Steven S. Zalcman

The Neurobiological Bases for Development of Pharmacological Treatments of Aggressive Disorders

Violence and aggression are major causes of death and injury, thus constituting primary public health problems throughout much of the world costing billions of dollars to society. The present review relates our understanding of the neurobiology of aggression and rage to pharmacological treatment strategies that have been utilized and those which may be applied in the future. Knowledge of the neural mechanisms governing aggression and rage is derived from studies in cat and rodents. The primary brain structures involved in the expression of rage behavior include the hypothalamus and midbrain periaqueductal gray. Limbic structures, which include amygdala, hippocampal formation, septal area, prefrontal cortex and anterior cingulate gyrus serve important modulating functions. Excitatory neurotransmitters that potentiate rage behavior include excitatory amino acids, substance P, catecholamines, cholecystokinin, vasopressin, and serotonin that act through 5-HT(2) receptors. Inhibitory neurotransmitters include GABA, enkephalins, and serotonin that act through 5-HT(1) receptors. Recent studies have demonstrated that brain cytokines, including IL-1beta and IL-2, powerfully modulate rage behavior. IL-1-beta exerts its actions by acting through 5-HT(2) receptors, while IL-2 acts through GABAA or NK(1) receptors. Pharmacological treatment strategies utilized for control of violent behavior have met with varying degrees of success. The most common approach has been to apply serotonergic compounds. Others included the application of antipsychotic, GABAergic (anti-epileptic) and dopaminergic drugs. Present and futures studies on the neurobiology of aggression may provide the basis for new and novel treatment strategies for the control of aggression and violence as well as the continuation of existing pharmacological approaches.

Association of Plasma Interleukin-18 Levels with Emotion Regulation and μ-Opioid Neurotransmitter Function in Major Depression and Healthy Volunteers

BACKGROUND Alterations in central neurotransmission and immune function have been documented in major depression (MDD). Central and peripheral endogenous opioids are linked to immune functioning in animal models, stress-activated, and dysregulated in MDD. We examined the relationship between μ-opioid receptor (OR)-mediated neurotransmission and a proinflammatory cytokine (interleukin [IL]-18). METHODS We studied 28 female subjects (14 MDDs, 14 control subjects) with positron emission tomography and [(11)C] carfentanil (μ-OR selective) during neutral and sadness states. With a simple regression model in SPM2 (Wellcome Trust, London, England) we identified brain regions where baseline μ-OR availability (nondisplaceable binding potential [BP(ND)]) and sadness-induced changes in μ-OR BP(ND) were associated with baseline IL-18. RESULTS Baseline IL-18 was greater in MDDs than control subjects [t(25) = 2.13, p = .04]. In control subjects IL-18 was correlated with negative emotional ratings at baseline and during sadness induction. In MDDs, IL-18 was positively correlated with baseline regional μ-OR BP(ND) and with sadness-induced μ-opioid system activation in the subgenual anterior cingulate, ventral basal ganglia, and amygdala. CONCLUSIONS This study links plasma IL-18 with sadness-induced emotional responses in healthy subjects, the diagnosis of MDD, and μ-opioid functioning, itself involved in stress adaptation, emotion regulation, and reward. This suggests that IL-18 represents a marker associated with emotion regulation/dysregulation at least in part through central opioid mechanisms.

Role of IL-1β and 5-HT2 receptors in midbrain periaqueductal gray (PAG) in potentiating defensive rage behavior in cat

