autosomal recessive inborn error of copper metabolism that leads to neurologic symptoms and variable degrees of hepatic damage. The most common characteristic signs clinically are liver disease, psychiatric disease, neurologic disease, or a combination of these. Early recognition by means of clinical signs and an early initiation of therapy using chelators or zinc-salts are essential for a good outcome and prognosis. This report describes a male suffering from Wilson disease who exhibited an unusual presentation that included psychological manifestations without hepatic involvement. He was initially treated for attention-deficit hyperactivity disorder and a seizure disorder until brain imaging established the diagnosis of Wilson disease.

Feline defensive rage is a form of aggression occurring in nature in response to a threatening condition and is elicited under laboratory conditions by electrical stimulation of the medial hypothalamus or midbrain periaqueductal gray (PAG). Since it has recently been shown that cytokines can modulate neurotransmitter release, the present study was designed to determine the effects of administration of interleukin 2 (IL-2) into the PAG upon defensive rage elicited from the medial hypothalamus. Microinjections of relatively low doses of IL-2 into the dorsal PAG significantly facilitated defensive rage behavior elicited from the medial hypothalamus. The specificity of this phenomenon was supported by the following findings: (1) IL-2 induced effects were dose- and time-dependent, (2) the facilitative effects of IL-2 could be completely blocked by pre-treatment of the injection site with either anti-IL-2 or anti-IL-2 receptor antibody and (3) IL-2 administration into the PAG showed no effect upon another form of aggression, namely predatory attack, elicited from the lateral hypothalamus. The findings further demonstrated that the effects of IL-2 were mediated by an NK(1) receptor mechanism since pre-treatment of the PAG with an NK(1) receptor antagonist completely blocked the facilitating effects of IL-2. Immunocytochemical observations supported these findings by demonstrating an extensive pattern of labeling of IL-2Ralpha in the dorsal PAG. The present study thus demonstrates that IL-2 in the dorsal PAG potentiates defensive rage behavior and is mediated through an NK(1) receptor mechanism.

Defensive rage behavior is a form of aggressive behavior occurring in nature in response to a threatening stimulus. It is also elicited by stimulation of the medial hypothalamus and midbrain periaqueductal gray (PAG) and mediated through specific neurotransmitter-receptor mechanisms within these regions. Since interleukin (IL)-2 modulates the release of neurotransmitters linked to aggression and rage, we sought to determine whether IL-2 microinjected into the medial hypothalamus would modulate defensive rage. Microinjections of relatively low doses of IL-2 into the medial hypothalamus significantly suppressed defensive rage elicited from the PAG in a dose-dependent manner and in the absence of signs of sickness behavior. Pre-treatment with an antibody directed against IL-2Ralpha or a GABA(A) receptor antagonist blocked IL-2's suppressive effects upon defensive rage. Since the suppression of defensive rage is also mediated by 5-HT(1) receptors in the medial hypothalamus, a 5-HT(1) antagonist was microinjected into this region as a pretreatment for IL-2; however, it did not block IL-2's suppressive effects. Immunocytochemical data provided anatomical support for these findings by revealing extensive labeling of IL-2Ralpha on neurons in the medial hypothalamus. IL-2 microinjected into the medial hypothalamus did not modulate predatory attack elicited from the lateral hypothalamus. In summary, we provide evidence for a novel role for IL-2 in the medial hypothalamus as a potent suppressor of defensive rage behavior. These effects are mediated through an IL-2-GABA(A) receptor mechanism.

