Much of the information that is available concerning the functions of catecholamines in regulating human behavior directly results from the use of a group of medications often called psychotropic drugs and antidepressant medications called thymoleptics. Other medications that impact on catecholamines include psychostimulants, such as dextroamphetamine and methylphenidate (commonly known by its trade name, Ritalin) and l-dopa (which has been used to treat Parkinsonism), as well as a medication that was initially used to treat hypertension. Most of these drugs affect more than one system (e.g., dopaminergic, noradrenergic, or serotonergic systems). Catechola-mines have been proposed as mediators of many psychiatric illnesses, including schizophrenia, Tour-ette's syndrome, depression, autism, attention deficit-hyperactivity disorder, stereotypic movements, tremors, and substance abuse. More generically, cate-cholamines also play a critical role in the stress response. Unfortunately, there is no definitive evidence for their role in the etiology of these illnesses. What is definite, however, is the role that catecholamines play in mediating the action of mood-altering and mind-altering drugs. There is speculation about which dopamine receptors these agents block to produce improvement, but the prevailing view is that the more traditional agents block D2 receptors, whereas the newer atypical agents (such as clozapine) may also block D4 (as well as D1-D3) receptors. These newer agents may also differ from the older agents in their ability to bind to serotonergic receptors ofthe 2A type. Nonetheless, as mentioned previously, the similarity between the D2 and D4 receptor families in terms of their structure and function lends insight into the pharmacologic efficacy of both newer and the more traditional antipsychotic agents on illnesses such as schizophrenia. The fact that agents that block dopa-mine receptors produce improvement in schizophrenia has led to the proposal that schizophrenia is caused by overactivity of the dopaminergic system. In support of this so-called dopamine hypothesis, one group has reported an increased density of D2 receptors in brains of schizophrenic patients using PET. Increased density of D2 receptors in postmortem brain tissue from patients with schizophrenia has also been reported. However, most patients have received neuroleptic treatment, which can cause these changes. Thus, it is not clear whether this increased density is an effect of the pathophysiology or the result of treatment. It is well established that reducing dopaminergic activity with neuroleptics inhibits hallucinatory activity and normalizes delusional or paranoid thinking. It seems probable that the dopaminergic systems, particularly the D2 and D4 systems, have a physiological role in keeping thinking and level of suspiciousness in bounds. Curiously, patients who respond well to antipsychotic medication have a decrease in plasma homovanillic acid (HVA), the principal metabolite of dopamine, during treatment, whereas nonresponders do not. What is odd about this finding is that most plasma HVA does not come from the central nervous system.
Antipsychotics improve other symptoms associated with schizophrenia, such as impaired thought processes and attentional problems. Thus, it seems that the dopaminergic system may also regulate associative processing and attention. Drugs that improve psychotic symptoms have another important effect: They produce emotional blunting or so-called "flat affect.'' Inasmuch as these drugs reduce dopaminergic activity, it seems that dopamine may play a role in affect regulation.
Another illness that may illuminate the role of dopamine in regulation of behavior is Tourette's syndrome. This is an illness with onset usually between the ages of 4 and 8 years of age; however, it can occur at any time. It is characterized by rapid, repetitive movements known as motor tics that can be as simple as eye blinking or as complex as assuming contorted body positions. In addition to these movements, vocal tics occur ranging from repetitive coughing and throat clearing to shouting obscene words (coprolalia). These utterances can be a great source of embarrassment to the affected individuals. Both the vocalizations and the motor tics respond to antipsychotic drugs that are, of course, dopamine receptor blockers. This effect on Tourette's symptoms occurs even though the patients are not psychotic. Although dopamine is known to play a role in integrating motor movements, there is a distinct possibility that it may also inhibit socially undesirable movements and vocalizations.
It seems that Tourette's syndrome is in some way related to obsessive-compulsive disorder (this latter illness being particularly prevalent in families of Tourette's patients). Obsessive-compulsive disorder is often responsive to drugs that increase serotonergic activity. However, in one study, two dopamine agonists (methylphenidate and dextroamphetamine) were significantly more effective than placebo in reducing the symptomatology of obsessive-compulsive disorder. Thus, there appears to be a complex interaction between the serotonergic and dopaminergic systems in the regulation of psychomotor activity.
The study of psychological depression and its treatment can also help to illuminate the role of catecholamines in the regulation of behavior. Drugs such as the tricyclic antidepressants and the mono-amine oxidase inhibitors, both of which increase norepinephrine in the synapse, are useful in treating depressed patients. As a result of these observations, it was first concluded that depression resulted from abnormally low activity of the noradrenergic system. It now appears, however, that increasing norepinephrine levels via drug treatment serves to compensate for unknown pathology in depression, affecting other transmitters besides norepinephrine.
