General Neuroscience

Dopamine in Addiction

Andy Ren


Abstract

Dopamine (DA) is a neurotransmitter that relays signals between various regions of the brain, primarily functioning in the neural pathway that processes rewarding stimuli. This function allows DA to play a pivotal role in survival, but also implicates it in a much more dangerous disease: addiction. DA has been shown to affect regions of the brain such as the nucleus accumbens and hippocampus, which are involved in creating and maintaining the addicted state. Addiction treatment is made especially difficult by symptoms of withdrawal, which cause extreme discomfort for the patient after cessation of drug use. Nevertheless, new methods and medications are continuously being discovered that have helped many people overcome addiction and will continue to make addiction a more manageable disease.

 

The Dopaminergic Pathway

Dopamine (DA) is an essential neurotransmitter that functions in both the central nervous system (CNS) and peripheral nervous system (PNS) [1]. Synthesized in the substantia nigra (SN) and ventral tegmental area (VTA), DA has become a popular area of research due to its importance in the brain’s reward pathway [2]. 

The DA pathway is characterized by excitatory DA inputs traveling from the VTA to the nucleus accumbens (NAc), the central brain region involved in receiving and processing rewards [3]. These signals are propagated via two classes of G-protein coupled receptors, abbreviated D-1 like receptors and D-2 like receptors [2]. These receptors are located in the striatum, a brain structure found in the frontal lobe [2]. D-1 like receptors stimulate the enzyme adenylyl cyclase to release cyclic adenosine monophosphate, a secondary messenger molecule, to amplify pleasurable feelings, while D-2 like receptors inhibit adenylyl cyclase, producing the opposite effect [2]. D-1 and D-2 like receptors work in concert to regulate the activation of neurons involved in the reward pathway [2]. When there is positive input into the reward system, DA binds at a higher rate to excitatory D-1 like receptors, creating feelings of arousal [3]. These feelings are translated into actions in the prefrontal cortex, which receives signals from D-1 and D-2 receptors to plan and coordinate movements in response to the pleasurable reward [3]. It also reinforces synapses in the hippocampus, the brain’s memory center, to leave a lasting impression of the experience, creating motivation for a person to seek it out again [4]. This function of DA is essential for survival, as it creates connections between necessities (such as food and sex) and pleasure, prompting the pursuit of these  necessities [5].

 

Effects on Addiction

From a survival standpoint, DA is both valuable to our existence and plays a central role in the harmful pathway of addiction [5]. 

DA release is controlled partially by the brain’s anticipation of reward rather than the actual reward [4]. In a normal circuit, if the reward received is greater than the brain’s predicted reward, the brain will increase DA production, and if the reward received is less than the brain’s predicted reward, the brain will decrease DA production [4]. Drugs cause DA to be released at five to ten times the body’s normal rate, exploiting this neurological system to overwhelm the brain’s reward system [5]. This causes the brain to release less DA in response to all stimuli and reduces both the number and sensitivity of DA receptors in the NAc [5]. When D1 and D2-like receptors were studied in mice, mutant  mice without D1-like receptors did not exhibit the addictive behaviors when exposed to cocaine that control wild-type mice exhibited, demonstrating that D1-like receptors seem to be responsible for stimulating the DA reward pathway in response to drug use [2][21]. 

In addition, mice that had been exposed to drugs showed a marked decrease in the sensibility of their D1-like receptors [2][22]. This decrease in receptor sensitivity, also known as desensitization, is a dangerous effect of drugs on the DA system because it can lead to the use of increased drug dosages [6]. D-1 like receptors are responsible for creating the rewarding effect in response to positive stimuli, and paired with the overall decrease in DA production by the brain, this weakened receptor function will correspond to weakened responses to stimuli, thus requiring greater doses of DA to obtain the same amount of pleasure experienced from previous drug use [6]. DA’s effects on the hippocampus in memory and motivation trigger the need for drug users to get the same “high” they had gotten before, and as the brain naturally releases less and less dopamine with repeated drug use, they are prompted to take increased doses seeking increased pleasure [7]. Studies have shown that drug-induced DA, especially, has a drastic impact on synaptic plasticity, epigenetically altering DNA in the brain and activating gene expression to strengthen connections between reward regions of the brain, increasing the urge to use drugs [8][9][23]. Decreased DA release is also associated with decreases in the function of the orbitofrontal cortex, cingulate gyrus, and dorsolateral prefrontal cortex, all of which are involved in self-control and executive decision [6]. A reduction in these functions further contributes to compulsive drug use and feeds into a vicious cycle in which desensitization causes drug users to progressively increase their dosages [6]. 

