A new study has found that specific regions of the brain are activated after a drug is taken intravenously but not when the same drug is taken orally, with increased activity correlating to an increased feeling of euphoria. The findings could lead to new treatments for addiction.
Drugs that are smoked or injected enter the brain quicker than those taken orally and, for that reason, can have a greater addictive potential. However, the brain circuits underlying why this happens remain unclear.
A new study by researchers at the US National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA), parts of the National Institutes of Health (NIH), has investigated how a drug’s route of administration impacts the brain’s response to it.
“We’ve known for a long time that the faster a drug enters the brain, the more addictive it is – but we haven’t known exactly why,” said Nora Volkow, one of the study’s corresponding authors. “Now, using one of the newest and most sophisticated imaging technologies, we have some insight. Understanding the brain mechanisms that underlie addiction is crucial for informing prevention interventions, developing new therapies for substance use disorders, and addressing the overdose crisis.”
The researchers recruited 20 healthy adult participants and, over three separate sessions, gave them either a small dose of a placebo or of the stimulant drug methylphenidate, commonly known as Ritalin, orally or intravenously. Methylphenidate is a safe and effective prescription medication used to treat ADHD that, when used in research, can be a useful model drug to safely study the relationship between how drugs affect the brain and the participant’s subjective drug experience.
After receiving the drug or a placebo, the researchers used PET imaging to examine differences in the participants’ dopamine levels and fMRI imaging to study brain activity. The PET scans gave an estimate of how fast dopamine increased in the brain in response to the drug’s route of administration. Consistent with previous studies, receiving methylphenidate orally caused dopamine to peak more than an hour after administration, whereas intravenous administration caused dopamine to peak within five to 10 minutes.
Studying the fMRI scans, the researchers noted that one region of the brain, the ventromedial prefrontal cortex, implicated in processing risk and fear, was less active after both oral and intravenous drug administration. However, only intravenous methylphenidate administration, not oral, activated two other regions, the dorsal anterior cingulate cortex and the insula. This finding was consistent among all 20 study participants.
The dorsal anterior cingulate cortex and the insula are part of the brain’s “salience network,” a collection of regions that select which stimuli deserve our attention by attributing value to the things in our environment. It’s important for recognizing and translating internal sensations, including the subjective effect of drugs, and studies have shown that people who sustain damage to the insula can have complete remission of their addiction. The current study contributes to the growing body of evidence about the important role the salience network appears to play in substance use and addiction.
The researchers also asked participants to track, in real-time, their conscious experience of euphoria – or drug reward – in response to both oral and intravenous doses of methylphenidate. After intravenous administration, it was noted that the activity of the salience network observed on fMRI scans was very closely associated with almost every participant’s subjective experience of feeling ‘high’. Increased activity in this part of the brain corresponded with participants reporting an increased high and decreased activity with decreasing euphoria. From this, the researchers theorized that the network identified in their study is relevant not only for the chemical action produced by the drug but also for the conscious experience of drug reward.
“I’ve been doing imaging research for over a decade now, and I have never seen such consistent and clear fMRI results across all participants in one of our studies,” said Peter Manza, lead and co-corresponding author. “These results add to the evidence that the brain’s salience network is a target worthy of investigation for potential new therapies for addiction.”
The next step for the researchers is to study whether inhibiting the salience network blocks the high associated with taking a drug, which could further support the salience network as an appropriate target to treat substance use disorders.
The study was published in the journal Nature Communications.
Source: NIH/NIDA