This study utilized anatomical and behavioral-pharmacological methods to determine the role of NK(1)-Substance P receptors in the midbrain periaqueductal gray (PAG) in defensive rage behavior in cats. For behavioral pharmacological experiments, monopolar stimulating electrodes were implanted in the medial hypothalamus for elicitation of defensive rage behavior and cannula-electrodes were implanted in the PAG for microinjections of receptor compounds. Microinjections of the NMDA antagonist, AP-7 (2 nmol), into the dorsal PAG blocked defensive rage elicited by medial hypothalamic stimulation, thus establishing the PAG as a synaptic region that receives hypothalamic inputs linked to defensive rage behavior. Microinjections of the NK(1) agonist, GR73632, into the same injection sites facilitated defensive rage in a dose-dependent manner, and also induced spontaneous hissing in five cats. The effects of GR73632 were reduced by pretreatment of the PAG with the NK(1) antagonist, GR82334 (16 nmol), microinjected into the same sites. Microinjections of GR73632 (8 nmol) into the PAG also suppressed predatory attack elicited by stimulation of the lateral hypothalamus. Immunohistochemical methods utilized to detect Substance P and Fos immunoreactivity revealed that neurons in the PAG activated after defensive rage-inducing medial hypothalamic stimulation lie in the same region as Substance-P-immunoreactive processes. Fos immunoreactivity was highest in the dorsomedial aspect of the rostral PAG after medial hypothalamic stimulation. Cats that were unstimulated or that exhibited predatory attack after lateral hypothalamic stimulation had low c-fos expression levels in the PAG. Substance P immunoreactivity was high throughout the dorsal PAG. The results indicate that NK(1) receptors in the PAG potentiate defensive rage and suppress predatory aggression in the cat.

Defensive rage in the cat occurs naturally in response to a threat and is also elicited by electrical or chemical stimulation over the rostro-caudal extent of the medial hypothalamus and dorsolateral aspect of the periaqueductal gray (PAG). This behavior is mediated over a descending projection from the hypothalamus to the midbrain PAG. The underlying hypothesis for the present study was that medial hypothalamic defensive rage neurons are excited in two ways: by NK(1) receptors and by an ascending input from the PAG. The first aspect of this hypothesis was tested by eliciting defensive rage by electrical stimulation of the PAG and then microinjecting a selective NK(1) agonist and antagonist into the hypothalamus. Microinjections of 16 or 12 nmol/0.25 microl of the NK(1) agonist, GR 73632, resulted in facilitation of defensive rage. These facilitatory effects were then blocked by pretreatment with the NK(1) antagonist, GR 82334. However, microinjections of GR 82334 alone had no effect. The second aspect of the hypothesis was tested by stimulating defensive rage sites in the PAG and using immunohistochemical methods to test for the presence of c-Fos in the hypothalamus. The results revealed the presence of c-Fos immunoreactivity in the medial but not lateral hypothalamus. Overall, the findings indicate that NK(1) receptors in the medial hypothalamus facilitate defensive rage elicited from PAG neurons whose axons project back to the medial hypothalamus. The likely ethological significance of the ascending input is that it allows for potentiation and prolongation of defensive rage in response to a threatening stimulus.

The neurochemistry of aggression and rage has largely focused on the roles played by neurotransmitters and their receptor mechanisms. In contrast, little attention has been given to the possible functions of other substances. Interleukin-1beta is an immune and brain-derived cytokine that is present in the hypothalamus. Functionally, interleukin-1 has been shown to induce the release of serotonin (5-HT), a neurotransmitter known to potently affect aggression and rage behavior. Thus, the goal of the present study was to test the hypothesis that interleukin-1beta in the medial hypothalamus could modulate defensive rage behavior in the cat. In the first experiment, electrical stimulation of sites in the medial hypothalamus from which defensive rage could be elicited and where microinjections of specific compounds were later placed, facilitated defensive rage elicited from the periaqueductal gray (PAG), thus demonstrating the functional relationship between these two regions. In the second experiment, microinjections of relatively low doses of interleukin-1beta into the medial hypothalamus potentiated defensive rage behavior elicited from the midbrain periaqueductal gray in a dose-related manner. In the third experiment, pretreatment with a selective 5-HT2 receptor antagonist, LY-53857, blocked the facilitating effects of interleukin-1beta upon defensive rage. These findings reveal for the first time that brain cytokines can dramatically alter aggressive behavior. In particular, interleukin-1beta in the medial hypothalamus potentiates defensive rage behavior elicited from the periaqueductal gray in the cat, and the potentiating effects of interleukin-1beta on this form of emotional behavior are mediated via a 5-HT2 receptor mechanism.