Feline defensive rage, a form of aggressive behavior that occurs in response to a threat can be elicited by electrical stimulation of the medial hypothalamus or midbrain periaqueductal gray (PAG). Our laboratory has recently begun a systematic examination of the role of cytokines in the regulation of rage and aggressive behavior. It was shown that the cytokine, interleukin-2 (IL-2), differentially modulates defensive rage when microinjected into the medial hypothalamus and PAG by acting through separate neurotransmitter systems. The present study sought to determine whether a similar relationship exists with respect to interleukin 1-beta (IL-1 beta), whose receptor activation in the medial hypothalamus potentiates defensive rage. Thus, the present study identified the effects of administration of IL-1 beta into the PAG upon defensive rage elicited from the medial hypothalamus. Microinjections of IL-1 beta into the dorsal PAG significantly facilitated defensive rage behavior elicited from the medial hypothalamus in a dose and time dependent manner. In addition, the facilitative effects of IL-1 beta were blocked by pre-treatment with anti-IL-1 beta receptor antibody, while IL-1 beta administration into the PAG had no effect upon predatory attack elicited from the lateral hypothalamus. The findings further demonstrated that IL-1 betas effects were mediated through 5-HT(2) receptors since pretreatment with a 5-HT(2C) receptors antagonist blocked the facilitating effects of IL-1 beta. An extensive pattern of labeling of IL-1 beta and 5-HT(2C) receptors in the dorsal PAG supported these findings. The present study demonstrates that IL-beta in the dorsal PAG, similar to the medial hypothalamus, potentiates defensive rage behavior and is mediated through a 5-HT(2C) receptor mechanism.

Soluble Interleukin-6 Receptor Induces Motor Stereotypies and Co-Localizes with Gp130 in Regions Linked to Cortico-Striato-Thalamo-Cortical Circuits

Soluble cytokine receptors are normal constituents of body fluids that regulate peripheral cytokine and lymphoid activity and whose levels are increased in states of immune activation. Soluble interleukin-6 receptor (sIL-6R) levels positively correlate with disease progression in some autoimmune conditions and psychiatric disorders. Particularly strong links between levels of sIL-6R and the severity of psychotic symptoms occur in schizophrenia, raising the possibility that sIL-6R is involved in this disease. However, there is no evidence that peripheral sIL-6R induces relevant behavioral disturbances. We showed that single subcutaneous injections of sIL-6R (0–1 µg), stimulated novelty stress-induced exploratory motor behaviors in male Balb/c mice within 20–40-min of injection. A progressive increase in vertical stereotypies was observed 40–80 min post injection, persisting for the remainder of the test session. Paralleling these stimulant-like effects, sIL-6R pre-treatment significantly enhanced stereotypy scores following challenge with GBR 12909. We found that peripherally administered sIL-6R crossed the blood-brain barrier, localizing in brain regions associated with cortico-striatal-thalamo-cortical (CSTC) circuits, which are putative neuroanatomical substrates of disorders associated with repetitive stereotypies. Peripherally administered sIL-6R co-localized with gp130, a transmembrane protein involved in IL-6 trans-signaling, in the nucleus accumbens, caudate-putamen, motor and infralimbic cortices, and thalamic nuclei, but not with gp130 in the ventral tegmental area, substantia nigra, or sensorimotor cortex,. The results suggest that peripheral sIL-6R can act as a neuroimmune messenger, crossing the blood brain barrier (BBB) to selectively target CSTC circuits rich in IL-6 trans-signaling protein, and inducing repetitive stereotypies. As such sIL-6R may represent a novel therapeutic agent for relevant psychiatric disorders.

The Neuroimmunological Basis of Behavior and Mental Disorders

This chapter summarizes current knowledge on the relationship between systemic autoimmune/inflammatory processes, brain pathology, and mental (dys) function. Several lines of evidence are presented, as well as the molecular mechanisms are instrumental in the initiation and maintenance of complex pathogenic circuits. Although the emphasis is on systemic lupus erythematosus and its associated neuropsychiatric manifestations, other disorders relevant to the immunological theory of mental disorders are also reviewed. Together with relevant immunopathology, the associated permissive conditions (e.g., breached blood-brain barrier) are discussed in the context of an upregulation in brain-reactive autoantibodies, neuroactive cytokines, complement components, and immune complexes. The gaps in our present knowledge and future directions are outlined at the end of the chapter.

