In a recent study published in Nature Communications, scientists have discovered how different drug administration methods affect brain function and the experience of drug reward. The findings are vital in unraveling the complex mechanisms behind drug addiction and in developing targeted interventions for substance use disorders.
Previous research has long established the connection between dopamine, a key neurotransmitter in the brain, and its role in the rewarding effects of drugs. This connection is a crucial factor in the development of addiction. However, there was a gap in understanding how different ways of introducing drugs into the body impact the brain’s response and the ensuing experience of reward or ‘high.’ This is where the current study comes into play, aiming to bridge this gap and offer new perspectives on addiction treatment strategies.
“In our laboratory we want to understand what makes drugs addictive to people, so that we can help prevent and treat addiction. One major factor determining the addictiveness of a drug is how fast it enters the brain, and consequently how fast the drug can boost brain dopamine levels,” explained study author Peter Manza, a research fellow at the Laboratory of Neuroimaging at the National Institute on Alcohol Abuse and Alcoholism.
“If someone takes a drug like methylphenidate (Ritalin) orally, it gets into the brain relatively slowly, produces slow dopamine increases, and is therapeutic for ADHD. However, if someone takes that same dose of methylphenidate by intravenous injection, it gets into the brain extremely rapidly, produces fast dopamine increases, and is suddenly highly rewarding and addictive. If we can understand what is happening differently in the brain during fast as opposed to slow dopamine increases, that might give us some insight into what makes drugs addictive more generally, and help us find new targets to treat addiction.”
The study involved 20 healthy participants. These individuals, none of whom had a history of drug abuse, underwent a series of scans and assessments under different drug conditions. The researchers administered methylphenidate, a stimulant medication commonly used to treat Attention Deficit Hyperactivity Disorder (ADHD) but known for its potential for abuse, in two different ways: orally and via intravenous injection. A placebo was also used to establish a baseline for comparison.
The key to this study was using advanced imaging techniques, including Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI), to observe the brain’s response in real-time. These methods allowed the researchers to track changes in brain activity and connectivity as the drug was administered. The participants’ heart rate and blood pressure were continuously monitored, and they were also asked to rate how ‘high’ they felt at regular intervals during the procedure.
The researchers found that oral consumption of methylphenidate led to a gradual increase in dopamine, reaching its peak over an hour after ingestion. In contrast, when methylphenidate was administered through intravenous injection, the surge in dopamine levels was notably rapid, reaching its peak within just 5 to 10 minutes post-administration.
The overall magnitude of systolic blood pressure was significantly affected by the drug condition, with the strongest and fastest increases observed in the intravenous methylphenidate condition. This observation aligns with the general understanding that faster drug delivery methods, like injections, often lead to more intense effects.
When participants received intravenous methylphenidate, they reported a more immediate and intense feeling of being ‘high’. This response was closely linked to the rapid increase in dopamine levels observed in the brain shortly after the drug was administered. In contrast, when methylphenidate was administered orally, the increase in dopamine levels in the brain was more gradual, and correspondingly, the participants reported a slower onset and less intense experience of feeling ‘high’.
A key finding was the distinct brain response based on the drug delivery method. For the slower, oral method, decreased activity was observed in the ventromedial prefrontal cortex, involved in emotional and reward processing. In contrast, with the faster, intravenous method, this decrease was accompanied by increased activity in areas like the dorsal and middle anterior cingulate cortex and left insula, which are part of the salience network. This network is crucial for detecting and responding to important stimuli and may play a key role in addiction.
Importantly, the study revealed increased connectivity between the left insula and dorsal anterior cingulate cortex, part of the salience network, and the bilateral dorsal caudate following fast drug delivery. This finding suggests these interconnected brain regions may significantly contribute to the experience of drug reward, especially with rapid drug delivery.
“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. Now, using one of the newest and most sophisticated imaging technologies, we have some insight,” said Nora Volkow, the chief of the NIAAA Laboratory of Neuroimaging and senior author on the study. “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 found a significant temporal association between the increase in connectivity between the dorsal anterior cingulate cortex and dorsal caudate regions of the brain and the participants’ self-reported ‘high’ ratings during the intravenous administration session. This finding suggests that the interaction between these specific brain regions plays a key role in the subjective experience of drug reward.
“There is one circuit in the brain–the salience network — that appears to become activated only during fast (and not slow) dopamine increases,” Manza told PsyPost. “This network might be crucial for the conscious experience of drug reward. We next want to see if modifying the activity of this network can block drug reward and serve as a potential treatment for addiction.”
“We originally thought that the brain’s so-called reward network – including a region called the nucleus accumbens – would also be preferentially active during fast but not slow dopamine increases. However, this was not the case, and it was only the salience network that specifically responded to the IV dose of methylphenidate.”
However, it’s important to recognize some limitations of this study. The research was conducted with a relatively small and specific group – healthy adults without a history of drug use. This raises questions about how these findings might translate to a broader population, particularly those with a history of substance abuse. Additionally, the drug was administered in a controlled, clinical environment, which is vastly different from how drug abuse typically occurs in real-world settings.
“These studies were performed in healthy adults without an extensive history of drug misuse, so it’s unclear if the brain responses we observed would be similar in people with addiction,” Manza said. “Also, in this study the drugs were administered by a healthcare professional during brain scanning in a laboratory environment. The context and manner in which people take drugs plays a crucial role in how the brain processes drug reward. So, this study likely does not capture the exact experience of someone recreationally taking a drug in their preferred environment.”
Future research in this area could look at larger and more diverse populations, including individuals with a history of substance use, to better understand the broader implications of these findings.
The study, “Neural circuit selective for fast but not slow dopamine increases in drug reward“, was authored by Peter Manza, Dardo Tomasi, Ehsan Shokri-Kojori, Rui Zhang, Danielle Kroll, Dana Feldman, Katherine McPherson, Catherine Biesecker, Evan Dennis, Allison Johnson, Kai Yuan, Wen-Tung Wang, Michele-Vera Yonga, Gene-Jack Wang, and Nora D. Volkow.
