Abstract
The complications of illicit drugs on the brain are eclectic and complex. This article delves specifically into the effects incurred on dopamine pathways and production by illegal drugs and how those effects present themselves in the brain. All illicit drugs pose the risk of developing an addiction, a highly prevalent topic discussed in this article. Cocaine encompasses neurological and mental alterations including decision-making dysregulation, memory-related issues, addictive behaviors, and dopamine accumulation. Heroin is tested in a mice study that includes evaluating the behavioral psychology of addicted mice. It also assesses how the operant conditioning of heroin alters neurological and mental function. Methamphetamine studies honed in on the cellular and neurological changes that proliferated during its usage including dopamine saturation, monoamine depletion, synaptic deterioration, and the development of Parkinsons disease (PD). It is concluded that illicit drugs bring about a myriad of dopaminergic and neurological issues that should be highlighted to take preventative measures against addiction and the availability of illegal drugs.
Introduction
Illicit (or illegal) drugs, such as cocaine and heroin, have effects that manifest so rapidly that they are infamous for their highly addictive and hazardous nature. The use of drugs often results in physical and psychological consequences that become difficult to treat over time. According to professors Louisa Degenhardt and Wayne Hall (2012), chronic disease, blood-borne viruses, injury, mental health problems, and suicidal thoughts are all issues associated with the constant use of illicit drugs. One alarming problem is addiction, where one cannot help but take the drug despite the many detrimental effects that culminate. Illegal drugs feed into addiction by impairing the brain’s reward system that elicits the sense of pleasure, which we know includes dopamine. Additionally, other effects, such as decision-making, drug-related memories, a balanced level of stimulation, and CNS and PNS processes, are all severely impaired, which makes it difficult to recover from substance abuse. Many studies have been conducted to test dopamine’s role in addiction, but additional research needs to occur for a definitive conclusion. This article will discuss the implications of illicit drug use in dopamine production and similar neurological problems.
Dopamine
Dopamine, also known as DA or 3,4-dihydroxyphenethylamine, is both a crucial neurotransmitter and hormone that is responsible for many bodily functions such as learning, mood, movement, heart rate, kidney function, blood vessel function, pain, pleasure, etc. The dopamine pathway begins as the amino acid tyrosine which eventually transforms into levodopa (L-dopa), a precursor amino acid, due to hydroxylation by tyrosine hydroxylase. Then, aromatic amino acid decarboxylase transforms L-dopa into the neurotransmitter dopamine. According to an article from Harvard Health Publishing, “Dopamine is most notably involved in helping us feel pleasure as part of the brain’s reward system … This feel-good neurotransmitter is also involved in reinforcement. That’s why, once we try one of those cookies, we might come back for another…” (Watson, 2024). Activities such as sex, shopping, or other quick mood boosters release dopamine. In many cases, we crave to re-experience those rapid pleasures. This well-known neurotransmitter has the possibility to be very dangerous in combination with illicit drugs because the drugs produce substantial amounts of dopamine in the brain. The brain attempts to neutralize these massive dopamine releases by reducing the production of dopamine or dopaminergic receptors. This can lead to greater consequences and dependence. Consequently, the consumer may be desensitized from a certain amount of the drug, and this will drive them to take higher doses of the same drug to obtain the same high that they experienced before.
Cocaine
Cocaine is an illicit drug that exerts its main psychoactive effects on the brain by triggering an excessive release of dopamine. As previously mentioned, dopamine modulates many bodily functions, so its buildup can negatively impact how it acts in the body. Dopaminergic (dopamine-making) cells regulate the amount of DA released: the molecules attach to receptor cells to stimulate electrical impulses which, in turn, control the function of the cell. A second regulatory mechanism occurs when dopaminergic cells reabsorb dopamine previously launched to limit the concentration of extracellular DA. When one consumes cocaine, it interferes with this mechanism, which causes receiver cells to consume dopamine that would otherwise be reabsorbed. This provokes an influx of dopamine in receiver cells which damages the body as it results in electrically hyperactive cells. In the limbic system, the cocaine “high” predominantly occurs in the nucleus accumbens. Dopamine molecules accumulate here to create a sensation of pleasure that coerces you to repeat the causative action (normally, orgasm, drinking water, etc.).
