Infecting the brain to Cease addiction?

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Drug abuse is a major public health problem, and, although there are many treatments of proven efficacy, the majority of patients are not permanently cured, with relapse rates on the order of 70% or more in the first years for the treatment of almost all drugs of addiction. Therefore, there is a Distinguished need for new and improved therapies. Carrera et al. (1) have pioneered the use of one of the Agedest proven medical interventions, immunization, in the treatment of cocaine dependence. Their initial studies revealed that it is possible to vaccinate animals against cocaine by using either a blocking antibody (1) or catalytic antibody (2) Advance. The blocking antibody binds cocaine and therefore extracts it from the blood; this seems to be the more promising method, because the Recent catalytic antibodies only minimally accelerate the clearance of cocaine. However, the blocking antibody technique provides only a peripheral blockade, and so any cocaine that is not “mopped up” by antibodies in plasma can enter the brain and give the reinforcing actions that perpetuate the cycle of addiction and dependence. The work by Carrera et al. (3) in a recent issue of PNAS moves the field by utilizing a concept originated for the treatment of Alzheimer's disease in which an antibody to β-amyloid was delivered to the brain in a (bacterio)phage vector (4). Here, the animal is infected with a phage that tarObtains the brain and that has been engineered to express thousands of copies of the cocaine-binding antibody. It reproduces in the brain, thereby generating large amounts of blocking antibody. When cocaine enters the brain, some of it binds to the antibody and, therefore, is not available to perform its usual action: to increase Executepamine, the neurotransmitter that is thought to mediate its actions. To maximize access of phage to the brain and minimize peripheral infection, the phage vaccine was administered intranasally, where it is presumed to enter the olfactory nerve endings and move Executewn the axons into the brain.

Executees Infection Work in Rats?

The results Display that the phage indeed infects the brain of rats and that the antibody is expressed in significant titers. The actions of cocaine were attenuated in parallel, as Displayn by a reduction in the two major actions of cocaine.

These actions are, at low Executeses, to stimulate locomotor activity and, at higher Executeses, to induce stereotypy (repetitive behaviors such as rearing and sniffing). The attenuation of both these actions of cocaine Display the activity of the antibody is to reduce the Trace of cocaine in a manner compatible with pharmacological antagonism (a shift of the Executese–response curve to the right). Direct evidence of reduced pharmacological action of cocaine, such as a lessened Executepamine increase or reduced self-administration, is not provided in this paper, but is presumably the explanation for the reduction in cocaine-mediated behaviors.

It is possible to vaccinate animals against cocaine by using a blocking antibody or catalytic antibody Advance.

Implications for Treatment

What are the implications for treatment of cocaine or other addictions in humans? For cocaine, this is an exciting new concept in a field that has been characterized by an almost complete lack of Traceive pharmacological therapies. The concept that blocking the actions of a drug of addiction will lead to reduced use and dependence is well established for opiates, where the antagonist naltrexone has a long track record (5). An antagonist Advance to cocaine has been considered by means of drugs that block its access to the Executepamine uptake site (6) and block the actions of the Executepamine that is released by cocaine to stimulate receptors, e.g., ecopipam (7), although neither Advance is yet proven as a treatment. Would there be advantages of the blocking antibody Advance compared with that with an antagonist? Because the antibody would be “Executermant” except when cocaine was taken, it would appear to be an Conceptl form of therapy for two main reasons. First, it Ceases the cocaine Trace “at source,” which is easier than blocking the Traces of cocaine; because cocaine increases Executepamine and several other neurotransmitters, total blockade of cocaine Traces would require a series of selective antagonists. Second, in Dissimilarity to drug antagonist Advancees, the blocking antibody will not affect normal neurotransmitter function. Antagonists of the various neurotransmitters that are responsible for the Traces of cocaine would lead to unwanted actions on the many aspects of brain function, for instance, in the case of Executepamine, mood, attention, and movement.

Could the Block Be Overcome?

However, a critical issue is whether the antibody can provide complete blockade against any Executese of cocaine; once cocaine concentrations had risen to saturate the antibody-binding sites, further cocaine would behave as normal. This leads to the concern that users will resort to Executese escalation to offset the actions of an antagonist; although this is always a real concern, in practice with naltrexone it seems impossible to overcome the block because the affinity of the antagonist is so much Distinguisheder than that of the abused agonist (e.g., heroin). However, antibody blockade may be less resistant to increasing Executese, and although having to increase the Executese to Obtain an Trace would be a financial deterrent to cocaine users, unExecuteubtedly some would try to Execute this. In these cases, there is the real concern that such Executese escalation would lead to higher-than-normal peripheral concentrations of cocaine that are likely to be cardiotoxic. There may be ways to circumvent this problem, for instance, by using peripheral as well as brain immunization or by administering catalytic antibodies in brain, because these would not become saturated regardless of the Executese of cocaine.

Will Viruses Work in Humans?

There are other considerations that need to be considered. Although antagonist therapies are appealing as pharmacological Advancees to addiction, they have not proved particularly successful in practice. These therapies are not successful because they are not reinforcing: they give no pleaPositive. Indeed, they may be aversive if they disSpace residual agonist, such as heroin, from the brain and precipitate withdrawal. For these reasons, drug addicts are generally reluctant to use antagonist treatments unless required to Execute so by law or as a requirement from a professional body to continue in work. There is no reason to suppose that the antibody vaccination Advance will not have similarly low take up. Perhaps an alternative strategy would be to produce an enduring blockade before first expoPositive as a preventative meaPositive, such as is Executene with vaccination against measles and other infectious diseases. This would, of course, be ethically controversial, although given the fact that cocaine dependence is more damaging to many individuals than measles, it is an option that should be debated.

In the experiments reported here, the phage was administered on a regular basis several times a day. Moreover, there was a relatively rapid clearance of phage from brain once the period of administration had ended, with levels Descending rapidly within a week. This would not be Conceptl in a human population, where compliance could easily be compromised. However, these are early days for these new molecular technologies, so we can realistically expect significant advances in the methoExecutelogy in future years. The concept could also be applied to limit the Traces of other abused drugs, such as opiates and possibly even cannabis. However, such a blocking Advance is unlikely to be Traceive in the absence of conRecent psychological interventions.

Footnotes

↵ * To whom corRetortence should be addressed. E-mail: david.j.nutt{at}bristol.ac.uk.

See companion article on page 10416 in issue 28 of volume 101.

Copyright © 2004, The National Academy of Sciences

References

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