On a basic level, the way our brains learn things is very simple. We experience a bad thing, we learn it’s bad or it hurts, we learn to avoid it. On the other hand, if we do something good and it has a good effect on us, we feel rewarded, continuing to do it again and again in order to receive more of that reward. Thus, we train ourselves to associate stimuli that creates a rewarding feeling as desirable. 

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The in-depth neuroscience behind reward and learning, however, is a lot more complicated than that. We don’t simply have one “feel-good” chemical and one “black-doom feeling” chemical. Our associations with reinforcing stimuli, the connection between a stimulus and a response, is dependent on the reliability of the expectation of the reward or punishment the subject has about the stimulus beforehand. However, when addictive substances such as cocaine, morphine, marijuana or alcohol are introduced to a body, the chemical compounds within them can affect the processes of reward learning on a chemical level, beyond the usual associations of aversion and reward.  

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Many individuals in the United States and around the world use some form of medicated substance in order to survive. Addiction is considered a separate issue from self-medication or voluntary recreational use, however. Though many addicted individuals begin consumption on a regular or recreational basis, once a person can no longer control their cravings, to the point that they no longer enjoy the process and simply continue out of compulsion, that is when it’s considered a problem.  

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As of 2017, 19.7 million people twelve or older within the United States have one or another form of Substance Abuse Disorder. 14.5 million have an alcohol use disorder, 7.5 million have an abuse disorder towards some form of illicit drug (most commonly pot,) and 27.8 million smoke cigarettes daily. 11.4 million smoke a whole pack each day! 

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Lawmakers and health experts see addiction as a major social issue, both for the health and the economics of citizen populations around the world, as the prevalence of such addiction and illicit substance abuse tends to be associated with poverty, poor economic decisions, delusions and hallucinations, and erratic behavior, and degenerating health. Addictive drugs work by positive reinforcement, via sympathetic synaptic circuits meant for regulating responses to more natural rewards. Like food and sex, when dosed repeatedly, addictive drugs can alter the neurons in the nucleus accumbens, prefrontal cortex and the ventral tegmental area. 

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There are, however, many ways in which drugs are being studied for their more positive effects on human beings. THC and CBD are common chemicals found in marijuana. Both are being studied for their use in pain relief. For patients diagnosed with cancer going through chemotherapy, a gentler pain reliever with less adverse side effects that can also increase appetite and ease anxiety would be of incredible value in this regard. Learning how THC produces its ‘high’ effect and CBD produces its relaxing one is essential for providing that.  

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Drugs are also being used in studies and experiments that focus on testing the mechanisms of learning and underlying addiction as a whole, uncovering how and why they work within and affect the physiology of a living being. How does a compulsion that occurs without any kind of reward form in an individual? Studying the activation of dopamine neurons, scientists have been able to observe that in games of chance such as gambling, dopamine neurons increase their firing rate when results of a gambit or any kind of game are greater than expected but decrease when results meet expectations or are worse than it. This leads to a behavioral pattern in which the individual is always pursuing a better and better result—or a harder, more intense high—in order to feel satisfied.

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The dorsolateral striatum has been observed to be linked to the formation of compulsions. When there is activity here, there is an increase in dopamine observed, and an increase in rewarding feelings. Blocking dopamine receptors here (but not in the nucleus accumbens, which might be associated with forming drug seeking behavior,) has been seen to reduce compulsions in individuals that were already clinically addicted.

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All of these processes seem to be associated very strongly with the pathway between the orbital frontal cortex and the dorsomedial striatum, which is associated with behavioral motivation. If activity along this pathway is strong, it can promote more goal-directed behavior, but if it’s suppressed, behavior can be more habit-driven, leading to more addictive behavior. 

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Thankfully, there’s lots of different ways you can design a trial to test this association, because reward learning can be studied even when it presents in the most basic behaviors. This means smaller, less complicated animals can be used and still display meaningful results. For example, a study in 2004 was conducted using rats with ventral hippocampal lesions, to study behavioral differences in reward learning with or without exposure to cocaine. A group of 39 rats were divided into four groups randomly, either receiving a needle injection of ibotenic acid plus cerebral spinal fluid, which would cause the ventral hippocampal lesions, or a regular control dose of cerebral spinal fluid. Then, they either received a cocaine or saline solution, given at 15 milligrams per day for five days, the last dose given at one week before testing began. 