Addiction can lead to a variety of harmful outcomes, the most notable being overdose. Since 1999, approximately 750,000 people have passed away due to overdose, around ⅔ of these deaths being caused by an opioid [11]. Opioids are usually prescribed as pain relievers and are especially addictive due to their inhibition of GABA interneurons in the VTA [12]. GABA usually acts as an inhibitor of DA neurons, thus when GABA is inhibited, DA release is stimulated, creating an addictive effect [12]. This is dangerous because opioids bind to specialized receptors in the CNS and PNS that function in slowing down the body to reduce sensation and relieve pain [11]. When an overdose occurs, an excess of opioid receptors are activated, resulting in slowed heart rate and respiratory depression, with coma or death possible in severe cases [13]. Other substances, such as CNS depressants and alcohol, can produce similar effects [13]. 

Addiction also has impacts that lie outside of health complications. Studies have shown that the poor self control addicts show in managing their usage is associated with lower wealth and increased criminal activity at a later age [14]. While the dangers of addiction are daunting, the DA system makes quitting an extremely difficult task with its aforementioned effect on memory and also its implications in withdrawal [15].

 

Withdrawal and Treatment

Withdrawal is characterized by a set of symptoms arising 1-2 days following sudden cessation of drug use. These include irritability, anxiety, sleep disturbance, decreased appetite/weight loss, restlessness, depressed mood, and physical symptoms that elicit significant discomfort [15]. After acclimating to the high levels of DA associated with drugs, the brain’s reward system classifies such high levels as normal, and when it doesn’t receive its usual dosage, it causes these depressive symptoms [16]. This is the main reason why quitting drug use can be challenging, as even gradually decreasing consumption can lead to physical and mental distress [16]. Drug use elicits positive DA responses in the brain, while ceasing drug use evokes negative responses, pushing users to want to continue using despite the dangerous side effects [16].

Despite the motivational aspect of DA in addiction, the brain’s plasticity allows for the rewiring of these harmful neurological pathways [5]. With time, synaptic connections formed in the reward systems of the brain that were strengthened by substance use will break apart naturally if DA input is stopped [5]. Therefore, most addiction treatments center around therapy and medication to suppress symptoms of withdrawal, the main cause of relapse after quitting [17]. The most common form of  therapy is cognitive behavioral therapy, in which the patient will communicate one-on-one with a therapist to re-evaluate their specific case of addiction. From there, the therapist can teach or recommend techniques such as relaxation and stress management to deal with the mental toll of overcoming addiction and withdrawal [17]. Additionally, new medications such as lofexidine and clonidine can play major roles in controlling withdrawal symptoms and are associated with higher rates of treatment completion [18]. 

Even after treatment, however, relapse is still possible and can be triggered by factors such as stress or cues like seeing people or being in places associated with previous usage [19]. These cues activate the hippocampus, stimulating memory recall of the pleasures correlated with drug use in order to recreate the motivational feeling users may not have felt in years [19]. Nevertheless, many patients have made full recoveries and have gone on to turn their lives around, showing that with strong determination and help from medical professionals, addiction is not an unbeatable disease [20]. 

 

The Future of Research

While addiction has been proven to be caused by the DA system, using this information to lessen or cure the effects of addiction is still a work in progress. A 2019 study identified a possible target for pharmaceutical treatment in the chromatin remodeler INO80, which was found to have strong expression in the NAc and was linked to mediating cocaine cravings following abstinence in rats [20]. Another study found a correlation between acupuncture and the lessening of withdrawal symptoms by increasing endorphin input into the NAc and reducing activity in the hippocampus [20]. The DA system is still an emerging field of research, and scientists are working tirelessly to better understand its mechanisms in hopes of discovering more molecules such as INO80 or methods such as acupuncture that can be of use in treating addiction.


References


  1. Klein, Marianne. (16/11/2018). Dopamine: Functions, Signaling, and Association with Neurological Diseases. Cellular and Molecular Neurobiology. https://doi.org/10.1007/s10571-018-0632-3. Retrieved: 11/11/2020.

  2. Baik, Ja-Hyun. (11/10/2013). Dopamine signaling in reward-related behaviors. Frontiers in Neural Circuits. https://doi.org/10.3389/fncir.2013.00152. Retrieved: 11/11/2020.

  3. Bamford, Nigel. (07/02/2018). Dopamine’s Effects on Corticostriatal Synapses during Reward-Based Behaviors. Neuron. https://doi.org/10.1016/j.neuron.2018.01.006. Retrieved: 11/11/2020.

