Fightor Flight Response

Hans Selye of the University of Montreal (Montreal, QC, Canada) proposed that the body has a uniform response to stress, whether resulting from strenuous muscular activity, prolonged food deprivation, or exposure to toxins. Pituitary hormones, steroid hormones, and adrenal catecholamines are secreted in large quantities in the general adaptation syndrome. The body goes through three sequential stages: (1) an alarm reaction, during which the body prepares for fight or flight; (2) resistance, during which biological changes counteract the deleterious effects caused by the stressing agent; and (3) exhaustion.

During the fight-or-flight response, the amygdalas activate the hypothalamus, which activates the adrenal glands to produce epinephrine and norepinephrine. The amydalas are part of the limbic system lying just beneath the thalamus, and they include the hypothalamus and hippocampus. The limbic system includes the basal ganglia, regions of the brain involved in movement and memory as well as emotions. People remember emotionally charged events.

During stress, the sympathetic and parasympathetic components of the autonomic nervous system increase the rate and force of contractions of the heart. Adrenergic neurons in the left stellate ganglia innervate the right ventricle; the right stellate ganglia innervate the anterior and lateral portions of the ventricles.

Even in the absence of stress, norepinephrine affects mood, sleep, and alertness, being at its lowest blood levels during sleep. People can develop an addiction to their own epinephrine and norepinephrine, and take pleasure in activities such as sky-diving, motor cycling, or mountain climbing to produce an adrenaline rush. They can also become addicted to endogenous enkephalins (endorphins), which have opiate-like effects, inducing pleasure and feelings of well being.

The neurotransmitter serotonin is released by strong emotions. In 1957, Julius Axelrod at the National Institutes of Health (Bethesda, MD), found that the enzyme monoamine oxidase (MAO) inactivates norepinephrine and other monoamines. In 1961, he found that neurotransmitters are removed from synapses by being taken back up into the presynaptic neurons that had secreted them, and are secreted again during later neuronal events. Drugs that block MAO activity prevent the breakdown of the monoamines, resulting in the storage of large amounts of the neurotransmitters in presynaptic vesicles until they are ready to be released again.

Serotonin (5-hydroxytryptamine; 5-HT) is involved in the regulation of the cardiovascular and respiratory systems, sleep, aggression, sexual behavior, food intake, anxiety, mood, motor output, neuroendocrine secretion, nociception, and analgesia.

Serotonin affects motor activity by inhibiting the impact of sensory information and by coordinating autonomic and neuroendocrine function during demanding motor activity. Terminals of neurons secreting 5-HT are located in the primary and secondary motor areas of the brain.

Serotonin plays a role in the modulation of social behavior and in reward processing. Deficiency of tryptophan, the serotonin precursor, leads to reduction in serotonin production, and brings about reductions in the level of cooperation shown by participants in an experimental game-playing experiment. Serotonin also plays a role in socially cooperative behavior (Wood, 2006).

The hormone melatonin induces sleep, but serotonin is involved in dreaming; both are produced in the pineal gland. If the brain has low serotonin levels, dreaming will not occur. Serotonin is also important in learning, memory, and mood. It is deficient in the brains of depressed patients. Serotonin deficiency can result in an inability to fall asleep at night, panic attacks, loss of concentration, and thoughts of suicide or attempted suicide.

Melatonin (5-methoxy-N-acetyltryptamine) is produced from tryptophan by the pineal gland, retina, and gastrointestinal tract, and it is bound by melatonin receptors. Nobel Prize laureate Julius Axelrod discovered the role of melatonin and the pineal gland in regulating sleep-wake cycles (circadian rhythms). Production of melatonin by the pineal gland is stimulated by darkness and inhibited by light. Melatonin inhibits secretion of luteinizing hormone and follicle-stimulating hormone from the anterior pituitary gland.

Alcohol lowers levels of serotonin in the brain, and many alcoholics have dreamless sleep, devoid of rapid eye movement activity. When alcoholics withdraw from alcohol, many experience delirium tremens (DTs), manifest by shaking, sweating profusely, anxiety, and hallucinations. Alcohol depletes the brain of serotonin, the levels of which may rise to higher than normal levels with the withdrawal of alcohol. Excessive production of serotonin is thought to cause the hallucinations, which characterize DTs.

Norepinephrine is synthesized from tyrosine, stored in presynaptic vesicles, and released from vesicles upon the arrival of axonal action potentials. After its release into synapses, unbound norepinephrine is taken back into presynaptic neurons by norepi-nephrine transporters, which terminate its effect. The reuptake process clears 70-90%

of the norepinephrine released into synapses. Norepinephrine remaining free in the synaptic cleft is metabolized by two monoamine oxide enzymes, MAO A and B.

Serotonin has an opposite effect from norepinephrine and epinephrine. In the face of a threatening environment, the serotonergic system increases feelings of well being, calm, relaxation, confidence, and concentration. Serotonergic neuronal networks counterbalance the effects of noradrenaline associated with arousal, fear, anger, tension, aggression, violence, obsessive-compulsive actions, overeating, and anxiety and sleep disturbances.

Serotonin, first isolated in 1948 by Maurice M. Rapport, was initially thought to be only a vasoconstrictor. The word serotonin implied a serum agent identified as a vasoconstrictor. The body of the average adult human possesses 5-10 mg of serotonin, 90% of which is in the intestine, and the rest is in blood platelets and the brain.

Serotonin was subsequently found to be a neurotransmitter with several subtypes of receptors: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7. The physiological function of each receptor subtype has not been established. With the exception of the 5-HT3 receptor, which is a ligand-gated ion channel related to N-methyl-D-aspartate (NMDA), GABA, and nicotinic receptors, all of the 5-HT receptor subtypes belong to the group of G protein-linked receptors. Specific agonists and antagonists for each receptor system are the focus of new drug development.