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Each group was assessed for accuracy of a completed task and the total time it took to complete, as well as presentations of unconditioned stimuli to prompt behavior. The results showed a clear deficit for the rats that had both neonatal ventral hippocampal lesions and doses of cocaine. Though all groups showed equal progress in learning the single new task after repeated unconditional stimulus sessions, the rats that had both the lesions and cocaine had trouble learning through conditioned stimuli taking longer for them to change behavior. 

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Using the trial, the scientists were able to conclude that the neonatal ventral hippocampal regions specifically impaired the reward approach behavior formation: the rats urge to approach the testing apparatus with the expectation of a reward. There was proven a high want for the reward, but a low complex thought for fulfilling that want. It was hypothesized that this combined lack of access to the ventral hippocampus and the exposure to cocaine caused an increase of impulsiveness because of this. Currently, the scientists working on the study hope to use this information to identify a trait marker such as this impulsiveness in human individuals, in order to determine an individual’s vulnerability to addiction in the future.  

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When people think of reward chemicals, they usually think they all work like dopamine, with its straightforward positive effect. However, other types of neurons besides dopamine can have more complicated effects. A review compiled in 2022 examined the effects of the activation of glutamate neurons in the ventral tegmental area (VTA) and how it related to the treatment and study of reward related disorders. Though this specific area is still very understudied, the review provides a great insight into the effects of glutamate in this specific area of the brain.  

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The most obvious use of glutamate in the VTA is behavioral regulation. However, the role that it plays in behavioral regulation is a little complicated and inconsistent, especially compared to dopamine. While dopamine tends to have only a positive effect, depending on the increase or decrease of its production, glutamate can function in both a positive and negative reinforcing role. It can be positive reinforcement when dopamine neurons aren’t active in the VTA, but too much glutamate production can cause adverse reactions. Studies done with rats have shown an excess of glutamate results in anxiety and escape behaviors such as jumping away from a situation.   

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As for glutamate’s role in drug addiction, the presence of µ-opioid receptors usually mediate the effects of opioids via inhibition. In other neurons, µ-opioid receptors completely inhibit GABA transmission and dopamine movement. The fact that they can also inhibit glutamate neurons in the VTA means that in theory, glutamate could have a role in the effect of opioids on the body, potentially aiding in the sudden onset of effects soon after administration of a drug. There might also be a CB1 receptor expressed on glutamate neurons in the VTA. CB1’s are found in cannabinoids, and studying the ratio it affects glutamate over GABA may be crucial for the effects of marijuana. 

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The VTA is also a central hotspot for the effects of nicotine. VTA dopamine neurons release dopamine in contact with it, and blocking dopamine signaling in the VTA can block a subject from forming a preference for nicotine. Application of nicotine to glutamate neurons has been observed to activate, making glutamate neurons firing on dopamine neurons, causing more dopamine activity within the area. Glutamate may also have an effect on learning and memory, sleep, wakefulness, and defense behaviors. Glutamate neurons have been observed to form asymmetrical synapses reaching far in many different directions, forming pathways, reaching in some cases all the way to the prefrontal cortex. It's possible that they could be essential for forming negative memories, adding fear to memories in the process of memory consolidation (negative reinforcement). 

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As for sleep, the VTA dopamine neurons are known to promote wakefulness. Glutamate neurons attached to them tend to promote more activity during wakefulness and REM sleep and decrease firing during non-REM sleep. Also, as stated before, when firing in excess glutamate neurons can activate danger signals and escape behavior in response to threatening stimuli. The glutamate neurons of the lateral hypothalamus have been observed to increase attention to predator odors in rats and induce defense behaviors as well. These glutamate neurons may reach out and send projections to the VTA glutamate neurons, which in turn are sent to the paraventricular nucleus (PVN) glutamate neurons to induce these escape behaviors, forming a large circuit between many areas of the brain.  

 

In conclusion, studies surrounding reward learning, and the effects that different addictive substances can have on the brain, are both extensive and essential to understanding how these processes work. With every new piece of understanding we uncover about how the brain works under these circumstances, the more empathy we are able to garner for individuals within our society afflicted with addiction, and the more likely we are to come up with solutions that can help these people, rather than simply persecuting them for things that they can’t control.