Unfortunately, cocaine surpasses the natural levels of DA accumulation, and it initiates an intense state of euphoria while building addictive behaviors. Even mice that were given cocaine avoided food and continued to use the drug until they died of starvation.
Furthermore, it is found that dopamine highs are heavily imprinted into memory-storing centers of the brain. Centers such as the amygdala and hippocampus are littered with the memories of cocaine and related apparatus. Typically, this brain function is balanced for experiences that previously brought pleasurable sensations (drinking water and finding a mate), but cocaine takes advantage of the mechanism as it leads to a strong desire to seek and take the drug. Lastly, the frontal cortex regulates decisions by weighing their outcomes. A nonaddicted person would typically abstain from cocaine usage because the frontal cortex emulates a brake: Hearing stories the horror stories of cocaine use and addiction veer them away. When cocaine is used excessively, it impairs this significant regulatory function, causing one to use cocaine non-stop without slowing down. This forms a positive destructive feedback loop, where the continuous use of cocaine triggers the dopamine rushes that compel the administration of the drug while knowing it deteriorates their body. The above mechanisms were derived from The Neurobiology of Cocaine Addiction, by Eric J. Nestler, M.D., Ph.D. (2005), and are further explained in the author’s work.
Heroin
Heroin is a well-known illicit drug that is highly addictive and dangerous because it is a central nervous system depressant. Although, initially, the evidence in which dopamine contributed to addiction was limited, this study on mice and heroin addiction clears things up on this issue. “We have confirmed the validity of the dopamine activation hypothesis for opioids,”
concludes senior author Christian Lüscher, Professor in Neuroscience at the University of Geneva (2018). In this study, researchers used mice to simulate the effects of dopamine dependence and further expand on past research that pertained to dopamine’s effects on addiction. The scientists began the experiment by using a fluorescent sensor recording DA levels in the nucleus accumbens since the accumulation of dopamine, especially with illicit drugs, occurs in that region. The mice were provided with two levers: One that was ineffective, and one that presented with heroin. The scientists also reduced the dosage from 50 to 25 µg/kg/infusion after six days to test the potency of the mice’s dependence. As a result of addiction, the mice learned quickly to discriminate between the active and inactive levers to receive a heroin intake. In less than a minute after a heroin self-administration, the mice’s levels skyrocketed (after 6 days of training: 144.9 ± 26.0 active lever presses versus 8.3 ± 2.5 inactive ones; after 12 days: 283.4 ± 28 versus 20.9 ± 9.3). As proven in the data, the active levers were the dominant choice.
Additionally, as the dosage of heroin was reduced, the amount of LPs increased, likely due to their fierce need for stimulation because as the effect of heroin was lowered, they had an increased need for that same level of stimulation. Even after thirty days without heroin, the mice continued to differentiate between active and inactive levers which exemplified the repercussions of severe addiction and relapse. Later, they used tracer molecules that helped the scientists identify that the activated dopaminergic neurons sent signals to the “medial shell” region of the nucleus accumbens, a highly prominent site when studying dopamine.
These findings already establish dopamine’s role in addiction, but the scientists conducted another examination of heroin’s effects by silencing dopamine neurons in addicted mice. They silenced the neurons to test the extent to which dopamine contributed to the start of addiction. By silencing these neurons, they were able to text how heroin would function as a medium for addiction without DA influence. The mice were given a lever that infused heroin which gave them the liberty to activate it whenever the urge struck. When dopamine’s euphoric tendencies were stifled early on in mice, it was observed that they were less likely to develop a severe heroin addiction (223 ± 60 lever presses
(LP) for 111 ± 25 infusions dropped to 23 ± 9 LP for 15 ± 6 infusions after 4 days of treatment condition). This shows that the inhibition of DA results in a decrease in self-administered heroin, proving that the drug directly reinforces addiction through dopamine production. Finally, scientists genetically manipulated DA neurons in mice to trigger once they were stimulated by light. This allowed the researchers to determine whether or not other alternative methods could alleviate heroin’s dopaminergic reinforcement. However, it was seen that the group of mice who had access to both heroin-inducting and optogenetic levers were more likely to utilize heroin for stimulation than the group that only received light stimulation.