The CCK(B) agonist, pentagastrin, has been shown to induce anxiety in human subjects. Similarly, in the cat model, pentagastrin facilitates the expression of hypothalamically activated emotional behavior. Because hypothalamically mediated emotional behavior is also accompanied by increased EMG activity in the jaw muscles, these experiments were designed to examine the combined effects of administration of pentagastrin with activation of hypothalamically mediated emotional behavior upon jaw muscle EMG activity. Electrodes were carefully lowered through previously placed guide tubes overlying the hypothalamus until a behavioral site was identified. Following the establishment of a stable threshold current for eliciting an emotional behavioral response, the skin overlying the ipsilateral masseter muscle was shaved and cleaned with alcohol, and surface electrodes were attached. The EMG was recorded, amplified, digitized, and stored in a microcomputer for analysis. Mean power frequencies (MPF) and latencies for behavior were calculated for baseline prior to infusion of all drugs. Following this, the effects of intravenous administration of pentagastrin and the CCK(B) antagonist LY288513 on the MPF were determined. The infusion of the CCK(B) agonist, pentagastrin (0.77, 1.92, and 3.84 microg/kg), decreased MPF in a time-related manner. The effects of pentagastrin 1.92 microg/kg were blocked by the CCK(B) antagonist, LY288513 (6.54 microg/kg). In addition, the infusion of LY288513 alone increased MPF. These results are surprising in that pentagastrin's anxiogenic properties would appear to make it likely to facilitate motor activity, not suppress it.

Background: Perpetrators of domestic violence frequently report symptoms of autonomic arousal and a sense of fear and/or loss of control at the time of the violence. Since many of these symptoms are also associated with panic attacks, we hypothesized that perpetrators of domestic violence and patients with panic attacks may share similar exaggerated fear-related behaviors. To test this hypothesis, we employed the panicogenic agent sodium lactate to examine the response of perpetrators to anxiety fear induced by a chemical agent., Methods: Using a double-blind, placebo-controlled design, we infused 0.5 mol/L sodium lactate or placebo over 20 min on separate days to a select group of subjects who perpetrate acts of domestic violence and two nonviolent comparison groups. We compared their behavioral, neuroendocrine, and physiologic responses., Results: Lactate administration elicited intense emotional responses in the perpetrators of domestic violence. Perpetrators evidenced more lactate-induced rage and panic and showed greater changes in speech, breathing, and motor activity than did nonviolent control subjects. There were no significant differences between the groups for any neuroendocrine or physiologic measure., Conclusions: These results are consistent with our hypothesis that some perpetrators of domestic violence have exaggerated fear-related behavioral responses.

Background: Episodic rages have been estimated to occur in as many as 30% of patients with Tourette's syndrome (Tourette's disorder), but their treatment has never been systematically investigated. We report on the results of an open-label pilot study using paroxetine for the treatment of Tourette's disorder-associated rage episodes., Method: Forty-five Tourette's/rage patients (DSM-IV) were treated with paroxetine, specifically to control their rages. Other symptoms such as tics, attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) were not targeted by this study. Treatment was deemed to be therapeutic when rage symptoms were diminished by 75% or more by patient report and were diminished in frequency by at least 1 point on a 4-point scale devised by the authors., Results: After 8 weeks on paroxetine treatment, 29 patients (76% of those who completed the study) reported that rages were significantly diminished or completely absent. Nine patients reported no significant change in rages. Seven patients did not complete the study (3 because of side effects and 4 whose rage frequency increased). The mean dose of paroxetine was 33 mg/day; minimum effective dose was 15 mg/day., Conclusion: We were unable to determine any factors that significantly altered the efficacy of paroxetine for treatment of Tourette's disorder-associated rage episodes. The great majority (87%) of the patients had both ADHD and OCD in addition to Tourette's disorder. The age, sex, and concomitant use of other medications revealed no significant differences in treatment outcome. The results suggest that paroxetine may have an important role in the clinical treatment of episodic rages in Tourette's disorder patients.

