From Abuse to Addiction – The Withdrawal Period Makes the Differenceby Viatcheslav Wlassoff, PhD | July 22, 2015
Drug addiction is hard to beat. Scientists have been on the hunt for the answers for a long time, and it seems they have finally cracked the addiction code. Contrary to popular notion, addiction does not form during the substance abuse phase but during the withdrawal period.
The withdrawal period after a prolonged period of substance abuse triggers changes at the DNA level that lead to addictive behavior. These findings hold hope for countless people who are wondering how they relapsed when they were trying so hard to stay away from drugs.
DNA changes during withdrawal periods
Addictive substances are known to trigger changes in the brain's reward circuits. For a long time, scientists believed that this development could explain why many of those who have a history of drug and alcohol abuse tend to relapse or exhibit drug-seeking behavior after being away from the addictive substance.
To test their hypothesis, scientists conducted several studies. These studies were mostly carried out on cocaine users because cocaine addiction is one of the hardest to beat. A staggering 80% of cocaine users who want to kick their habits experience relapse within six months of withdrawing. However, the findings of the study are equally applicable in cases involving other types of addictive substances like heroin, alcohol, nicotine, and methamphetamine.
According to one study, cocaine users exposed to triggers show increased activity in the ventral tegmental area (VTA) of their brains when they crave cocaine. The VTA sends signals to the medial prefrontal cortex (mPFC) region through networks that use dopamine, the neurotransmitter that is known to play a critical role in "reward" mechanisms.
Scientists have also discovered that brain-derived neurotrophic factor (BDNF) increased significantly in the VTA and mPFC regions of the rat brain when these laboratory animals were made to withdraw from cocaine use after they had been exposed to the substance repeatedly.
BDNF is known to influence and regulate synaptic connections. An elevation in the level of BDNF during the withdrawal period indicates that abstaining from cocaine or any other addictive substance after repeated exposure triggers changes at the DNA level. At this point of time, scientists believed that these DNA changes may cause the formation of addictive behavior. But they did not have definitive evidence.
Scientists in a later study tried to identify a therapeutic approach that would stop this addictive behavior from forming. The genes we inherit remain stable and do not change throughout our lifetimes. However, the expression of these genes may change due to the influence of epigenetic markers like DNA methylation. These markers can switch off, or switch on, or dim the functionality of genes. The researchers suggested that if they found a way to influence the epigenetic markers that are triggered during the withdrawal phase, they could prevent relapse.
In an experiment conducted on laboratory mice, the animals were conditioned to take cocaine when a light was switched on or a particular sound was made. Then they were made to go through a withdrawal period. After a withdrawal period of 30 days, the mice exhibited strong drug-seeking behavior in response to the light cue. However, they did not show this behavior when they were given the epigenetic drug RG108 that inhibits DNA methylation just before they received the light cue. What is more, after just a single dose of RG108 the animals did not exhibit addictive tendencies for many more days.
Alternate treatment methods to prevent relapse
Meanwhile, other scientists have been exploring alternate ways to prevent incidences of relapse in cocaine users during the withdrawal period. For instance, one group of scientists explored if drug-seeking behavior or a relapse can be prevented if the brain cannot remember the feelings of pleasure associated with the use of cocaine when presented with drug-related cues during the withdrawal phase.
Propranolol, a beta blocker, can prevent the brain from remembering memories associated with cocaine use. Propranolol is used to manage the symptoms of anxiety and hypertension. According to the scientists involved in the study, this beta blocker can be used in conjunction with exposure therapy to enhance therapeutic effectiveness.
Exposure therapy is a practice where recovering addicts are repeatedly exposed to craving-inducing cues. But their cravings are not satisfied. After undergoing this therapy for a certain length of time, the patients no longer experience cravings, even in the presence of the craving-inducing stimuli.
Scientists are hopeful that propranolol can boost the efficacy of the exposure therapy because there have been instances where this drug was successfully used to manage certain withdrawal symptoms in cocaine addicts undergoing the therapy.
Insights from the current findings
The above findings clearly point to a critical flaw in the prevailing therapeutic methods to manage and cure addiction. Certain widely-prescribed therapeutic methods target only a few areas of the brain of recovering addicts and not necessarily the areas that the above studies have found to be instrumental in preventing relapses. This is not an effective ploy.
What is more, scientists believe that therapists and counselors should take note of the fact that drug-seeking behavior in response to specific cues during the withdrawal period tends to increase for the first two months and starts to decrease after six months. So the treatment approach should be paced accordingly and patients should be encouraged to continue the program and not leave it midway.
Addiction is a complex neural mechanism. What makes it more challenging to treat is that several areas of the brain work in tandem to trigger and sustain addictive tendencies. The above-mentioned findings are groundbreaking because they bust many previously-held theories.
Li, X., DeJoseph, M., Urban, J., Bahi, A., Dreyer, J., Meredith, G., Ford, K., Ferrario, C., Loweth, J., & Wolf, M. (2013). Different Roles of BDNF in Nucleus Accumbens Core versus Shell during the Incubation of Cue-Induced Cocaine Craving and Its Long-Term Maintenance Journal of Neuroscience, 33 (3), 1130-1142 DOI: 10.1523/JNEUROSCI.3082-12.2013
Lu, H., Cheng, P., Lim, B., Khoshnevisrad, N., & Poo, M. (2010). Elevated BDNF after Cocaine Withdrawal Facilitates LTP in Medial Prefrontal Cortex by Suppressing GABA Inhibition Neuron, 67 (5), 821-833 DOI: 10.1016/j.neuron.2010.08.012
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Massart, R., Barnea, R., Dikshtein, Y., Suderman, M., Meir, O., Hallett, M., Kennedy, P., Nestler, E., Szyf, M., & Yadid, G. (2015). Role of DNA Methylation in the Nucleus Accumbens in Incubation of Cocaine Craving Journal of Neuroscience, 35 (21), 8042-8058 DOI: 10.1523/JNEUROSCI.3053-14.2015
Otis, J., & Mueller, D. (2011). Inhibition of ?-Adrenergic Receptors Induces a Persistent Deficit in Retrieval of a Cocaine-Associated Memory Providing Protection against Reinstatement Neuropsychopharmacology, 36 (9), 1912-1920 DOI: 10.1038/npp.2011.77
Pickens, C., Airavaara, M., Theberge, F., Fanous, S., Hope, B., & Shaham, Y. (2011). Neurobiology of the incubation of drug craving Trends in Neurosciences, 34 (8), 411-420 DOI: 10.1016/j.tins.2011.06.001
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