  4. Halber, Deborah. (29/08/2018). Motivation: Why You Do the Things You Do. Brain Facts. https://www.brainfacts.org/thinking-sensing-and-behaving/learning-and-memory/2018/motivation-why-you-do-the-things-you-do-082818. Retrieved: 17/11/2020.

  5. Tichelaar, Shelly. Dopamine and its effect on the brain. Smart Recovery Blog. https://www.smartrecovery.org/dopamines-role-in-addiction/. Retrieved: 11/11/2020.

  6. Volkow, Nora. (2009) Imaging dopamine’s role in drug abuse and addiction. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2008.05.022. Retrieved: 11/11/2020.

  7. Zehra, Amna. (19/03/2018). Cannabis Addiction and the Brain: a Review. Journal of Neuroimmune Pharmacology. https://doi.org/10.1007/s11481-018-9782-9. Retrieved: 13/11/2020.

  8. Volkow, Nora. (13/03/2015). The Brain on Drugs: From Reward to Addiction. Cell. https://doi.org/10.1016/j.cell.2015.07.046. Retrieved: 11/11/2020.

  9. Volkow, Nora. (16/11/2017). The dopamine motive system: implications for drug and food addiction. Nature Reviews Neuroscience. https://doi.org/10.1038/nrn.2017.130. Retrieved: 11/11/2020.

  10. Kranzler, Henry. (2008). What is Addiction? Alcohol Research & Health. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3860451/. Retrieved: 14/11/2020.

  11. (19/03/2020). The Drug Overdose Epidemic: Behind the Numbers. Centers for Disease Control and Prevention. https://www.cdc.gov/drugoverdose/data/index.html. Retrieved: 14/11/2020.

  12. Valentino, Rita. (24/09/2018). Untangling the complexity of opioid receptor function. Neuropsychopharmacology. https://doi.org/10.1038/s41386-018-0225-3. Retrieved: 14/11/2020.

  13. Smith, Cooper. (18/09/2020). What Is an Overdose? Addiction Center. https://www.addictioncenter.com/drugs/overdose/. Retrieved: 14/11/2020.

  14. Volkow, Nora. (11/09/2019). The Neuroscience of Drug Reward and Addiction. Physiological Reviews. https://doi.org/10.1152/physrev.00014.2018. Retrieved: 17/11/2020.

  15. Schlienz, Nicolas. (29/04/2017). Cannabis Withdrawal: A Review of Neurobiological Mechanisms and Sex Differences. Current Addiction Reports. https://doi.org/10.1007/s40429-017-0143-1. Retrieved: 17/11/2020.

  16. Kenny, Paul. (31/12/2014). What causes drug withdrawal? Brain Facts. https://www.brainfacts.org/ask-an-expert/what-causes-drug-withdrawal. Retrieved: 19/11/2020.

  17. Cognitive behavioral therapy. Mayo Clinic. https://www.mayoclinic.org/tests-procedures/cognitive-behavioral-therapy/about/pac-20384610. Retrieved: 22/11/2020.

  18. Pergolizzi, Joseph. (18/12/2018). The Role of Lofexidine in Management of Opioid Withdrawal. Pain and Therapy. https://doi.org/10.1007/s40122-018-0108-7. Retrieved: 22/11/2020.

  19. (16/03/2020). What Triggers a Relapse? “Cues” Give Clues. National Institute on Drug Abuse. https://teens.drugabuse.gov/blog/post/what-triggers-relapse-cues-give-clues. Retrieved: 24/11/2020.

  20. Xu, Benjamin. (16/10/2019). Advances in understanding addiction treatment and recovery. Science Advances. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795505/. Retrieved: 24/11/2020.

  21. Drago, J. (7/2/1996). D1 dopamine receptor-deficient mouse: cocaine-induced regulation of immediate-early gene and substance P expression in the striatum. Neuroscience. https://doi.org/10.1016/0306-4522(96)00145-5. Retrieved: 11/11/2020.

  22. Sim, Hye-ri. (2013). Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours. Nature Communications. https://doi.org/10.1038/ncomms2598. Retrieved: 11/11/2020.

  23. Grueter, Brad. (12/10/2011). Integrating synaptic plasticity and striatal circuit function in addiction. Current Opinion in Neurobiology. https://doi.org/10.1016/j.conb.2011.09.009. Retrieved: 11/11/2020.

Andy Ren

Andy Ren


Hi, I'm Andy Ren, a junior at the Peddie School in Hightstown, New Jersey. I'm an avid science student, and I especially enjoy biology. Outside of studies, I'm a swimmer on my school swim team and help tutor younger students.