Methamphetamine
Methamphetamine (meth), similarly to cocaine, is a central nervous system stimulant. However, meth typically yields longer neurological effects. As displayed in How is methamphetamine different from other stimulants, such as cocaine? (NIDA, 2021), meth takes about 12 hours for half of the drug to be removed from the body while cocaine only takes 1 hour. Methamphetamine also prevents the reabsorption of dopamine like cocaine. However, it also elevates dopamine release in the body, causing higher concentrations of dopamine to collect in the synapses because of its effects on monoamine metabolism, dopamine reuptake, and vesicular depletion. Methamphetamine also evokes euphoria like the previous two drugs. The inflated amount of dopamine intervenes in and impairs the brain’s reward circuit, unwarily leading to a long-lasting addiction.
Mechanistically speaking, there are many pathways, receptors, storage vesicles, and so on, that are affected or potentially deteriorated by the over-administration of methamphetamine. Its advantageous lipophilicity allows it to cross the blood-brain barrier which helps its effect to manifest easily. According to the Psychiatric Times article by Anna Moszcynska, PhD (2016),
“Because its chemical structure is similar to that of monoamines, methamphetamine is recognized as a substrate by DA, serotonin, and the noradrenaline plasma membrane transporter in the brain and transported into neurons and neuronal terminals.” Methamphetamine will facilitate its voyage through neurons, and it will cross the neuronal membrane through passive diffusion. Once it enters the terminals, methamphetamine invades monoamine storage vesicles and depletes them of neurotransmitters. High levels of cytoplasmic DA (from storage depletion) will lead to a series of reactions that will damage dopaminergic terminals. Plus, it can prevent monoamine metabolism; the breakdown of certain neurotransmitters such as dopamine, serotonin, and noradrenaline; because it inhibits monoamine oxidase, the enzyme that catalyzes these reactions. This can lead to an oversupply of monoamines that can accumulate and damage other CNS and PNS systems. For example, this triggers a release of monoamines (DA) into the synaptic cleft, which is affected by competitive antagonism in which methamphetamine interferes with dopamine uptake receptors. These processes along with others overstimulate dopaminergic pathways in the nervous system.
Finally, chronic methamphetamine users have an increased risk of developing Parkinson’s disease (PD). Parkinson’s disease is infamous for being attributed to a lack of dopamine, and as discussed before, prolonged meth use is associated with severely diminished dopaminergic neurotransmission. Methamphetamines’s effects on the nigrostriatal pathway are primarily why addicts are more likely to develop PD than non-users.
Conclusion
Developing comprehensive treatments and building a proper understanding of illicit drugs are crucial for aiding those struggling with crippling addictions. Although dopamine’s role in addiction is still quite vague, as explained above perpetual dependence, decision-making dysregulation, tolerance to DA, neuronal damage, memory invasion, compulsion, and more, are all reasons to become increasingly wary of its potential outcomes. If new research begins, and those addicted to dopamine are willing to remove an overbearing toll on their life, we can eliminate the extensive issues associated with illicit drug use and dopamine once and for all.
Written By: Nobin Nath
Works Cited
Corre, J., van Zessen, R., Loureiro, M., Patriarchi, T., Tian, L., Pascoli, V., & Lüscher, C. (2018). Dopamine neurons projecting to medial shell of the nucleus accumbens drive heroin reinforcement. eLife, 7. https://doi.org/10.7554/elife.39945
Degenhardt, L., & Hall, W. (2012). Extent of illicit drug use and dependence, and their contribution to the global burden of disease. The Lancet, 379(9810), 55–70. https://doi.org/10.1016/s0140-6736(11)61138-0
Moszczynska, A. (2016, September 30). Neurobiology and clinical manifestations of methamphetamine neurotoxicity. Psychiatric Times.
https://www.psychiatrictimes.com/view/neurobiology-and-clinical-manifestations-metha mphetamine-neurotoxicity
NIDA. 2021, April 13. How is methamphetamine different from other stimulants, such as cocaine?. Retrieved from
https://nida.nih.gov/publications/research-reports/methamphetamine/how-methamphetam ine-different-other-stimulants-such-cocaine on 2024, July 17
Watson, S. (2024, April 18). Dopamine: The pathway to pleasure. Harvard Health. https://www.health.harvard.edu/mind-and-mood/dopamine-the-pathway-to-pleasure 3. Nestler E. J. (2005). The neurobiology of cocaine addiction. Science & practice perspectives, 3(1), 4–10. https://doi.org/10.1151/spp05314