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that there is no mechanism to control either its access to transporters or its removal from transporters. Thus cocaine's effects on signaling are controlled by external factors (dose, frequency of administration) and are not "normal or expected'' by the brain. This must be one of the fundamental reasons why the effects of cocaine are so different and striking, and so powerful.

As noted above, cocaine also potentiates neurotransmission by serotonin and norepinephrine. Although inhibition of uptake of norepinephrine and serotonin are not mainly responsible for the rewarding properties of the drug, these actions do have effects. For example, inhibition of norepi-nephrine uptake contributes to the cardiovascular effects of cocaine. Inhibition of serotonin uptake has complicated effects; and serotonin, at some receptors, inhibits the rewarding effects of cocaine and dopamine. In any case, we are mainly concerned with the ► rewarding/reinforcing/

addicting properties of cocaine which occurs by its action at the DAT.

Involvement of Specific Brain Regions

Cocaine can alter the metabolic activity (which reflects neuronal activity) of many brain regions (Everitt and Robbins 2005; Schmidt et al. 2005). When cocaine is taken the first few times, the ► nucleus accumbens and parts of the ► prefrontal cortex exhibit metabolic changes. But as more cocaine is taken repeatedly over a long time, more regions in the brain are affected as well (Porrino et al. 2007). These include the striatum, ► amygdala, ► hippocampus, and cortical areas. The progression from casual drug use to ► dependence is accompanied by and likely due to this enlargement of the pattern of activity in the brain. These changes in activity are accompanied by changes in proteins, and some of them are

[Owens a Gentry 2002)

Cocaine. Fig. 4. Antibodies can bind drugs before they enter the brain. The right side of the figure shows a brain capillary and brain drug receptors in close proximity. If the drug (shown by a small filled circle) cannot get out of the circulation because it is bound to an antibody ("Y" shaped structure), then the drug cannot have any effect in the brain. On the left side of the figure, injection of antibodies or antigens is shown schematically in a box. With permission of M Owens.

related to dopaminergic neurotransmission. This shift in activity and changes in protein levels likely have implications for treatment. Preventing or blunting the shifts, perhaps by using medications or behavioral treatments or both, could reduce or prevent dependence.

A striking finding is that the changes in brain found in cocaine addicts are long-lasting! It takes many months, perhaps more than a year, for the drug-related changes to revert to normality (Fig. 3). The persistence of these changes in brain over many months likely underlies one of the most striking features of addiction - that it is chronic and relapsing. The drive to take drugs persists over many months, and attempts to stop seeking and taking drugs often meet with failure because the duration and power of the brain changes are sometimes underestimated. This has very important implications for treatment. It seems reasonable to consider that treatments in some form should persist as long as the brain changes persist. This means that treatment in many cases will be a long-term process.

Attempts to Develop Medications for Cocaine Abusers: Small Molecules

A significant effort has been made toward developing medications for cocaine addicts (Vocci and Elkashef 2005). As of this writing (February 2009), no compound has been approved specifically for this purpose, although some existing compounds seem useful in this regard. There are different kinds of medications. When we talk of small molecule medications, we can divide them in roughly two classes - substitutes and blockers. "Substitute'' medications tend to be similar to the drug itself but may also have some different or additional properties that make the medication especially helpful. Blockers simply block the action of the drug but cannot produce its effects.

Substitution therapy has worked reasonably well for opiate abuse (e.g., ► methadone) or ► nicotine abuse (nicotine patch). Hence, a major direction for medications for cocaine use is the development of substitutions. Because DAT is the target of cocaine as described above, many possible substitution medications also target this transporter. While no substitute has yet been approved, there are several possible compounds under consideration. One is RTI-336 (Fig. 1), which is more selective for DAT than cocaine. In other words, it has much less of an effect on serotonin and norepinephrine uptake than it does on dopamine uptake. It also likely enters the brain more slowly than cocaine and has a longer half-life than cocaine. If it passes clinical trials, it will be a new medication for cocaine abuse.

Other dopamine-related compounds under consideration include dopamine D3 receptor partial agonists, and

► disulfuram, an inhibitor of dopamine beta hydroxylase. Aside from DAT inhibitors, which are basically cocaine-substitution medications, there are other neurotrans-mitter-targeted compounds that are very promising. Compounds that enhance ► GABA's actions, such as

► tiagabine, ► toperimate, and baclofen, have been tested and are being pursued. Compounds that have multiple actions such as dual dopamine and serotonin releasers are being studied as well. A stimulant, ► modafinil, may also be promising.

Antibodies as Therapeutic Agents

Antibody therapy for cocaine abusers is an interesting approach. Antibodies (already formed) against cocaine could be injected (passive immunization) to bind to cocaine and prevent it from entering the brain. Alternatively, specially prepared large molecules with many cocaine molecules attached to it could be used as a vaccine (active immunization). In the latter case, antibodies usually take some weeks to reach useful levels in the serum. In both cases, cocaine is bound by antibodies in the serum so that it cannot enter the brain (Fig. 4). An advantage of that approach is that we need not block the action of neuro-transmitters such as dopamine in the brain. Many physiological functions depend on dopamine, and blocking dopamine as a drug abuse therapy would affect all of those physiological functions, and therefore have many side effects. But preventing cocaine from entering the brain with an antibody avoids those problems. This approach has been proven in animal studies where the behavioral effects of cocaine are reduced by the injection of antibodies (Orson et al. 2008).

The utilization of catalytic antibodies is possible in passive immunization procedures. Catalytic antibodies are those that can metabolize and break down cocaine rather than simply bind the cocaine molecule. This is obviously desirable and some progress has been made in this area as well.

This is an experimental approach and no vaccine or antibody preparation has been approved for use in humans yet. However, progress in clinical trials is being made by several companies. But there are still some issues that need to be addressed (Orson et al. 2008). A major issue is being able to induce higher more effective levels of antibodies more reliably.

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