A tryptophan-free diet results in a fall in brain serotonin levels after 4 hours. Lacking the inhibitory regulation of serotonin, neuronal activity is insufficiently modulated, resulting in the person becoming angry, depressed and impulsive, losing control of emotions.

In August 2004, fluoxetine hydrochloride (Prozac), a selective serotonin reuptake inhibitor (SSRI), was found in drinking water in the United Kingdom. How it got there, no one knows. Is it possible that mind-altering drugs might someday be added to drinking water the same way that fluoride is added to prevent caries?

Prozac is the most frequently prescribed drug in the United States. In Listening to Prozac (Knopf), published in 1993, and Against Depression (Viking), published in 2005, Peter D. Kramer discusses drugs, called SSRIs that are widely used to treat depression. They inhibit the reuptake of synaptic serotonin into presynaptic neurons. They have helped many persons, but their use also has created many problems. In Forbes magazine (November 2004), the following statement was made: "The 1990s made pill-popping for happiness an acceptable therapeutic alternative for millions of even mildly depressed patients."

Placebo controlled trials in children and adults showed that 60 of 9,219 (0.65%) patients given the SSRI drug paroxetine, compared with 20 of 6,455 given placebo (0.31%), had what was called a hostility event, that is, commiting violent acts.

When monkeys have low serotonin levels, they become aggressive. This response is thought to be a model for violence against oneself or family members, possibly related to a failure to counteract epinephrine effects. High aggressiveness in monkeys was correlated with low levels of metabolic products of serotonin in spinal fluid. In humans, low levels of serotonin metabolites in spinal fluid also correlate with the severity of physical aggression.

As Peter Kramer has written, "Assertiveness gets you what you need, and correlates with high brain-serotonin levels. Uncontrolled violence against oneself or others correlates with low brain-serotonin levels."

SSRIs are involved in the actions of the three best known neurotransmitters-serotonin, norepinephrine, and dopamine-monoamines metabolized by the enzyme MAO. MAO inhibitors inhibit SSRI action. These three amines have been found to be low in the brains of patients who are clinically depressed. SSRIs prevent the breakdown of these monoamines. Persons beginning to take Prozac may experience epinephrine-related effects after 3 or 4 days, perhaps a reaction to the transiently high levels of serotonin. On March 22, 2004, the Food and Drug Administration warned that SSRIs might cause anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsiveness, extreme restlessness, hypomania, and mania.

Serotonin has been implicated in cognition, affecting memory, perception and attention, mood, aggression, sexual drive, appetite, energy level, pain sensitivity, endocrine function, and sleep. Patients with schizophrenia are thought to have abnormal dopamin-ergic and serotonergic neurotransmission. Their cerebral ventricles may be enlarged, and their temporal lobe volume decreased, but such structural manifestations are not specific. The focus was initially on dopamine.

The NMDA hypothesis, called the glutamatergic dysfunction hypothesis, of schizophrenia is based on the action of glutamate on NMDA receptors on GABAergic, serotonergic, and noradrenergic neurons that inhibit two major excitatory pathways in the retrosplenial cortical neurons. (Coyle, 1996).

Serotonin receptors are decreased in the cerebral cortex and striatum in aging persons. Serotonin receptors are increased in suicide victims with major depression. Patients with chronic fatigue syndrome have decreased numbers of serotonin transporters in the anterior cingulate (Watanabe et al., Mind/Brain Symposium, 2002). Drugs used to treat patients with depression increase the levels of serotonin and noradrenaline in the brain.

Schizophrenia is manifest by impaired cognition and failure of appreciation of reality. Patients with schizophrenia have positive symptoms, such as hallucinations, mood disorders, or negative symptoms, such as impaired interpersonal relations, social withdrawal, and difficulty in holding a job. Positive symptoms are related to decreased dopaminergic activity. Negative symptoms, such as catatonia, are related to serotonergic activity.

Clozapine and other antagonists of serotonin and D2 dopamine receptors, including risperidone, olanzapine, sertindole, ziprasidone, and quetiapine, improve patients because of their effects on several brain regions (Bryan L. Roth and Herbert Y. Meltzer, The Role of Serotonin in Schizophrenia, Neuropsychopharmacology).

Wooley, Shaw, and Gaddam first advanced the hypothesis that decreased serotonergic activity was the cause of schizophrenia. Research over the next 25 years did not support this hypothesis, even though there were decreased densities of specific types of 5-HT receptors in the brains of schizophrenic patients.

Interest in the role of serotonin in schizophrenia increased when numerous 5-HT receptor subtypes were found. The extraordinary ability of the drug clozapine to improve patients with schizophrenia was attributed to its ability to block 5-HT2A receptors.

Serotonin has been linked to aggressive behavior as a result of activation of the limbic system (olfactory bulb, amygdala, and hypothalamus), the prefrontal cortex, and a region of the periaqueductal gray (Wood et al., 2006).

Tiihonen et al. (1997) examined the serotonergic system with single photon emission computed tomography in 52 subjects (21 impulsive violent offenders, 21 age- and sex-matched healthy controls, and 10 nonviolent alcoholic controls. The specific binding of iodine-123-P-carbomethoxy-3(4-iodophenyl) tropane to serotonin transporters in the mid-brain of violent offenders was lower than that in the healthy control subjects, thought to be due to occupation of the serotonin transporters by increased amounts of synaptic serotonin or to an impairment or absence of the presynaptic serotonergic neurons themselves.

Serotonin deficiency is related to a broad array of emotional and behavioral problems, ranging from depression, premenstrual syndrome, anxiety, alcoholism, insomnia, violence, aggression, suicide, and compulsive gambling.

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