Defensive rage behavior is mediated over a descending pathway from the medial hypothalamus to the dorsolateral midbrain periaqueductal gray (PAG) where further integration of this response takes place. The present study sought to determine the roles of CCK-A and CCK-B receptor activation in the PAG in modulating defensive rage behavior. The 'hissing' component of the defensive rage response was used throughout the experiment as the measure of defensive rage behavior. The basic design of the experiment involved placement of monopolar electrodes into the medial hypothalamus from which defensive rage could be elicited and cannula electrodes into the dorsal PAG for purposes of identifying defensive rage sites in this region and for microinjections of CCK compounds into these sites at a later time. Microinjections of the selective CCK-B receptor antagonist, LY288513 (1.05, 4.2, 17.0 nmol/0.25 microliter), into the PAG suppressed the hissing response in a dose- and time-dependent manner. Microinjections of the CCK-B agonist, pentagastrin, (0.5 and 1.0 nmol/0.25 microliter) facilitated the occurrence of defensive rage behavior. Moreover, administration of LY288513 (17 nmol/0.25 microliter) 55 min prior to pentagastrin (1.0 nmol/0.25 microliter) delivery blocked the facilitatory effects of pentagastrin. Administration of the CCK-A antagonist, PD140548 (34 nmol/0.25 microliter), into the PAG failed to alter response latencies for defensive rage behavior. In contrast, microinjections of the CCK-B antagonist, LY288513 (4.2, 17.0 nmol/0.25 microliter), facilitated the occurrence of predatory attack behavior elicited from the lateral hypothalamus. This finding demonstrates the specificity of the effects of CCK-B receptor blockade upon hissing. A combination of immunocytochemical and retrograde tracing procedures using microinjections of Fluoro-Gold (8%, 6 microliters) into the PAG were employed to identify the possible loci of CCK neurons that project to the PAG. The data revealed that neurons labeled for both CCK and Fluoro-Gold were located in the dorsolateral aspect of the midbrain tegmentum, identifying this region as a source of CCK inputs to the PAG. Overall, the findings demonstrate that CCK-B receptors in the PAG potentiate defensive rage behavior and likely suppress predatory attack.