Dynamic interactions between plasma IL-1 family cytokines and central endogenous opioid neurotransmitter function in humans

Evidence in animal models suggests IL-1 family cytokines interact with central endogenous opioid neurotransmitter systems, inducing or perpetuating pathological states such as persistent pain syndromes, depression, substance use disorders, and their comorbidity. Understanding these interactions in humans is particularly relevant to understanding pathological states wherein this neurotransmitter system is implicated (ie, persistent pain, mood disorders, substance use disorders, etc). Here, we examined relationships between IL-1β, IL-1ra, and functional measures of the endogenous opioid system in 34 healthy volunteers, in the absence and presence of a standardized sustained muscular pain challenge, a psychophysical challenge with emotionally and physically stressful components. Mu-opioid receptor availability in vivo was examined with [11C]carfentanil positron emission tomography (PET) scanning. Sex and neuroticism impacted IL-1 family cytokines; higher baseline IL-1β and IL-1ra was identified in females with lower neuroticism. Higher baseline IL-1β was also associated with reduced μ-opioid receptor availability (amygdala) and greater pain sensitivity. The pain challenge increased IL-1β in females with high neuroticism. Strong associations between IL-1ra (an anti-nociceptive cytokine) and μ-opioid receptor activation (VP/NAcc) were identified during the pain challenge and the resulting analgesic effect of μ-opioid receptor activation was moderated by changes in IL-1β whereby volunteers with greater pain induced increase in IL-1β experienced less endogenous opioid analgesia. This study demonstrates the presence of relationships between inflammatory factors and a specific central neurotransmitter system and circuitry, of relevance to understanding interindividual variations in regulation of responses to pain and other physical and emotional stressors.

A pilot study investigating tumor necrosis factor-α as a potential intervening variable of atypical antipsychotic-associated metabolic syndrome in bipolar disorder.

Background: Strong associations exist between tumor necrosis factor-&agr; (TNF-&agr;) and metabolic syndrome (MetS). Although TNF-&agr; is associated with bipolar depression (BD), its role in atypical antipsychotic (AAP)–associated MetS in BD is unclear. Here, we investigate the potential intervening role of TNF-&agr; in the indirect relationship between AAP treatment and MetS in BD. Materials and Methods: Using a cross-sectional design, 99 euthymic BD volunteers were stratified by the presence or the absence of MetS (National Cholesterol Education Program Adult Treatment Panel III). Serum TNF-&agr; concentration, determined via chemiluminescent immunometric assays, was compared between groups (ie, MetS or no MetS). We investigated the intervening effect of TNF-&agr; on the relation between AAP treatment and MetS in BD using regression techniques. Results: Treatment with those antipsychotics believed associated with a higher risk for MetS (ie, AAPs: olanzapine, quetiapine, risperidone, paliperidone, clozapine) was found to be associated with significantly greater TNF-&agr; (F1,88 = 11.2, P = 0.001, mean difference of 1.7 ± 0.51) and a higher likelihood of MetS (F1,88 = 4.5, P = 0.036) than in those not receiving treatment with an AAP. Additionally, TNF-&agr; was greater (trending toward significance; T52 = 2.0, P = 0.05) in BD volunteers with MetS and was found to have a statistically significant effect on the indirect relationship between AAP treatment and elevated waist circumference in these BD volunteers. Discussion: These results identify TNF-&agr; as a potential intervening variable of AAP-associated MetS in BD, not previously identified in this population. Future prospective studies could assess the predictive potential of TNF-&agr; in determining risk of AAP-associated MetS in BD. Given previous evidence relating TNF-&agr; and mood state in BD, this study increases the importance in understanding the role of TNF-&agr; in “mind–body” interactions and renews discussions of the utility of research into the clinical efficacy of TNF-&agr; antagonist treatment in mood disorders.

