f brain monoamine metabolism. These amines include norepinephrine, dopamine, and serotonin. The involvement of catecholamines in the pathogenesis of depression was invoked as early as 1965. A de.ciency in brain serotonin was theorized in 1967, while a role for dopamine in depression was for-mally proposed in 1975. The drugs that are used to treat depression basically act to increase neurotransmitter concentration in the synaptic Cheap Generic Cialis Cheap Generic Cialis cleft either by (1) decreasing neurotransmitter degradation or (2) inhibiting neurotransmitter reuptake. An example of a class of drugs that interrupt neurotransmitter degradation is the monoamine oxidase (MAO) inhibitors. MAO is a mitochondrial enzyme that exists in two forms (A and B). Its major Is Cialis Addictive Is Cialis Addictive role is to oxidize monoamines such as norepinephrine, serotonin, and dopamine by removing the amine grouping from the neurotransmitters. Under normal circumstances, MAO acts as a �safety valve� to degrade any excess transmitter molecules that may spill out of synaptic vesicles when the neuron is in a resting state. MAO inhibitors prevent this inactivation. In their presence, Achat Cialis Achat Cialis any neurotransmitter molecules that leak out of the synaptic vesicles survive to enter the synapse intact. Receptors are thus exposed to a greater amount of the neurotransmitter. Several clinically utilized MAO inhibitors such as phenylzine and tranylcypromine are irreversible inhibitors of both MAO-A and MAO-B What Is Cialis What Is Cialis (presumably via covalent � 1997, 2003 Taylor & Francis binding). The irreversible inhibition of MAO means that neurons so affected must synthesize new enzyme before normal biological activity is reestablished. Research indicates that the antidepressant effect of these drugs is primarily due to inhibition of MAO-A. Relatively new MAO inhibitors are of the reversible type and include moclobemide. MAO inhibitors were the .rst widely used antidepressants, but because of various undesirable side effects they are employed today in only a more limited number of cases. People who are treated with MAO inhibitors, for example, must be careful of their diet. They should not eat food rich in tyramine or other biologically active amines. These foods include cheese, beer, and red wine. Individuals on MAO inhibitors are unable to inactivate tyramine present in the food. Because tyramine causes the release of endogenous norepinephrine, patients are susceptible to increased blood pressure (e.g., potential Buy Cheap Cialis With Dr. Prescription Buy Cheap Cialis With Dr. Prescription lethal cerebral hemorrhages) and cardiac arrhythmias. Fortunately, another group of antidepressant drugs was developed to take the place of MAO inhibiters. These drugs are called tricyclics, because all have chemical structures resembling a three-ring chain. Imipramine was the .rst of the tricyclic antidepressants (TCAs), No Rx Cialis No Rx Cialis synthesized as a �me-too� follow-up to chlorpromazine. All TCAs inhibit the presynaptic reuptake of the monoamine neurotransmitters norepinephrine and serotonin. By inhibiting reuptake more neurotransmitter is left in the synaptic cleft, thus potentiating their effects. The relative effect on serotonin or norepinephrine reuptake inhibition varies from one TCA to another. In addition to the blockade of neurotransmitter uptake, most TCAs have direct af.nities for several heterogeneous receptors. As scientists improved their techniques for detecting low levels of amines, they began to measure the amine concentrations in postmortem human brains. Several researchers measured levels of serotonin and norepinephrine in the brains of people who had com-mitted suicide as a result of depression and compared the levels to individuals of the same age who had been killed in accidents. The suicides� brains had lower levels of serotonin. Subsequent studies also revealed that certain depressed patients had lower levels of serotonin metabolites in their cerebrospinal .uid. These .ndings accelerated the effort to develop drugs that would be effective on serotonergic neurons. This new class of antidepressants, with relatively few side effects, is the selective serotonin reuptake inhibitors (SSRIs). This group of compounds has a selective effect on the presynaptic reuptake of serotonin and has assumed the role of .rst-line anti-depressant agents in the management of depression. Most SSRIs have only modest clinically relevant effects on other brain systems. As such, their clinical pro.le is primarily a re.ection of their effect in enhancing the synaptic availability of serotonin. The prototypic drug in this class is prozac, which has received considerable publicity since its entry into the market. Fortunately, initial concerns relating to increased suicide risk have not been con.rmed with larger clinical trials. As the name of this class of drugs implies, the mechanism by which they work to alleviate depression is by selectively blocking the reuptake of serotonin. Mania While neuroleptics can effectively treat the depression present in