Recently, our laboratory has demonstrated that predatory attack behavior in the cat, elicited by electrical stimulation of the lateral hypothalamus, is suppressed following activation of the region of the medial hypothalamus from which defensive rage behavior is elicited [Han, Y., Shaikh, M.B., Siegel, A., Medical amygdaloid suppression of predatory attack behavior in the cat: II. Role of a GABAergic pathway from the medial to the lateral hypothalamus, Brain Res., 716 (1996) 72-83.]. The mechanism for this suppression is a direct GABAergic projection from the medial to lateral hypothalamus. The present study tested the hypothesis that the inhibitory relationship between these two regions of hypothalamus is reciprocal, namely, that a GABAergic neuron, which also projects from the lateral to medial hypothalamus, serves to suppress defensive rage elicited from the medial hypothalamus. Monopolar stimulating electrodes were implanted into lateral hypothalamic sites from which predatory attack behavior was elicited. In addition, cannula-electrodes were implanted into the medial hypothalamus for elicitation of defensive rage behavior and for microinjections of GABA compounds. Initially, in the absence of drug administration, the effects of dual stimulation of the lateral and medial hypothalamus upon response latencies were compared with those following single stimulation of the medial hypothalamus alone. Dual stimulation significantly (p<0.01) suppressed defensive rage behavior elicited from the medial hypothalamus. Then, administration of the GABAA receptor antagonist, bicuculline (10-60 pmol), into medial hypothalamic sites from which defensive rage was elicited blocked the suppressive effects of lateral hypothalamic stimulation. The GABAA receptor agonist, muscimol (0.3-30 pmol), microinjected into the medial hypothalamus, suppressed defensive rage elicited by single stimulation of the medial hypothalamus in a dose dependent manner. These suppressive effects of muscimol upon defensive rage were blocked following pretreatment with bicuculline (60 pmol). Administration of muscimol into adjoining regions of the lateral hypothalamus had no effect upon defensive rage, indicating its site specificity. Bicuculline (60 pmol) delivery into the medial hypothalamus had no effect upon defensive rage, suggesting the, presence of a phasic rather than tonic mechanism. A combination of immunocytochemical and retro grade tracing procedures were then employed to determine the origin of the putative GABAergic pathway projecting to the medial hypothalamus. In this experiment, the retrograde tracer, Fluoro-Gold (8%, 0.5 microl), was microinjected through a cannula-electrode in the medial hypothalamus from which defensive rage had been elicited. Following survival periods of 5-6 days, cats were perfused with 4% paraformaldehyde and brain tissue was processed for immunocytochemical staining of GABA neurons. Retrogradely labeled, immunopositively labeled, as well as Fluoro-Gold and GABA labeled cells, were identified in the lateral hypothalamus. Each type of neuron was distributed over wide regions of the lateral hypothalamus, extending from the area immediately caudal to the optic chiasm to the level of the posterior hypothalamus. Together, the behavioral pharmacological and anatomical data provide evidence of a direct inhibitory projection from the lateral to medial hypothalamus whose functions are mediated by GABAA receptors. When coupled with our previous findings, these results reveal the presence of reciprocal GABAergic inhibitory pathways between the medial and lateral hypothalamus. The findings suggest that functions associated with either the lateral or medial hypothalamus, but not both, can be activated at a given time.

Forty adolescents and adults who exhibited aggressive behavior within the six months prior to evaluation by physically attacking another person or destroying property were evaluated with brain SPECT imaging. A control group of 40 psychiatric patients who had never been reported to exhibit aggressive behavior were also studied. The brain SPECT studies were read blind to aggressiveness by nuclear physician on two separate occasions. The interreading reliability was very high. The brain SPECT patterns of the group with aggressive behavior showed significant differences from the control group in several areas of brain. These findings were most often seen in the following combination: decreased activity in the prefrontal cortex, increased activity in the anteromedial portions of the frontal lobes, leftsided increased activity in the basal ganglia and/or limbic system in comparison to the whole brain and focal abnormalities in the left temporal lobe. These findings indicate a possible cerebral perfusion profile for those who exhibit violent or aggressive behavior. Several case studies and the implications for treatment are discussed.

Previous studies have shown that, at certain dose levels, ethanol can exert a powerful, facilitatory effect on aggressive behavior in both animals and humans. In the cat, however, it was discovered that ethanol differentially alters two forms of aggression that are common to this species. Defensive rage behavior is significantly enhanced, whereas predatory attack behavior is suppressed by ethanol administration. One possible mechanism governing alcohol's potentiation of defensive rage behavior is that it acts on the descending pathway from the medial hypothalamus to the midbrain periaqueductal gray (PAG)-an essential pathway for the expression of defensive rage behavior that uses excitatory amino acids as a neurotransmitter. This hypothesis is supported by the finding that the excitatory effects of alcohol on defensive rage behavior are blocked by administration of the N-methyl-D-aspartate antagonist alpha-2-amino-7-phosphoheptanoic acid (AP-7) when microinjected into the periaqueductal gray, a primary neuronal target of descending fibers from the medial hypothalamus that mediate the expression of defensive rage behavior. Thus, the present study establishes for the first time a specific component of the neural circuit for defensive rage behavior over which the potentiating effects of ethanol are mediated.