These observations are nevertheless informative. It seems probable that norepinephrine, by regulating its own activity, and in concert with other transmitters, plays a role in the relief and prevention of depression if not in the cause of depression. Norepinephrine may regulate mood, level of emotional arousal, sleep/ wakefulness states, and appetite (all of which are often disturbed in depression). However, as mentioned previously, it should be kept in mind that with the advent and demonstrated efficacy of the selective serotonin reuptake inhibitors in the treatment of major depression, the implications of abnormalities within the serotonergic system cannot be ignored.
Autism is a serious psychiatric condition that begins in infancy or early childhood. It is characterized by a qualitative impairment in interaction and socialization. Autistic children appear to be oblivious to their surroundings but ironically can react with a temper tantrum if a single toy is moved from its usual location. They often lack both verbal and nonverbal communication skills. Speech may be limited to repeating a word over and over (perseverations), and they may not even point to something they want in order to obtain it. Autistic individuals exhibit a restriction of activities and engage in a variety of odd behaviors, such as sniffing, twirling and spinning, and inordinate interest in the single function of an object (i.e., staring at a wheel spinning on a toy car for hours). They also sometimes present with violent or self-injurious behavior and temper tantrums. Some patients may possess striking talents beyond their apparent cognitive capacity (often referred to as savant-like traits). A few can masterfully play the piano without ever receiving instructions or memorize an entire city's bus routes.
The pervasive developmental disorders are illnesses that may vary in presentation. They may present with only one feature of autism or most of the features (but by definition not all). Although elevated serotonin levels in whole blood seem to be the most consistent finding in autism, there have been reports of increased norepinephrine levels in the plasma of these children when compared to normal control groups. Additionally, the effectiveness of dopamine-blocking neuroleptics on attention and improvement of certain behaviors in autistic children cannot be ignored. One investigation of biological markers in children with pervasive developmental disorder reported that the group that responded to treatment had lower initial plasma levels ofHVA.
Attention deficit-hyperactivity disorder (ADHD) is characterized by overactivity, fidgetiness, impulsivity, and distractibility. It is more frequently seen in males and there is usually a family history of the disorder. The illness begins in early life but often is not diagnosed until the child is in school because its pathology becomes more evident when more controlled behavior is required. There is strong evidence for the involvement of the catecholaminergic systems in this illness. Prevailing theories propose a decrease in turnover of both dopamine- and norepinephrine-like effects. Oddly, increases in noradrenergic activity in the activating systems of the brain produce emotional arousal and many of the attentional abnormalities of ADHD. In addition, normal adults given the psychostimulants used to treat ADHD in children show the expected activating effects. Interestingly, in the rat, many experimental manipulations have also implicated the dopaminergic system's role in locomotor activity. The quantification of motoric overactivity was directly correlated to two observations within the dopaminergic system. The first was the degree of dopaminergic damage sustained, and the second was onset ofDi receptor supersensitivity.
Despite the fact that much of our knowledge regarding the impact of catecholamines on behavior has come from observations related to medication trials, recent advances in genetic techniques also further our hopes for future breakthroughs. Certain neurological illnesses, such as hereditary progressive dystonia and supranuclear palsies, have been linked to abnormalities in tyrosine hydroxylase gene expression. Pioneering efforts to investigate the genetic components of other neuropsychiatric conditions are under way. Two such illnesses may be schizophrenia and bipolar disorder. In these illnesses, classical modes of inheritance are not evident. However, there is clinical evidence via adoption, twin, and family studies that implicates a hereditary component to these illnesses. Being able to approach this problem from multiple perspectives employing the evolving fields of molecular biology and genetics may eventually result in the identification of the precise genetic deficits and locations of these complicated illnesses. Currently, several research groups are exploring catecholaminergic-re-lated markers in these fields.
The role of catecholamines in substance abuse has received substantial attention. Most drugs of abuse behaviorally work on the premise of being strong positive reinforcers. These include agents such as nicotine, morphine, cocaine, and the amphetamine group. Increased dopamine levels in mesocortical regions have been identified with the use of amphetamines, cocaine, and even nicotine. In the case of cocaine and the stimulants, the increase is produced by blocking the dopamine transporter system. As discussed previously, dopamine has also been implicated in the production of hallucinations. Many of the agents that increase dopamine levels, such as l-dopa, amphetamines, and cocaine, are also capable of inducing hallucinations.
In the realm of stress, many different corporal systems interact to help the human organism respond. There is usually activation of the adrenergic neurons in the hypothalamus. There is a close link between the cortisol and adrenergic response. In fact, increases in norepinephrine induce cortisol-releasing hormone production. Stimulation of the adrenergic nervous system causes elevations in plasma epinephrine and norepinephrine levels. These produce an increase in glucose. Furthermore, epinephrine induces the breakdown of fats from adipose tissues. In these situations, epinephrine and norepinephrine promote increased heart rate and blood pressure. The purpose of these changes is to facilitate the delivery of needed material for fight or flight. Situations often perceived as stressful to the body include strenuous physical exertion, acute anxiety states, and serious cardiovascular compromise.
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