Neurotransmitters Can Also Function As Epigenetic Marks
The most common epigenetic marks involve methylation of DNA (which usually inhibits gene transcription) and the acetylation and methylation of histones. Acetylation opens or loosens the winding of DNA around the histones and facilitates transcription, while methylation of histones leaves the DNA tightly wound and inhibits transcriptional activation.
Researcher Ashley E. Lepack and colleagues have identified a surprising type of epigenetic mechanism involving neurotransmitters. They report in a 2020 article in the journal Science that neurotransmitters such as serotonin and dopamine can act as epigenetic marks. Dopamine can bind to histone H3, a process called called dopaminylation (H3Q5dop). In rats undergoing withdrawal from cocaine, Lepack and colleagues found increased levels of H3Q5dop in dopamine neurons in a part of the midbrain called the ventral tegmental area (VTA), a part of the brain’s reward system. When the investigators reduced H3Q5dop, this decreased dopamine release in the reward area of the brain (the nucleus accumbens) and reduced cocaine seeking. Thus, dopamine can be both an important transmitter conveying messages between neurons and a chemical mark on histones that alters DNA binding and transcriptional regulation.
Researcher Jean-Antoine Girault provided commentary on the article by Lepack and colleagues, writing that “[t]he use of the same monoamine molecule as a neurotransmitter and a histone modification in the same cells illustrates that evolution proceeds by molecular tinkering, using available odds and ends to make innovations.”
Editor’s Note: Epigenetic marks may remain stable and influence behavior over long periods of time. They are involved in the increased reactivity or sensitization to repeated doses of cocaine through DNA methylation. Such sensitization can last over a period of months or longer. If the methylation inhibitor zebularine is given, animals fail to show sensitization. Now a newly identified epigenetic process, dopaminylation, is found to alter histones and is associated with long-term changes in cocaine-seeking.
The clinical message for a potential cocaine user is ominous. Cocaine not only creates a short-term “high,” but its repeated use rewires the brain not only at the level of changes in neurotransmitter release and receptor sensitivity, but also at the genetic and epigenetic level, changes that could persist indefinitely.
The sensitization to motor hyperactivity and euphoria that occur with cocaine use can progress to paranoia and panic attacks and eventually even seizures (through a process known as kindling).
The dopaminylation of histones in the VTA could lead to persistent increases in drug craving and addiction that may not be easily overcome. Thus, the appealing short-term effects of cocaine can spiral into increasingly adverse behaviors and drug-seeking can become all consuming. While these adversities do not emerge for everyone, the best way to ensure that they do not is to avoid cocaine from the start.
Manic episodes that include a feeling of invincibility, increased social contacts, and what the DSM-5 describes as “excessive involvement in pleasurable activities that have a high potential for painful consequences” are a time that many are at risk for acquiring a substance problem. For the adolescent who has had a manic episode, ongoing counseling about avoiding developing this type of additional long-term, difficult-to-treatment psychiatric illness could be lifesaving. Describing the epigenetic consequences of substance use may or may not be helpful, but may be worth a try.
Disrupting Memories of Cocaine Use Might Prevent Relapse
Cocaine users who want to abstain from the drug may find that encountering people or places who remind them of past cocaine use can increase their cravings for the drug and lead to relapse. Researchers are studying animals to see if disrupting the link between an environmental cue and the memory of cocaine’s effects could reduce cravings for the drug.
In a 2016 article in the journal Neuropsychopharmacology, researcher Melissa S. Monsey and colleagues reported that in rats, the amnesia-causing natural compound garcinol can weaken the cues that lead to a cocaine-seeking. Garcinol is derived from the rind of kokum (or Garcinia indica) fruit, which is native to the west coast of India.
Monsey and colleagues delivered the garcinol during a period when the rats’ brains were reconsolidating memories that linked an environmental cue with the pleasurable effects of cocaine.
For 12 days, the rats in the study could press a lever and receive an intravenous infusion of cocaine that was paired with a light and a sound. Then the lever stopped working for 8 days. Next, the researchers observed how the rats behaved when the light and sound returned.
The light and sound were meant to remind the rats of the previous times they received cocaine, prompting their brains to reconsolidate the memory linking the light/sound with the pleasurable effects of cocaine.
Half of the rats were given an injection of garcinol during this memory reconsolidation period. While all of the rats continued to seek out cocaine, in the garcinol-treated rats, the light/sound was no longer linked to cocaine. Their cocaine-seeking behavior from then on was unrelated to the light/sound, and the link between the light/sound and cocaine could not be reinstated in these rats.
This research on rats may help clarify how cravings are produced in the brain, and how they might be prevented or treated.
