Why are some drugs of abuse more addictive than others?

 This is a central question to the addiction field yet it remains largely a mystery. All drugs of abuse have a similar effect on the brain: they all result in increased amounts of the neurotransmitter dopamine (DA) in an important brain region called the mesolimbic pathway (also known as the reward pathway). One of the core components of this pathway is the ventral tegmental area (VTA), which contains many neurons that make and release DA. VTA neurons communicate with neurons in the nucleus accumbens (NAc). This means that the axons of VTA neurons project to and synapse on NAc neurons. When VTA neurons are stimulated, they release DA onto the NAc, and this is a core component of how the brain perceives that something is pleasurable or “feels good.” Many types of pleasurable stimuli (food, sex, drugs, etc.) cause DA to be released from the VTA onto the NAc (See the yellow box in the diagram below). In fact, all drugs of abuse cause this release of DA from VTA neurons onto NAc neurons.

*Important note: many other brain regions are involved in how the brain perceives the pleasurable feelings of drugs besides the VTA and NAc, but these regions represent the core of the pathway.

Check out these videos for a more detailed discussion of the mesolimbic pathway.

But if all drugs of abuse cause DA release, then why do different drugs make you feel differently? This is a very complicated question but one component of the answer is that different drugs have different mechanisms and dynamics of DA release.

For the opioid drugs like heroin, morphine, and oxycodone, they are able to bind to a special molecule called the Mu Opioid Receptor (MOPR). This action on the MOPR results in an indirect activation of DA neurons in the VTA and a release of DA in the NAc. While all opioid drugs reduce the feeling of pain and induce a pleasurable feeling, they have slightly different properties at the MOPR.

The different properties of the opioids may be a reason why some are more abused than others. For example, a number of studies have suggested that oxycodone may have greater abuse potential than morphine. This means that oxycodone is more likely to be abused morphine.

But do the different properties of morphine and oxycodone on the MOPR affect DA release and is this important to why oxycodone is more likely to be abused than morphine?

This is the question that scientists at the University of Michigan sought to address. Using several different sophisticated techniques, the scientists looked at differences in DA release in the NAc caused by morphine and oxycodone, two common opioid drugs.

Rats were injected with either morphine or oxycodone and then DA release was measured using either fast-scan cyclic voltammetry or microdialysis. I’ve discussed microdialysis in a previous post but in brief, it involves drawing fluid from a particular brain region at different time points in an experiment and then measuring the neurotransmitters present (using advanced chemistry tools that I won’t explain here).

Voltammetry is a more technically complicated technique. In brief, it uses electrodes to measure sensitive voltage changes. Since a molecule has specific electrochemical properties, these voltage changes can be related back to a specific molecule, such as the neurotransmitter DA as in this study. Voltammetry may even allow greater temporal resolution (easier to detect very precise changes at very short time frames, like seconds), which may make it more accurate than microdialysis (which can only measure neurotransmitter release on the scale of minutes).

Because each technology has its own limitations and potential problems, the authors used both of these techniques to show that they are observing the same changes regardless of the technology being used. Showing the same observation multiple times but in different ways is a common practice in scientific papers: it increases your confidence that your experiment is actually working and what you are observing is real and not just some random fluke.

The authors administered a single dose of either morphine or oxycodone to rats and then measured the DA release in the NAc as described above. What they found were very different patterns!

Morphine resulted in a rapid increase in DA (less than 30 seconds) but by 60 seconds had returned to normal. In contrast, oxycodone took longer to rise (about 20-30 sec before a significant increase was detected) but remained high for the entire 2 minutes that it was measured. The difference in DA release caused by morphine and oxycodone is striking!

Many other changes were observed such as differences in DA release in different sub-regions of the NAc, different effects on phasic release of DA (DA is often released in bursts), and differences in the other neurotransmitters such as GABA (morphine caused an increase in GABA release too while oxycodone did not). I won’t discuss these details here but check out the paper for more details.

Of course, do these differences in DA release explain why oxycodone is more often abused than morphine? Unfortunately no, there are many other factors (for example, oxycodone is more widely available than morphine) to consider. Nevertheless, this is some intriguing neuroscientific evidence that adds one more piece to the addiction puzzle.