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The Neuroendocrinology


Love, Hate And Aggression

E-Newsletter No. 29

Neuroendocrinology is the study of the control by the brain of the secretion of hormones. This includes the action of the hormones on the brain, and also the effects on behaviors related to the brain actions. As emotions are an essential accompaniment of these behaviors, we have to consider these as well.

Neurons respond to and integrate a wide range of types of input, defined by their functions and by their rich variety of transmitters and humoral factors. The networks in which these neurons are situated function to generate outputs over very wide time domains, and their diverging output generate patterns of hormone secretion and behavior that can show marked plasticity and adaptation.

Those activities that have most interested neuroendocrinologists, typified by reproduction, regulation of metabolism, salt and water balance, and coping with stressors, obviously involve behaviors as well as brain-regulated hormone secretion. The organization of the behavior appropriate to each activity is based on neural circuits that also regulate the classical neuroendocrine outputs in these activities. We also know that strong sensations, feelings or emotions are aroused to motivate, drive or accompany these activities. Common to all of these activities can be aggressiveness against con-specifics in fighting over a sexual partner, protecting young, competing for food and water, or defending territory.

The accompany emotion is hate, and on the face of it, because aggressiveness is the common feature of the competition for limited resources, this emotion may be more prevalent that its opposite, love. The emotional accompaniment of social affiliation and bonding is love. However, some may prefer to restrict the use of hate to describe only an emotion associated with wantonly destructive behaviors rather than self-protective aggression. We have some insights into the neuroendocrine background to these behaviors and emotions from studies on oxytocin and vasopressin, mainly in animals.

Affiliation And Oxytocin

Oxytocin released within the brain during mating in the female prarie vole leads to changes that bond the female to her partner (TINS 1998; 21:71-5). The release of oxytocin in the mother's brain at birth is also important in evoking maternal behavior, particularly if the environment is not conducive to this. Oxytocin has widespread actions on the maternal behavior circuits, at least in sheep and rats (Exp Physiol 2000; 855: 1115-1245); Prog. Brain Res 2001; 133:59-66).

Whether the occasional catastrophic failure of a human mother to bond to, but on the contrary, to hate her baby is a failure of this mechanism is not known (Br J Psychiatry 1997; 171: 175-181). At the present time, we know of no naturally occurring defects in the oxytocin gene or its receptor that might underline this or any other defect in behavior. However, male mice with engineered inactivation of the oxytocin gene cannot form "social memories," that is, they cannot recognize through smell a con-specific to which they have been recently exposed (Nat Gen 200; 25: 284-8). Such mice are also more aggressive against intruding con-specifics (Horm Behav 2000; 37: 144-55). Overall, the actions of oxytocin in the brain on behaviors forgivably allow the term "love hormone" to be applied to it.

Aggression And Vasopressin

The idea that vasopressin might have actions in the brain in line with its peripheral actions (protecting body fluid volume, osmolarity, blood pressure, and stimulating ACTH secretion), is also substantiated. The actions of vasopressin on behavior indicate an apparently opposite action to oxytocin, and contribute to aggressive behavior, a characteristic of adult males.

Injection of vasopressin into the lateral septum or amygdala of the brain evokes aggressive behavior in rodents (Prog Brain Res 1998; 119: 437-48). The expression of the local vasopressin mechanisms is dependent on male sex steroids (Prog Brain Res 1998; 119:3-20), and the density of the vasopressin network of fibers in the lateral septum of the brain in male rats is inversely related to aggressiveness among individuals, perhaps reflecting greater vasopressin activity with aggressive behavior. Nonetheless, although female prairie voles are less aggressive than males, aggression in females is also stimulated by vasopressin, and blocked by its V1a antagonist (PNAS 1999;96;12601-4).

Interestingly, there is an important exception: in male prairie voles vasopressin, acting through V1a receptors, evokes bonding to the first sex partner (Prog Brain Res 1998; 119: 483-99). But, perhaps this "monogamous" behavior might also be interpreted as protecting the partnership, because males are more aggressive after mating.

This transition after mating to aggressiveness towards intruder males depends on vasopressin action in the lateral septum, and vasopressin content here is increased, perhaps related to the increase in circulating testosterone. However, it is different for different species. In mice, as contrasted to prairie voles, there are species in which males are paternal, but also more aggressive. In these species the vasopressin mechanisms are more prominent than in nonpaternal, less aggressive species (Horm Behav 1999; 36: 25-38). The differences in vasopressin mechanisms in such closely related species are evidently a consequence of mutations in the regulatory elements of the V1a receptor gene, and different patterns of distribution in the brain.

The neural substrates of aggression have been deeply probed in the golden hamster (Exp Physiol 2000; 85S: 855-905). Here, offensive aggression involves interaction between vasopresin and serotonin mechanisms in the anterior hypothalamus section of the brain. Essentially, vasopressin is released during aggressive behavior and acts through V1a receptors to facilitate the behavior. Serotonin acting via 5-HT, 1A receptors, suppresses activity of this vasopresin system and aggression.

