Dopamine circuits are more specific and better organized than NE and
serotonin systems. Dopamine neurons are involved in controlling movement,
regulating memory, sexual and reward-seeking behaviors and the regulation of
pituitary hormones. Increased dopamine activity is associated with
Decreased dopamine activity in a specific movement controlling circuit
originating from cells in the substantia nigra are associated with Parkinson's
disease. Slowing of thinking and movement and depression often precede the more
obvious movement disorder which characterizes the disease. The main treatment
has been to replace the missing dopamine with l-Dopa (levodopa). With time and
disease progression, however, dopamine replacement becomes less efficacious and
new adverse effects, including the development of motor fluctuations and
drug-induced involuntary movements (dyskinesias) emerge.
When dopamine is slightly modified to 6-hydoxy dopamine, it becomes a potent
neurotoxin that can kill dopamine producing neurons. The toxicity of
6-hydroxydopamine involves the generation of reactive oxygen radicals, the
impairment of mitochondrial function, and enzyme inhibition. Antioxidants,
including catalase, vitamin E, and ascorbic acid, provided protection against
Liao et al suggested that: Formation of 6-hydroxydopamine (6-OHDA) in the
striatum following methamphetamine treatment plays a role in
methamphetamine-induced nigrostriatal dopaminergic toxicity. Inhibiting both
monoamine oxidase with pargyline and catechol-O-methyl-transferase with
pyrogallol lead to an accumulation of 6-OHDA in the striatum; this effect
was increased by the addition of methamphetamine which is a potent dopamine
Increased dopamine activity in the brain stem will cause unpleasant symptoms
suggesting digestive tract problems - nausea, vomiting, hiccups, excessive
salivation and a burning tongue. Increased dopamine in the motor circuits will
tend to produce odd, involuntary movements, muscle twitching and bizarre
posturing. Early signs of increased dopamine activity include agitation with
critical, suspicious thinking and depression. Increased sexual drive and
antisocial aggression may occur with disordered arousal.
Dopamine and Schizophrenia
All discussions of schizophrenia should begin with the recognition is that
the diagnosis is often uncertain and covers a range of disorders that have
different causes and different consequences. The focus has been on dopamine
neurons and drugs that block dopamine. Few people with the diagnosis
escape drug treatment and psychiatrists generally believe that schizophrenics
have to take drugs every day for the rest of their lives. This is an irrational
belief that obstructs the study of the natural course of the disorder and
prevents the discovery of better methods of management. You can argue two ways:
1. Drugs used to treat schizophrenics are wonderful inventions that control
the disease and allow patients to live in the community.
2. Antipsychotic drugs are chemical straight-jackets that are toxic and leave
patients more disabled than they would have been if no drugs were ever used.
A corollary to argument 2 is that if other solutions were developed for
schizophrenics, such as diet revision, nutrient supplementation, and
rehabilitation in natural settings, better long-term results may be achieved.
Phenothiazines were the first drug class available to treat schizophrenia.
They were called antipsychotics, major tranquilizers, and neuroleptics.
Chlorpromazine was the grand-daddy drug and numerous offspring were developed
and marketed. These drugs have multiple modes of action and the antipsychotic
effect is attributed to dopamine blocking. With long term use, drug-induced
Parkinson's disease is a major, disabling adverse effect.
Kapur suggests that
delusions develop when excessive dopamine release occurs in response to mundane
events. Delusions are the stories that patients construct to explain increased
salience of common events. Antipsychotic drugs block dopamine-2 neuroreceptors
and reduce the salience of ordinary experiences: the patient may say that the
government continues to spy on him, but that it doesn't bother him anymore. Kapur
claims that resolution of symptoms occurs within the first week of antipsychotic
All early antipsychotics inhibit dopamine (DA) neurotransmission by blocking
postsynaptic DA receptors. Other neurotransmitter systems, such as those for
serotonin (5-HT), glutamate, noradrenaline and acetylcholine, are also
implicated, and atypical antipsychotics are also antagonists of serotonin (5-HT)
receptors. Blocking DA receptors in some brain regions is also responsible for
negative effects such as Parkinson's effects and hormonal changes.
Excessive Use of Dopamine Blocking Drugs
Newer dopamine-blocking antipsychotic drugs are prescribed inappropriately
and excessively to children and elderly patients. The “atypical antipsychotics,”
clozapine, olanzapine, quetiapine and risperidone have all been used to treat
elderly patients, especially those with dementia. There is no evidence
that any of these drugs will alleviate dementia in any way. They are used, for
example, as “chemical straight jackets” to immobilize nursing home residents.
Among the problems created by these drugs are Parkinson’s disease, weight gain,
hyperglycemia and diabetes 2. Janssen-Ortho, the company that markets Risperdal
(risperidone), issued drug safety information bulletin [i]
linking the drug to increased risk of strokes in elderly patients. Since there
is significant doubt that this drug should be used in any elderly patients, the
increased risk of diabetes and stroke is a definitive contraindication. The
strength of the association between antipsychotics and diabetes varies. A number
of reports implicate chlorpromazine, clozapine, and olanzapine. An Ontario study
involving 20,000 patients in nursing homes revealed that 25% of the residents
are prescribed antipsychotic medications within the first year of admission.
[i] Janssen-Orthos. Risperdal and Cerebrovascular
adverse events in Placebo-controlled dementia trials. Letter Oct. 11, 2002
[ii] Murray, T. Antipsychotic use high in Ont. Nursing
homes. Medical Post May 25, 2004. Reporting on a study by researchers at the
Institute for Clinical Evaluative Sciences in Toronto, Ontario, conducted
between 1998 and 2000.
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