The present study tested the hypothesis that the pathway from the medial hypothalamus to the midbrain periaqueductal gray (PAG) subserving defensive rage behavior in the cat facilitates the occurrence of this response when elicited from the PAG by utilizing excitatory amino acids as a neurotransmitter or neuromodulator. Cannula electrodes were implanted into the PAG for the elicitation of defensive rage behavior as well as for microinjections of excitatory amino acid antagonists and N-methyl-D-aspartic acid (NMDA). Monopolar stimulating electrodes were also implanted into the medial hypothalamus from which this response could also be elicited and, when stimulated at subthreshold levels for elicitation of behavior, could also facilitate the occurrence of PAG elicited defensive rage. Initially, dual stimulation of the PAG and medial hypothalamus facilitated the occurrence of defensive rage elicited from the PAG. Then, the identical dual stimulation paradigm was repeated with the same current parameters following the infusion of various antagonists for different receptors into the PAG defensive rage sites. The results indicate that infusion of either kynurenic acid [(0.1-2.0 nmol), a non-selective excitatory amino acid receptor antagonist] or D-2-amino-7-phosphonoheptanoic acid (AP7) [(0.1-2.0 nmol), a specific NMDA receptor antagonist], produced a dose and time dependent blockade of the facilitatory effects of medial hypothalamic stimulation. In contrast, microinjections of relatively larger doses of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) [(4 nmol), a non-NMDA receptor (quisqualate and kainate) antagonist] or atropine [(4.4 nmol), a muscarinic receptor antagonist] had little effect upon medial hypothalamically elicited facilitation of the PAG response. In a second experiment, NMDA [0.1-1.0 nmol] was microinjected directly into PAG defensive rage sites in the absence of medial hypothalamic stimulation. In these animals, drug infusion mimicked the effects of dual stimulation by producing a dose and time dependent decrease in response latencies. A third experiment was designed to further test the hypothesis by neuroanatomical methods. Here, the retrograde label, Fluoro-Gold, was microinjected into defensive rage sites within the PAG and following a survival time of 5-6 days, the animals were sacrificed. The brains were then processed for immunocytochemical analysis of cells that immunoreact positively for aspartate and glutamate. The results indicated the presence of many retrogradely labelled and immunocytochemically positive cells within the rostro-caudal extent of the medial hypothalamus as well as others that were double labelled.(ABSTRACT TRUNCATED AT 400 WORDS)

Several studies have indicated that patients with panic attacks have a higher rate of suicide attempts as well as deaths from suicide. Additionally, several investigators have presented case reports of individuals manifesting suicidal and violent behaviors directly and temporally associated with panic attacks. We report on four additional cases and suggest that these findings may explain, in part, the increased rate of suicidal behavior among patients with panic attacks found by some investigators. Furthermore, these case reports offer preliminary evidence that the relationship between violent behavior and the panic state may be clinically significant and deserving of further elucidation.

Although this article focuses on psychopharmacology, pharmacotherapy is only part of a comprehensive treatment program. Treatment should be individualized to the patient's condition and level of intellectual functioning (e.g., conduct disorder, mental retardation). Clinicians should be acquainted with the Food and Drug Administration's regulations and the Physician's Desk Reference's guidelines. Psychoactive agents should be prescribed judiciously under careful clinical and laboratory monitoring, especially when given on a long-term basis. Knowledge of potential short- and long-term side effects is imperative to minimize impairment (cognitive, sedation) and to maximize achievement of adaptive behaviors. Aggressiveness is a low-frequency behavior and therefore difficult to assess. Aggressiveness with an explosive affective component and rage seems to be more responsive to pharmacotherapy than aggressiveness alone. Children who present with covert conduct disorder symptoms, such as stealing and lying, might not be as responsive to psychoactive agents as the conduct disorder with explosive characteristics. The neuroleptics are considered the standard drugs for the treatment of aggression but sedation and concern over tardive dyskinesia have led investigators to explore and study other classes of drugs. Lithium carbonate has been studied in short-term clinical trials and has been shown to be an effective alternative to the neuroleptics. Carbamazepine and propranolol seem to be promising agents but require further critical assessment in children and adolescents. Stimulants should be considered the first choice of treatment in coexisting conduct disorder and ADHD or in milder forms of aggression. In conclusion, there is a need for systematic investigation of the effectiveness and safety of psychoactive agents in children and adolescents with aggressiveness, explosiveness, and rage outbursts. There is some supportive evidence that some patients with these target symptoms are good responders to certain drugs. Future research should compare pharmacotherapy to psychosocial treatment and the combination of both.

