Dopamine

The Parkinson's-Reversing Breakthrough

Is There A Cure for Parkinson Disease

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Dopamine, once an inconspicuous intermediate in the biosynthesis of norepinephrine, is now the most widely researched catecholamine. During the late 1950s, Carlsson utilized a variety of experimental approaches that demonstrated the presence of dopamine in the brain and its function as a neurotransmitter.

Three dopaminergic pathways are present in the brain: The nigrostriatal pathway contains three-quarters of brain dopamine, has cell bodies originating in the substantia nigra and terminating in the corpus striatum, and is associated with motor control. The mesolimbic-mesocortical pathway, with cell bodies in the ventral tegmental area and projections to the limbic system, is involved with behavior, more specifically, reward and addiction; defects in this system may account for some of the symptoms of schizophrenia. The cell bodies of the tuberoinfundibular pathway originate in the ventral hypothalamus and terminate in the anterior pituitary gland, and its activation is responsible for inhibition of the release of prolactin from the anterior pituitary [1,2,8].

Based on their pharmacological and structural properties, five subtypes of dopamine receptors have been identified, and these have been grouped into two families: D1-like, which includes D1 and D5, and D2-like that consists of D2, D3, and D4 subtypes. The two families are present in common (striatal) and distinct regions of the brain. Each of these subtypes is a G-protein transmembrane receptor. Activation of D1 receptors stimulate adenylyl cyclase leading to the formation of cAMP by activating the stimulatory G protein Gs, while the D2 receptors inhibit adenylyl cyclase and cAMP levels by activating the inhibitory G protein Gi [1-2].

Carlsson detected high levels of dopamine in the basal ganglia. Depletion of dopamine in the substantia nigra with reserpine caused Parkinsonian symptoms, which were alleviated by administration of the dopamine precursor levodopa. (This is a classic example of replacement therapy). Unlike dopamine, levodopa crosses the blood-brain barrier, making it useful for the treatment of this neurological disorder. Other drugs used for the treatment of Parkinson's disease include those that are dopamine agonists (bromocriptine, pergolide) and inhibitors of dopa decarboxylase (carbidopa), MAO-B (selegiline) or COMT (entacapone), enzymes that catalyze the inactivation of levodopa or dopamine [9-10].

The development of antiparkinson drugs was based on a rational approach, namely, determination of the neurochemical defect in the disorder followed by treatment with specific drugs that corrected the defect. By contrast, drugs possessing antipsychotic effects were first found to be clinically effective and, based on their effects, neurobiological theories were subsequently formulated that sought to explain the cause(s) of schizophrenia.

The first "typical" antipsychotic drugs, chlorpromazine and haloperidol, appeared in clinics in the mid-1950s and 1960s. These prototypes were followed by some dozen drugs that were more similar than different in their wide spectrum of receptor interactions and adverse neurological effects [11]. In 1976 Seeman noted a striking correlation between the clinical potency of antipsychotic drugs (expressed as the average daily dose used to treat schizophrenia) and their activity in binding to and blocking the D2- receptor in the striatum in vitro [12]. These findings, linking an increased functional activity of dopamine and schizophrenia, were reinforced by the observations that the dopamine-releaser amphetamine elicits stereotyped behavior in animals analogous to that seen in some psychotic patients, and high doses of amphetamine can cause a psychotic-like state in humans. Moreover, the D2-receptor agonists apomorphine and bromocriptine have been shown to worsen the symptoms of schizophrenic patients. When coupled with other clinical findings, it appears that D2-receptor antagonist antipsychotics are more effective in treating the positive symptoms of schizophrenia than the negative or cognitive symptoms.

Clozapine is an effective antipsychotic drug that has a different spectrum of pharmacological effects and is devoid of the extrapyramidal side effects that plague the chlorpromazine (phenothiazine) and haloperidol (butyrophenone)-like drugs. With the appearance of clozapine, the prototype of a series of "atypical" antipsychotic drugs introduced in the United States in 1989, this weak D2- receptor blocker and potent serotonin 5-HT2A antagonist, has undermined the earlier focus on dopamine as the exclusive cause of schizophrenia [11,13].

One of our greatest societal challenges deals with a better understanding of the nature of drug dependence and more effective approaches to its treatment. Drugs capable of producing a dependent state and their compulsive use, such as opioids, cocaine, amphetamines, nicotine, and alcohol, produce different behavioral effects. However, they appear to share a common link, namely, all these drugs activate the mesolimbic dopaminergic pathway leading to a release of dopamine in the nucleus accumbens. Activation of this pathway is thought to be responsible for the rewarding or positive reinforcing effects of these drugs and their continued use. (Compulsive gambling and sexual behavior may be added to this list). Chemical or surgical interference with this dopamine pathway reduces the rewarding properties of such drugs [14]. As noted above for schizophrenia, serotonin may also play a role in mechanisms of reward.

Attention-deficit-hyperactivity disorder (ADHD), makes its appearance in childhood, and is characterized by increased motor activity and impulsive behavior and difficulty in maintaining attention and focus. Recent evidence suggests that ADHD may result from reduced levels of dopamine in the hippocampus and amygdala. Amphetamines and methylphenidate increase the postsynaptic levels of dopamine and have long been used to effectively treat ADHD [15]. Dopamine inhibits prolactin release, and D2-antagonist antipsychotic drugs stimulate lactation, a side effect seen even in male patients. There are many physical and chemical causes of nausea and vomiting. Drugs that enhance dopaminergic activity, such as those used to treat Parkinson's disease, cause emetic effects, while dopamine antagonists, including some antipsychotics and metoclopramide, have antiemetic properties.

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Understanding And Treating ADHD

Understanding And Treating ADHD

Attention Deficit Disorder or ADD is a very complicated, and time and again misinterpreted, disorder. Its beginning is physiological, but it can have a multitude of consequences that come alongside with it. That apart, what is the differentiation between ADHD and ADD ADHD is the abbreviated form of Attention Deficit Hyperactive Disorder, its major indications being noticeable hyperactivity and impulsivity.

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