There is correlative evidence from human studies for this interaction in subjects with personality disorder and a life-history of aggression against others. Reduced activity of brain serotonin mechanisms is associated with impulsive aggression in humans (Arch General Psychiatry 1998; 55: 708-14).

It has been known for a long time that isolation of infant rhesus monkeys from their mothers has long-lasting behavioral consequences, including their showing unpredictable and excessive aggressive behavior (Am Scientist 1971; 59: 538-49). Similarly in rodents, early life experiences, including treatment with vasopressin, program aggressiveness (Stress 1999; 3: 97-106). This is likely to be through change in the relative expression of vasopressin and serotonin mechanisms.

Mice cross-fostered onto a less aggressive species of mouse show less aggressiveness as adults and have reduced levels of vasopressin in the bed nucleus of stria terminalis in the brain (Horm Behav 2001; 40: 51-64). Conversely, hamsters exposed to aggression in adolescence, when adult, show submission rather than aggression to their control peers, but are highly aggressive to their juniors, which are not threatening.

Interesting, hamsters exposed to aggression in adolescence show low cortisol responses to challenge with a threatening con-specific; perhaps a parallel with the changes in hypothalamic-pituitary-adrenal (HPA) axis responses seen in post traumatic stress disorder (PTSD: see below). The adolescent exposure to aggression programs down-regulation of the anterior hypothalamic vasopressin system, leaving the V1a receptors sensitized, and has opposite effects on the serotonin system.

It is hypothesized that this provides the basis for context-dependent abnormal aggressiveness. Submissiveness in the context of exposure to an aggressive equal, but extreme aggressiveness when the aggressive response, involving activation of the vasopressin mechanism and inhibition of the serotonin circuit, is triggered by exposure to a harmless junior. How such changes are induced and fixed is not clear. These studies suggest that, in contrast with oxytocin, the "love hormone," vasopressin acts in the brain to engender alongside aggression the emotion of hate.

PTSD: Neuroendocrine Sequelae To Extreme Stress

A legal defense of a terrorist recently on trial has been that his actions resulted from PTSD, arising from his up-bringing in a context involving transfer of hatred from the older generation (J Am Acad Psych Law 2000; 28: 171-8). Obviously PTSD also affects victims of terrorist acts. The diagnostic criteria for PTSD were defined in 1980 (diagnostic and Statistical Manual of Mental Disorders [DSM]-III, 1980, 1994), and described long-lasting symptoms following exposure of an individual to extremely stressful life events (Psychiat Clin North Am 1998; 21: 359-79).

Affected individuals show enhanced vigilance and sensitivity to environmental threats, with hyperresponsiveness to innocuous stimuli. Despite other features of chronic stress, there is a low circulating level of cortisol, with evidence of enhanced sensitivity to glucocorticoid feedback (Curr Opin Neruobiol 2000; 10: 211-8), though the adrenal may be sensitized to ACTH (Biol Psychiatry 2001; 50: 238-45). Yet, the activity of brain signaling mechanism (CRH) to the adrenal glands is increased (Peptides 2001; 22: 845-51), perhaps allowing enhanced responses to a perceived threat, though it is not clear whether HPA axis responses are altered (Neuropsychopharmacology 1999; 21: 40-50).

However, by no means all individuals subjected to a traumatic event develop PTSD (only about 9%), and this includes those who are the witnesses to, as well as those who are victims of acts of extreme violence. There are indications that individual differences in the initial HPA axis response to a trauma are a determinant: In particular, a low acute cortisol response to the traumatic event increases the risk of developing PTSD (Biol Psychiatry 1998; 44: 1305-13).

Animal models, showing similar changes in cognition and corticosterone responses to those seen in PTSD, are being established, including identifying strains with a genetic predisposition (Biol Psychiatry 2001; 50: 231-7). However, exposure of rats to a severe (but not necessarily painful or harmful) stressor in a single episode can modify responses, tested days or weeks later, to homo- or hetero-typic stressors in opposite directions, depending on the initial stressor (Neuroendo 1993; 58: 57-64, Eur J Neurosci 2001; 13: 129-36, Eur J Pharmacol 2000; 405: 217-24). Greater responses are associated with an increased store of vasopressin in the external median eminence of the brain.

Reducing Aggressiveness (And Hatred?)

Returning to destructive aggression, for individuals who want help, therapeutic prospects may involve oxytocin agonists, vasopressin V1a and V1b V3 antagonists, blockade of androgen actions, and enhancement of serotonin mechanisms (J Pharmacol Exp Ther 1999; 288: 1125-33). Conversely, understanding the neurobiology of pacification strategies may be fruitful (Science 2000; 289: 586-90). Of interest here is that in a social defeat paradigm, the defeated male rat releases oxytocin and not vasopressin in the medio-lateral septum of the brain (Brain Res 2000; 872: 87-92).

Research into the neurobiology of aggression has faced political and ethical issues, but the use of ethnologically relevant animal models overcomes some of the problems, permitting investigation with neuroendocrine expertise. Of course, it goes without saying, that prevention of the adverse programming in early life of the brains, and the emotions of people through other measures should clearly be the aim, the goal, and the vision.

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