Editor’s Note: In 2012, Yan-Xue Xue and colleagues reported in the journal Science that in humans, psychological techniques can be used to help a patient unlearn the association between an environmental cue and the effects of a drug, using the same theory of the memory reconsolidation period. When patients in recovery from heroin addiction were prompted to revisit memories of heroin use 10 minutes before extinction training (in which they looked at heroin or heroin paraphernalia without receiving the drug), they ended up with fewer cravings for heroin 1, 30, and 180 days later compared to patients who did extinction training without revisiting memories of past heroin use (and thus without opening the memory reconsolidation window, which researchers believe opens 5 minutes to an hour after someone engages in active recall).
Animal Studies Suggest That Oxytocin May Treat Addictions
Oxytocin, the hormone that promotes emotional bonding, also regulates a variety of behaviors. Two recent studies suggest that in rats, an injection of oxytocin can prevent drug-seeking behavior.
In the first study, researcher Gary Aston-Jones found that oxytocin reduced the rats’ interest in methamphetamine. The effect was strongest in the rats that started out with the strongest interest in the methamphetamine.
In the second study, researcher Luyi Zhou and colleagues determined that oxytocin also reduced cocaine-seeking behavior in rats. In addition, the oxytocin reversed changes in the brain’s glutamate signaling pathway that were caused by cocaine use.
Both studies, which were presented at the 2016 meeting of the Society of Biological Psychiatry, suggest that oxytocin is a promising potential treatment for drug addictions.
RTMS May Treat Cocaine Addictions
In a pilot study, repeated transcranial magnetic stimulation (rTMS) reduced cocaine cravings and usage among people with cocaine addiction.
RTMS is a non-invasive treatment in which a magnetic coil placed near the skull transmits electrical signals to the brain. It is an effective treatment for depression, and there is growing evidence that it may also be able to treat addictions.
Participants in the pilot study by researcher Antonello Bonci and colleagues received rTMS directed at their dorsolateral prefrontal cortex or pharmacological treatments (including medications to manage depression, anxiety, and sleep problems) over a 29-day study period. Among the rTMS recipients, 69% remained cocaine-free during the study period, compared to only 19% of those treated with medications. Those who received rTMS also reported fewer cravings.
There were few side effects among those who received rTMS, and there was a 100% compliance rate among the 32 participants, meaning they all showed up for each of their sessions.
Bonci and colleagues are working on a larger study that will compare rTMS treatment to a sham procedure rather than to a medication regime.
In Rats, Dad’s Cocaine Use Affects Son’s Spatial Memory
Evidence is mounting that certain behaviors by parents can leave marks on their sperm or eggs that are passed on to their offspring in a process called epigenetics. In a recent study by researcher Mathieu Wimmer and colleagues, male rats that were exposed to cocaine for 60 days (the time it takes for sperm to develop fully) had male offspring who showed diminished short- and long-term spatial memory compared to the offspring of male rats that were not exposed to cocaine. Female offspring were not affected in this way.
The spatial tasks the offspring rats completed depended heavily on the hippocampus. Wimmer and colleagues believe that cocaine use in the fathers decreased the amount of a brain chemical called d-serine in the offspring. D-serine plays a role in memory formation and the brain’s ability to form synaptic connections. Injecting the offspring of rats who were exposed to cocaine with d-serine before the spatial memory tasks normalized the rats’ performance.
Modafinil May Help Cocaine Users Prevent Relapse
There is currently no Food and Drug Administration–approved treatment for cocaine addiction. One reason may be that in studies of treatments for cocaine use, participants may have a wide variety of exposure to cocaine. Some may be regularly using cocaine, while others may have gone some time without using the drug. A recent study by Margaret Haney and colleagues addressed some of these challenges by comparing the addiction treatment modafinil to placebo in different scenarios—such as when cocaine users have access to cheap cocaine versus expensive cocaine—and determining under which circumstances modafinil reduces the use of smoked cocaine.
In the study, presented at a scientific meeting in 2015, Haney and colleagues reported that among people who were not currently smoking cocaine, modafinil reduced cocaine use compared to placebo, but modafinil did not reduce cocaine use among people who had recently smoked cocaine. Modafinil also reduced cocaine use when the drug was expensive, but not when participants had access to cheap $5 cocaine. According to the researchers, these findings suggest that modafinil may be more useful at preventing relapse than at helping current users of cocaine achieve abstinence.
Editor’s Note: While they are not FDA-approved, two other treatments can reduce cocaine use, according to placebo-controlled studies: the antioxidant N-acetylcysteine (NAC) and the anticonvulsant topiramate.
