How can knowledge of the dopamine system help us to understand the commonalities that exist between appetitive motivated behaviors? What if I told you that cupcakes and cocaine had more in common that you think? Scientists are working to better understand the neural mechanisms of those that struggle with compulsive behaviors, whether it has to do with overeating or drug addiction. In 2017, a record breaking number of seventy-two thousand overdose deaths occured. The Center of Disease Control estimates a rise of around ten percent in the last year. To give you a sense of the gravity this number retains, it totals up to be larger than peak yearly death tolls from both HIV, car crashes, or gun deaths. Consider the recent deaths of well known individuals such as Tom Petty, Anthony Bourdain, Mac Miller, Heath Ledger, etc. Even this week while trying to kill off the controversial comedian from her popular sitcom ‘The Conners’, writers chose to attribute the death of Roseanne Barr to an opioid overdose. The irony of that pseudo hit job was hardly lost on anyone. Even a sitcom comedian playing a mouthy suburban housewife can succumb to the demons of the day.
Professor Stephan Steidl has been working to find answers about what brain systems in mice produce these addictive behaviors. More specifically, he focuses on a particular brain area, the mesopontine tegmental area and its inputs that work on the dopamine system. Dopamine acts as the reward center in the brain for all and any type of reward. In particular, the projection from the Ventral Tegmental Area (VTA) to the Nucleus Accumbens. Take for instance, cocaine, a stimulant drug that acts directly on the dopamine system. Dopamine transporters are slowed down which means that dopamine stays in the synaptic terminal for a longer period of time, enhancing its effects. There are also drugs which work to indirectly modulate the dopamine system like the opioid morphine. During the use of morphine, the inhibitory neurons, GABA, will work in the VTA to inhibit the dopamine neurons. Under normal conditions, GABA inhibits dopamine production. Morphine works to inhibit these inhibitory GABA neurons. Therefore, the effects of dopamine would ultimately increase and produces these pleasurable feelings.
Not only do drugs activate dopamine as this “reward center” but so do reward predictors. In the case of a conditioned stimulus, when the dog hears a bell, he knows he is going to get food. Not only is his dopamine system activated in response to the food but it can be conditioned to be activated in response to what was once a neutral stimulus, the bell.
Although we have a basis of understanding how dopamine acts both directly and indirectly in the neural circuitry, there are many questions that we must answer before determining how scientists can work to solve problems at large. Through a scientific lens, the opioid epidemic or excessive obesity cannot be solved until we can better understand the complexity that arises in these brain areas and neural circuitries. Dopamine neurons in the midbrain receive different inputs from many different brain areas. There are different sources of input that may convey different information about dopamine. There are different areas that contribute to different effects.
Professor Steidl’s research focuses primarily on the laterodorsal tegmentum (LDT).. He uses optogenetics to selectively manipulate the mesopontine inputs to the VTA. Optogenetics uses light gated ion channels to excite channelrhodopsin 2 (ChR2) which will then depolarize and further active these specific cells. When we shine this blue light in the VTA, it excites terminals in the LDTg (transport protein). The animal will then learn to press a lever roughly 300x. If we block these dopamine receptors with NpHR and Arch used to inhibit, the rats will lever press significantly less. This leads us to believe that the dopamine system is important for acquisition of motivated behaviors. Researchers use a “real time” place preference in mice where the mice will always have free choice to turn on the light which will them stimulate the VTA. During the experiment, there are two options for chambers for the mouse to enter. If they choose to enter one chamber, the light will turn on. As a control, there is a baseline test done with no light in either chamber. When this light turns on, the animal will receive stimulation. We are then able to compare the time each mouse spent in each chamber. Researchers found that the animal will spend significantly more time in the light induced chamber. After three days and this control test, the mice still perform showing spent more time in the light induced chamber.
Steidl makes a point to mention an important feature in his research that applies to an epidemic in opioid addiction. Although not surprising, through sensitization, a repeated drug administration shows to change conditions in the brain. It seems at the forefront of society we are seeing more frequently opioid related deaths. There is an undoubtable correlation between repeated use and sensitization. During pre exposure of amphetamine and salience in mice, the amplification of dopamine is more sensitive to following amphetamine exposure. Animals with pre exposure to this drug show a sensitization effect which makes them work harder and become more motivated to obtain the drug. We can conclude that as a result of repeated drug exposure, glutamate is enhanced.
In the article written by Richard Friedman for the New York times, he speaks about Dr. Volkow’s study of those addicted to cocaine, heroin, alcohol and methamphetamines. Her research focuses on the number of dopamine receptors and their role in predicting drug usage. In her study addicts were reported to show a significant reduction in their D2 receptor levels. These same levels were shown to persist even after drug use ceased. Similarly to what Stedil observed in his mice with pre exposure to drugs, likewise, these people become exceptionally less responsive to these rewards which in turn causes them to seek chemical means to enhance their daily lives. Dr. Volkow also mentions that those with low D2 receptor levels also show lower activity in their prefrontal cortex, generating diminishing abilities to think critically, exercise self control, and show restraint. This same concept of lower levels of D2 can also be applied to those with obesity linked to overeating. Similarly, food, like drugs, excites the reward circuit in the brain, causing individuals to consume these high fat and sugar loaded foods. This reward circuit then creates a vicious cycle in which they would begin to crave these foods to induce the rewarding effects.
References:
https://loyolauniversitychicago-my.sharepoint.com/personal/rmorrison_luc_edu/_layouts/15/onedrive.aspx?slrid=1154899e%2Dd04b%2D6000%2D32be%2Df23ef814c311&FolderCTID=0x01200052F973E683B96F4F97B49148A837C07C&id=%2Fpersonal%2Frmorrison%5Fluc%5Fedu%2FDocuments%2FNEUR%20300%20%2D%20Fall%2018%2F%2809%2E11%2E18%29%20%2D%20%20Stephan%20Steidl%2FSteidl%20et%20al%2E%202017%5FNBRopioid%20review%2Epdf&parent=%2Fpersonal%2Frmorrison%5Fluc%5Fedu%2FDocuments%2FNEUR%20300%20%2D%20Fall%2018%2F%2809%2E11%2E18%29%20%2D%20%20Stephan%20Steidl
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