Rage reaction was induced in mice by ip amphetamine sulfate (APT) 15 mg/kg. Mice appeared hyperreactive after 6 min and then squeaked and fought each other. These manifestations were most distinct in 15-30 min and subsided after 40-70 min. At 20 degrees C and 25 degrees C, the occurrence of rage reaction was 85.0% and 90.0% respectively. The ED50 of APT for eliciting rage reaction was 11.8 +/- 2.1 mg/kg ip. No significant difference in the induction of rage reaction was observed between male and female mice but ambient temperature affected the occurrence of this reaction. Neuroleptic drugs (chlorpromazine, haloperidol, tardan and clozapine), anxiolytic drugs (diazepam and meprobamate) and reserpine suppressed the rage reaction induced by APT in mice. Phenobarbital and pentobarbital (at sedative doses), atropine, scopolamine, phentolamine and propranolol exerted no influence on APT--induced rage reaction. Amantadine, levodopa and apomorphine at lower doses potentiated the rage inducing effect of APT. Moreover, at higher doses amantadine or levodopa alone also evoked rage reaction similar to that induced by APT. Therefore, it may be deduced that the APT-induced rage reaction results from increased release of dopamine in limbic system and has nothing to do with the simultaneous epinephrine release. The available data indicate that the APT--induced rage reaction in mice deserves to be recommended as an animal model for screening potential neuroleptic drugs. The merits and shortcomings of this new model are discussed.

In the present investigation, the dichotic word listening performance of a sample of 25 dysphoric neuropsychiatric patients who endorsed multiple partial seizure-like symptoms was compared with that of matched samples of normal controls and patients with mood disorders who did not endorse multiple seizure-like symptoms. Eighty percent of the patients who endorsed multiple episodic phenomena failed the dichotic listening task, compared with 8% of normal controls and 28% of patients with typical mood disorders. After treatment with carbamazepine, a subsample of polysymptomatic patients manifested significantly fewer seizure-like symptoms. This clinical improvement was typically associated with markedly improved dichotic listening performance in most cases. The results are consistent with our previous hypothesis that "subclinical" electrophysiological dysfunction may severely disrupt the normal transmission and processing of auditory information. Because it is sensitive to this type of presumed cerebral dysfunction and relatively specific, impaired dichotic listening performance is likely to be a useful clinical marker for this complex neuropsychiatric syndrome.

Rage reaction was induced in mice by sc 4-aminopyridine (4-AP) 6 mg . kg-1. Mice appeared hyperreactive after 8-12 min and then squeaked and fought each other. These manifestations were most distinct in 10-30 min and subsided after 40-60 min. The occurrence of rage reaction on this dose level was around 90%. At higher doses 4-AP caused convulsions and death after evocation of rage reaction. The ED50 of 4-AP for eliciting rage reaction was 4.7 +/- 0.7 mg . kg-1 sc. No significant difference in induction of rage reaction was seen between male and female mice of different body weights. Both neuroleptic drugs (chlorpromazine, haloperidol, tarden and clozapine) and anxiolytic drugs (diazepam, chlordiazepoxide, and meprobamate) inhibited 4-AP-induced rage reaction in mice. Barbiturates, Chloral hydrate, methaqualone, morphine hydrochloride, aspirin, phenytoin sodium, diphenhydramine hydrochloride, atropine sulfate, and procaine hydrochloride did not affect rage reaction. The 4-AP-induced aggressive behavior, similar to that induced by electric footshock or isolation, has the merits of convenience to deal with and time saving. Hence we recommended it as a screening method for drugs with neuroleptic and anxiolytic activities.