Medications that Regulate Glutamate Transporters Can Reduce Cocaine Craving
Glia are brain cells that surround neurons and synapses, protecting and insulating them. Chronic cocaine use and withdrawal changes the way certain glial cells, called astrocytes, interact with neurons. In particular, chronic cocaine use and withdrawal can shrink astrocytes and cause them to pull away from neurons. Cocaine use and withdrawal also interfere with the way the neurotransmitter glutamate is cleared from synapses and transported into astrocytes.
New research shows that certain medications that regulate and increase the movement of glutamate from the synapse into glial cells can reduce cravings for cocaine.
In studies of rats chronically exposed to cocaine and then denied access to it, treatment with these glutamate-targeting medications reduces the rats’ cocaine-seeking behaviors. The medications include N-acetylcysteine (NAC), an antioxidant that can reduce habitual behaviors, including addictive behaviors; riluzole, a treatment for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease; the antibiotic ceftriaxone; and propentofylline, which has been explored as a possible treatment for dementia and stroke.
New Study Suggests RTMS Can Reduce Cocaine Use and Cocaine Cravings
Repeated transcranial magnetic stimulation, or rTMS, is a non-invasive treatment in which a magnetic coil placed near the skull transmits electrical signals to the brain. It is an effective treatment for depression, and now it appears it may also be useful in the treatment of addictions.
A pilot study by Alberto Terraneo and colleagues published in European Neuropsychopharmacology in 2016 compared rTMS treatment delivered to the dorsolateral prefrontal cortex to pharmacological treatment in 32 patients who wanted to stop using cocaine. Those in the rTMS group received one session of the treatment per day for five days, followed by one session per week for three weeks. Those who received rTMS had a higher number of cocaine-free urine tests than those who had been treated with pharmacological treatments. Among those who received rTMS, 69% had a positive outcome, compared to 19% of the control group. RTMS also reduced cravings for cocaine. Both treatments improved depression.
Antonello Bonci, another author of the study who is also scientific director at the US National Institute on Drug Abuse, suggested that rTMS may work by “scrambling” the pattern of neural activity that leads to cocaine craving.
Now that there is some evidence suggesting that rTMS may be useful in the treatment of addictions, the researchers are planning a placebo-controlled study of rTMS treatment for cocaine use, in which they will give some patients a sham treatment instead of real rTMS.
Other studies are examining whether rTMS can be used to treat smoking and alcohol use disorders in addition to depression.
Statins Reduce Drug-Craving in Mice
Statins are drugs that are typically used to lower cholesterol. Recent research on the drugs has focused on their effects on the brain.
In 2015 Claudia Chauvet and colleagues reported in the journal Neuropsychopharmacology that the brain-penetrating statins simvastatin and Atorvastatin reduced cocaine seeking behaviors in mice that were taught to self-administer cocaine and then were denied access to it for 21 days compared to pravastatin, a statin that does not penetrate the brain as thoroughly. The researchers found that the brain-penetrating statins also reduced nicotine seeking, but not food reward seeking. The statins also worked in mice that had stopped seeking cocaine but relapsed due to stress, allowing them to abstain from cocaine seeking again.
Statins are considered a very safe treatment in humans. The ability of statins to prevent relapse to addictions in mice may mean that one day they could be used to treat addictions in people as well. A review article by Cassie Redlich and colleagues in the journal BMC Psychiatry in 2014 indicated that statins may reduce recurrence of depression in people. The researchers found that simvastatin had a protective effect while Atorvastatin was associated with increased risk of depression, so the choice of statins may be important for both depression and addiction.
Exercise Improves Fitness, May Help Reduce Cocaine Use
In studies of rodents, running on a wheel reduces cocaine self-administration. A recent study by Richard de la Garza and colleagues investigated whether running or walking on a treadmill can reduce cocaine cravings and use in humans. In the study of 24 participants who had been using cocaine an average of 19.7 years, participants were randomized to run, walk, or sit for 30 minutes three times per week for four consecutive weeks. After exercising, the participants reported having less craving for cocaine. Fitness measures such as body weight and resting heart rate improved in both walkers and runners. While not statistically significant, by the end of the study there was a trend indicating that exercise improved abstinence from cocaine and decreased daily craving for cocaine.
Editor’s Note: Exercise Increases brain-derived neurotrophic factor (BDNF) and neurogenesis. In rodents, cocaine is associated with decreases in BDNF in the frontal cortex, and injecting BDNF there decreases cocaine seeking. Whether this BDNF effect or the general effects of exercise on mood and conditioning account for these positive cocaine effects remains to be ascertained.
