The Nucleus Accumbens is a structure of the brain that is integral to the reward circuit responsible for many reward related aspects of behavior and emotions, one of them is associative learning. Associative learning is when one forms a response associated with a particular stimulus, so when we feel pleasure from a stimulus this drives us to want more of that stimulus. This has been found to be the reason drugs are so addictive. Cocaine has become a drug of abuse that is far too common and prevalent in the United States and addiction to it is a continuously growing problem. When cocaine is injected or taken, it elicits a pleasurable reaction due to the high volume of dopamine released so this pleasurable feeling becomes associated with the drug. Since this feeling is now associated with cocaine, it is highly likely that the user will go out and seek it again to achieve this feeling until they become so addicted that feeling that they become dependent on it. Research on this topic shows how cocaine addiction can be combated.
In research presented by Doctor Mitchel Roitman we see how cocaine leads to phasic changes in dopamine signaling in rats. This type of signaling is highly involved in goal oriented behavior and associative learning. In this experiment, the rats had catheters inserted into their jugular veins and had cocaine intravenously delivered through them. Then, a method called fast-scan cyclic voltammetry was used to measure signaling in the nucleus accumbens core and shell. The results of this study show that intravenous cocaine delivery in the rats leads to a spike in dopamine signaling in both the core and shell of the nucleus accumbens. The overall argument of this study was to show the effects of GLP-1R, a peptide involved in the modulation of metabolism, agonism as a mitigating factor for spikes in dopamine release in the nucleus accumbens core and shell. To test this theory, the researchers introduced Exendin-4, a GLP-1R agonist, to the rats after 10 cocaine deliveries and saw that it significantly decreased cocaine evoked dopamine signaling in the nucleus accumbens core, however they did not see the same results with the nucleus accumbens core.
In a similar research study titled “Glucagon-like peptide-1 receptor activation in the ventral tegmental area attenuates cocaine seeking in rats,” researchers looked further into this topic. Not only did this study reinforce the findings of Dr. Roitman, but it also found specific dosages of exendin-4 that curbed cocaine induced dopamine signaling. In this study the researchers delivered exendin-4 one hour prior to cocaine injection instead of after and used lever responses after priming these rats for cocaine to test how much they seek out cocaine. Their results indicated, as predicted, that GLP-1R agonism decreased cocaine seeking in rats, but it also had an adverse effect of reducing the rats food intake. This is because the GLP-1R agonist is also a modulator for food intake since nutritive substances also increase dopamine signaling in the nucleus accumbens. To combat this, the researchers went on to figure out the dose of exendin-4 that can be given to reduce cocaine induced dopamine signaling while not suppressing food appetite and found that lower doses of extending can achieve this.
Dr. Roitman’s research shows how cocaine is a reinforcing drug since its pathway involves the reward circuit and that GLP-R1 activation leads to reduced dopamine signaling evoked by cocaine. The second research mentioned above shows that cocaine seeking can be reduced by administering GLP-R1 agonist without suppressing appetite. Combining these two research studies shows that GLP-R1 activation using low doses of exedin-4 is a possible pharmaceutical solution to combat addiction to cocaine.
Although these studies are groundbreaking, they have their limitations. As Dr. Roitman expressed during his presentation, one limitation to this study is that it would be a mistake to make blanket statements regarding reward circuits and saying that rewarding behaviors cause these high dopamine signals. This is shown in some studies where the aversive stimuli has been the one that causes high dopamine signaling in rats instead of the palatable stimuli.
GLP-R1 agonist is already a FDA approved drug that is used to help regulate patients with type II diabetes, obesity and morbid obesity, hopefully with further research using GLP-R1 and exendin-4 there will be an FDA approved pharmaceutical drug to help the increasing amount of people addicted to cocaine. Not only can this affect those who chose to abuse cocaine and would like to stop, but it could possibly prevent infants who come into the world addicted to cocaine from suffering extreme withdrawal symptoms.
Fortin, Samantha M, and Mitchell F Roitman. “Central GLP-1 Receptor Activation Modulates Cocaine-Evoked Phasic Dopamine Signaling in the Nucleus Accumbens Core.” Physiology & Behavior, U.S. National Library of Medicine, 1 July 2017, www.ncbi.nlm.nih.gov/pubmed/28315693.
Hernandez, Nicole S, et al. “Glucagon-like Peptide-1 Receptor Activation in the Ventral Tegmental Area Attenuates Cocaine Seeking in Rats.” Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, Springer International Publishing, Sept. 2018, www.ncbi.nlm.nih.gov/pubmed/29497166.
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