Eighty patients (randomly assigned in 51 cases) with diverse diagnoses, were prescribed propranolol or carbamazepine for temper outbursts. Results suggested that both medications were beneficial. The diagnosis of attention deficit disorder predicted preferential response to propranolol, and a diagnosis of intermittent explosive disorder predicted preferential response to carbamazepine. Results, however, were not entirely consistent and require confirmation.

Experience with the use of tranquilizing drugs in the control of anxiety and in attempts at behavior modification, prompted a controlled study in the use of the benzodiazepines at the Utah state prison. It appeared that the benefits derived from the administration of these drugs in prisoner control were nearly outweighed by the frequent appearance of paradoxical rage reactions and increase in hostility and aggressive tendencies in these individuals. A double blind, cohort, prospective, randomized study was set up comparing Valium and Serax in their antianxiety qualities and their tendency to produce increased aggression and paradoxical rage reactions. Guidelines are proposed for the use of benzodiazepines and Serax is suggested as a superior drug to Valium for this purpose if indeed a tranquilizer of this type is indicated.

Recent clinical observations and psychiatric diagnostic findings of drug-dependent individuals suggest that they are predisposed to addiction because they suffer with painful affect states and related psychiatric disorders. The drugs that addicts select are not chosen randomly. Their drug of choice is the result of an interaction between the psychopharmacologic action of the drug and the dominant painful feelings with which they struggle. Narcotic addicts prefer opiates because of their powerful muting action on the disorganizing and threatening affects of rage and aggression. Cocaine has its appeal because of its ability to relieve distress associated with depression, hypomania, and hyperactivity.

The use of propranolol to treat unprovoked rage episodes in brain-damaged patients has recently been reported. The authors report three cases that indicate a role for its use in the treatment of overall aggressiveness in brain-damaged or mentally retarded patients.

A double-blind, placebo-controlled crossover study was conducted to examine the effects of pindolol for the treatment of 11 patients with impulsive, explosive behaviors and other emotional-behavioral abnormalities as a consequence of brain disease or injury. Pindolol treatment was associated with significant therapeutic benefits without sedation and without the use-limiting side effects that occur with propranolol.

The authors gave 22 chemical workers neurological, psychiatric, and neuropsychological examinations and placed them in one of two groups according to their degree of exposure to trimethyltin chloride spillage during January 1978. Other chemicals to which they had been exposed were dimethyltin dichloride and methyl chloride. Specific and nonspecific symptoms of intoxication of the CNS showed a significantly greater frequency in the highly exposed group, including cycles of depression and destructive rage, each lasting a few hours. These observations should alert diagnosticians to this type of occupational exposure.

Emotional rage and fear were found to destroy the differential inhibition and the short-term memory in cats. Stelazine, haloperidol, amitriptyline, imizine, chlordiazepoxide, diazepan and benactyzine prevented these disturbances. Chlorpromazine, as well as stelazine and haloperidol in high doses, enhanced these disturbances. The tranquillizers and the antidepressants normalized the higher nervous activity at a greater dose range than neuroleptics and were more preferable for the elimination of the negative consequences of the strong emotional reactions.

In selected patients with episodic behavioral disorders, rapidly absorbed benzodiazepines can be given orally to abort paroxysmal symptoms in their prodromal stages or to disrupt a cycle of continuous, serial symptoms. A case example illustrates each use.

A review of the pharmacology and use of the drug physostigmine is presented. Of particular interest is the drug's capability to reverse excessive somnolence or paradoxical responses caused by intravenous diazepam (Valium®) and other clinically available benzodiazepines. Its use for the treatment of anticholinergic syndrome is discussed and incidence and characterization of side effects documented. Recommendations are made for appropriate emergency use.

Subjects with a history of violent or psychotic behavior while under the influence of alcohol were infused with a 25% alcohol solution. Based on electroencephalograms, blood alcohol concentrations and behavioral observations, the results confirm the probable existence of a discrete syndrome of pathological reaction to alcohol without reference to the amount of alcohol consumed.