bipolar disorder, the metal ion lithium exerts a therapeutic effect on the other aspect; it relieves the � 1997, 2003 Taylor & Francis symptoms of mania. For many years the only treatment for mania was sedation. Before the advent of neuroleptics, manic patients typically received large doses of barbiturates that simply rendered them unconscious. When they woke up, their manic behavior would take up where it had left off. Later, psychiatrists preferred to pre-scribe sedating neuroleptics, such as chlorpromazine, for their manic cases because those drugs did not put the patients to sleep, but while chlorpromazine effectively hampers a maniac�s activity it does not affect the underlying disorder. In contrast to neuroleptics, the simple metal lithium, introduced to psychiatry in the mid-1960s, truly aborts the manic condition. Unlike the neuroleptics, lithium does not cause sedation, nor does it transform mania into depression. Instead, it appears to restore the patient to a normal state of mind. The calming effect of lithium was discovered by accident in a .awed experiment during the 1940s. While investigating whether urine from manic patients contained some toxic nitrogenous substances (uric acid), John Cade, an Australian psychiatrist, mixed uric acid with a number of metals to increase solubility. When lithium urate was administered to guinea pigs they appeared to be calmed. Cade then tested lithium in another salt, lithium carbon-ate, to determine whether the key factor in the �calming effect� was the uric acid or the lithium. This lithium also �calmed� the guinea pigs. Impressed with these results he proceeded with experiments to administer lithium salts to manic patients in the clinic. We now know that there is nothing abnormal about the urine of manic patients. In all probability, lithium appears to calm guinea pigs only because it makes them sick. Nevertheless, his clinical results were suf.ciently positive that Cade published the results in an obscure Australian journal in 1949. In 1954, a Danish psychiatrist con.rmed Cade�s .ndings and the use of lithium began to spread in Europe. It was not until the mid-1960s, however, that lithium was marketed commercially in the United States, but it was not used for the treatment of mania until 1970. The precise mechanism of action of lithium remains unknown. Methylphenidate (Ritalin�) One of the most controversial CNS-acting drugs in contemporary society is methylphenidate (Ritalin�). This drug is structurally related to amphetamine and is a �mild� stimulant that has abuse potential similar to amphetamine. Methylphenidate is classi.ed as a Schedule II controlled substance. It is effective in the treatment of narcolepsy and attention-de.cit hyperactivity disorder (ADHD). Its use in ADHD has caused the greatest controversy. ADHD is a frequently diagnosed disorder particularly among juveniles, boys being diagnosed at three to four times the rate of girls. Symptoms are generally thought to include inappropriate levels of attention and concentration, inappropriate levels of distractibility and impulsivity of some sort, and a combination of both of these. A psychologist, psychiatrist, or pediatrician typically diagnoses the condition but diagnostic methods remain controversial. Since 1990, the number of American children taking Ritalin has more than dou-bled to between 1.5 million and 2.5 million. Defenders of the drug give testament to the profound effect it can have in turning problem adolescents into model students. � 1997, 2003 Taylor & Francis Proponents point to studies showing that 75 percent of children on Ritalin experi-ence positive effects. Opponents label the drug as �kiddie cocaine� and assert that the current state of ADHD diagnosis and treatment is tenuous at best. Undoubtedly, the truth lies somewhere in between, with the proper diagnosis being the key. It is a diagnosis that really did not exist prior to the late 1970s to early 1980s. A correct diagnosis is basically rati.ed when the medication works. One of the unfortunate realities of Ritalin use has been its propensity for abuse. A number of studies have revealed that grade-schoolers have obtained the drug from their peers who are undergoing therapy for ADHD. In one study published in 2001, 651 students aged 11�18 from Wisconsin and Minnesota were focused on. The researchers found that more than a third of the students who took ADHD medica-tion said they had been asked to sell or trade their drugs. Users have crushed the pills and snorted the powder in order to get a �cocaine-like� rush. It is hoped that newer-generation products, e.g., time-release medications, will be less prone to this abuse since their formulation makes them more dif.cult to crush. Curare Curare is a natural product isolated from trees and bushes of the Strychnos and Chondodendron geni. The active principle (d-tubocurarine) is a water-soluble and heat-stable alkaloid that can be extracted, heated, and concentrated to produce a pasty residue containing a high concentration of curare. This extract has been used for centuries in South America as an �arrow poison.� Curare