Brain study hints at why some people drink alcohol even though it will hurt them

How many times have you been at a bar with that one friend who orders another tequila shot even though they definitely don’t need it?

This friend isn’t stupid — when it comes down to it, they likely know they will suffer just as much as anyone when they wake up hungover in the morning. For some people, drinking alcohol when you know it will hurt you is not so much a matter of choice as it is a compulsion.

The brain’s internal braking system doesn’t seem to work for people with alcohol addiction, and now scientists think they know why.

What’s new — In a study done in rats published Wednesday in the journal Science Advances, researchers show that a small group of neurons in the amygdala — the brain’s fear center — appear to play an outsized role in whether or not a person continues to drink even when they know it will hurt them.

The finding speaks to a paradox within how we as humans experience and overcome fear. But they could also lead to treatments for problematic drinking.

“Everybody has these neurons,” Markus Heilig, a professor of neuropsychiatry at Linköping University in Sweden, tells Inverse. Heilig is the senior author of the new study.

“Based on what we know from other basic research, they are broadly important to overcome becoming passive — ‘freezing’ — in the face of fear,” he explains. These neurons help us survive and overcome the most fear-inducing events in our lives — and judge risks. But in some people, that function seems to go too far.

“Why these cells are hyperactive in this minority is not clear,” Heilig says.

What they discovered — In the study, the researchers gave rats alcohol and then taught them that they would receive an electric shock if they sought out the alcohol.

The idea was to create a negative association for the rats — if they drank, they would pay for it in pain. About one-third of the rats drank anyway, compelled to imbibe the booze offered to them even though they knew it would come with a shock.

By closely examining the neuronal activity in the rats’ brains, the researchers found that activity in brain cells known as PKCδ+ inhibitory neurons, which are found in the amygdala, accounted for some 75 percent of whether or not the rats would drink compulsively even in the face of punishment.

Heilig speculates that these rats may have heightened levels of the enzyme PKCδ.

“That could be for genetic reasons, but could also be due to something called epigenetic regulation,” he says. Epigenetic regulation refers to when “life experiences tune up or down the activity of the machinery that produces proteins from the DNA template,” thereby altering how genes function.

Why it matters — The results give fresh insight into the neurobiology underlying addiction. In a separate study, Heilig and his team found that the amygdala controls another behavior associated with addiction — choosing alcohol over a more compelling reward.

“I think it relates to the fact that both choosing a drug and continuing to take it despite negative consequences probably is much less driven — as used to be thought — by ‘reward,’ but rather by the incentive to get rid of negative emotions,” Heilig says.

“This is what my post-doc mentor, now director of the National Institute on Alcohol Abuse and Alcoholism, George Koob, has called ‘the dark side of addiction.’”

Together, Heilig and his team’s investigations suggest how the brain processes fear may be integral to understanding why some people are driven to seemingly self-destructive or harmful behaviors. Identifying specific neurons in this process could also lead to treatments that target these neurons’ activity in the individual.

Digging into the details — One of the most important outcomes of this study may be what the finding enables us to do as far as treating compulsive alcohol use goes.

In this research, the scientists test this idea by knocking down the PKCδ protein in neurons. By tamping down the enzyme’s activity in the rat brains, the researchers managed to restore the rats’ ability to abstain from drinking in the face of punishment.

Heilig points out that there may be medications out there that block the activity of this protein already — or scientists could develop new medication.

“Medications that inhibit other enzymes exist, so this is not too far-fetched,” he says.

What’s next — This study goes some way to elucidating how individuals’ neurobiology may tip them to addiction and other compulsive behaviors. Still, it doesn’t explain why there is such variation.

“It could be for genetic reasons, but we also know that life experience, such as early life traumatization, contribute,” Heilig says.

“The important lesson is we can’t treat everyone the same; we need to identify at-risk individuals early and initiate what I would call ‘personalized prevention’ measures,” he says.

More immediately, Heilig says his team is working on translating these findings — particularly the possibility of a medical intervention to treat compulsive drinking — into humans.

“We have a least one pharmacological mechanism that in rats is able to normalize both the pathological alcohol choice and the compulsivity. I just hope it will make it to the clinic,” he says.

Abstract: Alcohol intake remains controlled in a majority of users but becomes “compulsive,” i.e., continues despite adverse consequences, in a minority who develop alcohol addiction. Here, using a footshock-punished alcohol self-administration procedure, we screened a large population of outbred rats to identify those showing compulsivity operationalized as punishment-resistant self-administration. Using unsupervised clustering, we found that this behavior emerged as a stable trait in a subpopulation of rats and was associated with activity of a brain network that included central nucleus of the amygdala (CeA). Activity of PKCδ⁺ inhibitory neurons in the lateral subdivision of CeA (CeL) accounted for ~75% of variance in punishment-resistant alcohol taking. Activity-dependent tagging, followed by chemogenetic inhibition of neurons activated during punishment-resistant self-administration, suppressed alcohol taking, as did a virally mediated shRNA knockdown of PKCδ in CeA. These findings identify a previously unknown mechanism for a core element of alcohol addiction and point to a novel candidate therapeutic target.