Short- and Long-Term Effects of Interleukin-2 Treatment on the Sensitivity of Periadolescent Female Mice to Interleukin-2 and Dopamine Uptake Inhibitor

Interleukin (IL)-2, a T-helper 1 (Th1) cell-derived cytokine, which potently modulates dopamine activity and neuronal excitability in mesolimbic structures, is linked with pathological outcomes (e.g., schizophrenia, depression, etc.) that at least partly reflect alterations in central dopaminergic processes. It has been suggested that dopamine neurons undergo pruning during adolescence and abnormalities in pruning predispose individuals to behavioral disorders. Since IL-2 is known as a neurodevelopmental factor affecting associated behavioral processes, the present study tested whether IL-2 can modulate stereotypic behaviors in both the periadolescent and adult periods. This study determined whether IL-2 treatment would produce long-lasting changes in sensitivity to a later challenge with IL-2 or GBR 12909, a highly selective dopamine uptake inhibitor. Four experiments were conducted. Firstly, a decrease in novelty-induced stereotypic behavior was observed in BALB/c periadolescent mice (38 days of age) following IL-2 administration (0.4 µg/2 ml) relative to vehicle control. In the second experiment, an initial dose of IL-2 was given in the periadolescent period, but did not affect rearing responses. A second dose of IL-2 given to the animals 30 days later as adults, resulted in a significant increase in rearing behaviors relative to control animals. In the third experiment, separate groups of experimental and control mice were administered GBR 12909, a highly selective dopamine reuptake inhibitor, 30 days following treatment with either IL-2 or vehicle. It was noted that this experimental group, which initially received IL-2, exhibited stereotypy, as evidenced by increased sniffing behavior. A fourth experiment revealed that IL-2 administered in periadolesecence and adulthood had no effect on other motor responses, indicating that IL-2 selectively modulates selective stereotypic behaviors. The results provide evidence, for the first time, that long-term changes in stereotypy in periadolescent mice are linked to an IL-2 mechanism, possibly utilizing dopamine.

Interleukin-2 Treatment Induces an Acquired Behavioral Response Pattern (Repetitive Stereotyped Movements) Mediated by Dopamine D1 and D2 Receptors

Interleukin (IL) -2 is implicated in the etiology of psychiatric disorders (e.g., schizophrenia, psychosis) involving an increased expression of repetitive stereotyped movements. However, little is known about the underlying pharmacological mechanisms or behavioral processes. Of further importance, we sought to identify underlying pharmacological mechanisms. We found that dopamine D1 receptors underlie the development of IL -2induced stereotypic movements while D1 and D2 receptors are required for the expression of IL-2-induced stereotypies. These findings raised the intriguing possibility that IL-2 treatment induced anacquired behavioral response patternrequiring concurrent stimulation of D1 and D2 receptors. Thus, we determined whether stimulation of D1 and D2 receptors following t ermination of IL-2 treatment would re-instate the expression of

Cytokines and Aggressive Behavior

Studies conducted in rodents, primates and humans have provided evidence that proinflammatory cytokines may play an important in the regulation of aggression and rage behavior. More recent studies conducted in the cat have generated more direct evidence of cytokine involvement in modulating rage behavior. Activation of IL-I receptors in the medial hypothalamus and periaqueductal gray (PAG) potentiates defensive rage behavior in the cat. Facilitation of defensive rage is mediated through 5-HT2 receptors in the medial hypothalamus and PAG. Activation of IL-2 receptors in the medial hypothalamus and PAG differentially affect defensive rage behavior. In the medial hypothalamus, IL-2 receptors suppress defensive rage and this effect is mediated through GABAA receptors; in the PAG, IL-2 receptors facilitate the occurrence of defensive rage behavior and such effects are mediated through substance P NK1 receptors. With respect to peripheral mechanisms, LPS administration induces the release of a cascade of proinflammatory cytokines. Among the cytokines released, TNF-〈 appears to play a significant role in the induction of the suppressive effects of LPS upon defensive rage and in sickness behavior in the cat. Concerning the central mechanisms regulating LPS induced suppression of defensive rage and sickness behavior, serotonin 5-HT1A and PGE2 receptors in the medial hypothalamus appears to play key roles in controlling these processes.