Prozac transporters

Atomoxetine (Straterra , originally tomoxetine or tomoxetin, 3) was first described and synthesized by chemists at Eli Lilly in the late 1970s and was one of the few compounds that was known to display meaningful selectivity for the norepinephrine reuptake transporter (NET) versus the serotonin reuptake transporter (SERT) and the dopamine reuptake transporter (DAT) (Barnett, 1986 Molloy and Schmiegel, 1997). Atomoxetine was one of several structurally related and commercially successful monoamine reuptake inhibitors that were developed by Lilly for the treatment of various psychiatric disorders (Eig. 17.4). Fluoxetine (43) and duloxetine (44) have both gained approval in the United States as Prozac and Cymbalta , respectively, and nisoxetine (45) is widely used as a tool in biology. 

The problem is that all drugs exert a number of different effects, some of which are wanted and some of which are not (the side effects). In researching the activity of fluoxetine (Prozac), scientists noticed a discrepancy between the time the drug acts on serotonin transporters and the time at which the patient s symptoms are relieved. Many patients do... 

Some naturally occurring neurotransmitters may be similar to drugs we use. For example, it is well known that the brain makes its own morphine (i.e., beta endorphin), and its own marijuana (i.e., anandamide). The brain may even make its own antidepressants, it own anxiolytics, and its own hallucinogens. Drugs often mimic the brain s natural neurotransmitters. Often, drugs are discovered prior to the natural neurotransmitter. Thus, we knew about morphine before the discovery of beta-endorphin marijuana before the discovery of cannabinoid receptors and anandamide the benzodiazepines diazepam (Valium) and alprazolam (Xanax) before the discovery of benzodiazepine receptors and the antidepressants amitriptyline (Elavil) and fluoxetine (Prozac) before the discovery of the serotonin transporter site. This un-... 

FIGURE 2—22. If an inhibitor of the transport carrier binds to its own binding site, it prevents neurotransmitter molecules from being able to bind to their sites. This figure shows an antidepressant, fluoxetine (Prozac), binding to the serotonin transporter. When this drug binds to the serotonin transporter, it essentially bumps serotonin neurotransmitter molecules out of their seats on the transport carrier. This causes inhibition or blockade of neurotransmitter transport into the neuron. Sodium binding is also decreased, and the tires go flat, so that transport is halted. 

FIGURE 2-24. Shown here is how the antidepressant fluoxetine (Prozac) disrupts neurotransmitter from shuttling into the neuron. In this case, binding of the transport carrier by fluoxetine prevents serotonin neurotransmitter molecules from taking a seat on the shuttle. Thus, there is no ride for the serotonin into the neuron. This means that the neurotransmitter serotonin remains in the synapse until it diffuses away or is destroyed by enzymes. 

When antidepressants block the function of the transporter system, Wegerer et al. (1999) found, the transporter system grows strong in response by increasing in density. This effect was found in young rats after only 2 weeks of exposure to Prozac. 

Figure 3.1 How Prozac (fluoxetine) blocks reuptake of serotonin. Normally the serotonin reuptake transporter carries serotonin back into the neuron. Prozac binds to the transporter, causing serotonin to build up outside the neuron.

Cocaine inhibits the transporters for norepinephrine, serotonin, and dopamine. Binding of cocaine to the dopamine transporter Inhibits reuptake of dopamine, thus prolonging signaling at key brain synapses indeed, the dopamine transporter Is the principal brain cocaine receptor. Therapeutic agents such as the antidepressant drugs fluoxetine (Prozac) and imipramlne block serotonin uptake, and the tricyclic antidepressant desipramine blocks norepinephrine uptake. I... 

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