Traumatic experiences in childhood have a more significant impact on the brain than acute trauma in adulthood. Let’s look into the field of developmental trauma, and one of the ways this is so impactful… memory.
Developmental Trauma
The field of developmental trauma is a new interdisciplinary area of study exploring how traumatic events during childhood affect an individual’s brain and nervous system [1].
Developmental trauma is the early, persistent, repeated attacks on healthy development. This includes abuse, neglect, maltreatment, disrupted attachments, exposure to violence, or distress not typical for a child. This type of trauma at such a critical period of development has been found to have a profound impact on the general health and well-being of individuals well into adulthood [2]. The impacts on the mind, brain, and body are not simply outgrown. Childhood trauma causes chronic activation of the stress response system, dysregulating the nervous system, and leading to an imbalanced fight or flight response [1]. This impacts relationships, resilience, and overall worldview. And causes affective, physiological, cognitive, behavioral, self, and relational symptoms [2].
The ACE Study
The first study looking into this correlation was the Adverse Childhood Experiences (ACE) study by the CDC and Kaiser Permanente published in 1998 [3]. This survey asks a series of questions meant to measure how many traumatic events happened in an individual’s childhood. Each question answered ‘yes,’ is one point. Significant evidence supports that increased ACE scores are correlated with decreased overall mental and physical health and well-being. For example, chronic illness, risk-taking behaviors, and suicidality all significantly increase as ACE scores increase. Additionally, individuals with higher ACE scores have a significantly greater chance of dealing with the United States’ top ten leading causes of death [3].
Memory
Artstract created by Hadlie Dahlseid.
One reason trauma is so impactful on anxiety is due to the learning and memory mechanisms of the brain. During a stressful event, glucocorticoid levels are increased, causing stronger associations with the event, and a stronger and longer-lasting memory. Stressors concurrently activate glucocorticoid receptors and NMDA receptors in the dentate gyrus of the hippocampus. When NMDA receptor and glucocorticoid receptor activity converge, histone phosphorylation is impacted. This ultimately leads to gene transcription related to memory consolidation of stressful events [4].
NMDA Receptors
Signaling pathway after activation of glucocorticoid and NMDA receptors [4].When glutamate binds to a NMDA receptor, an ERK-MAPK signaling pathway is triggered. This is a key pathway involved in learning and memory [4].
Glucocorticoid Receptors
With the release of glucocorticoids, the glucocorticoid receptor interacts with ERK, facilitating the phosphorylation of downstream nuclear kinases, specifically Elk and MSK of the ERK/MAPK pathway. The glucocorticoid receptor acts like a scaffold in this process.
Histones
Next, the glucocorticoid receptor phosphorylates and acetylates histone H3, forming the H3S10p-K14ac mark. These histone modifications are epigenetic mechanisms that lead to altering chromatin structure, promoting the transcription of genes. This results in the entry of immediate-early genes (IEGs) which are essential for memory formation associated with the stressful event [4].
Dealing with Trauma
So now what do we do with all this information? Trauma-informed care is an approach to social services that recognizes and responds to effects of trauma, while creating a safe space that reduces the risk of re-traumatization [5]. This includes practices to regulate the nervous system, therapies and medications such as those used to treat other anxiety disorders, and understanding the impacts of trauma on the brain and nervous system. Recognizing that trauma is something that happened to someone, not something wrong with someone, is vital. Society needs to shift from asking “what’s wrong with you?” to “what happened to you?”. We can start doing this by understanding the science behind childhood trauma.
References
[1] van der Kolk, B. (2014). The Body Keeps the Score: Brain, Mind, and Body in the Healing of Trauma. Penguin Books.
[2] Perry, B. D., & Winfrey, O. (2021). What happened to you?: Conversations on trauma, resilience, and healing. Flatiron Books.
[3] Felitti, V. J., Anda, R. F., Nordenberg, D., Williamson, D. F., Spitz, A. M., Edwards, V., Koss, M. P., & Marks, J. S. (1998). Relationship of Childhood Abuse and Household Dysfunction to Many of the Leading Causes of Death in Adults: The Adverse Childhood Experiences (ACE) Study. American Journal of Preventive Medicine, 14(4), 245–258. doi:10.1016/S0749-3797(98)00017-8.
[4] Reul, J. M. (2014). Making memories of stressful events: A journey along epigenetic, gene transcription, and signaling pathways. Frontiers in Psychiatry, 5. https://doi.org/10.3389/fpsyt.2014.00005
[5] What is trauma-informed care?. University at Buffalo School of Social Work – University at Buffalo. (2024, May 29).
Beyond reviewing the current literature, the paper emphasizes how stress influences memory formation through molecular, epigenetic, and neurobiological mechanisms. It highlights how stress can shape long-term memories and affect future behavior, with implications for psychiatric disorders such as PTSD.
The Excitatory Amino Acid Transporter (EAAT) mechanism plays a crucial role in regulating glutamate levels in the brain, which is essential for maintaining normal brain function and preventing neurotoxicity. Understanding and appreciating the importance of this system is not just a scientific concern—it directly relates to public health, mental well-being, and the potential for developing treatments for neurological and psychiatric disorders.
Why the EAAT Mechanism Matters
1. Glutamate: A Double-Edged Sword
Glutamate is the most abundant excitatory neurotransmitter in the brain. It is essential for learning, memory, and overall communication between neurons. However, too much glutamate in the extracellular space becomes toxic—a condition called excitotoxicity, which damages or kills neurons.EAATs prevent this by rapidly clearing excess glutamate from synapses after neurotransmission, maintaining safe concentrations and protecting neurons1.
Figure 1. Glutamate-glutamine cycle. Glutamate (Glu−) released after excitatory transmission is collected by astrocytic EAAT transporters 1 and 2. The glutamate is then either converted into α-ketoglutarate (α-KG) via glutamate dehydrogenase (GDH) or transaminase reaction and enters the TCA cycle, or else is converted into glutamine (Gln) by glutamine synthetase (GS). Astrocytes excrete Gln back into the extracellular environment via the Na+ driven SNAT3 transporter, which is then taken up by an as yet unconfirmed neuronal Gln transporter. Neurons then convert Gln back to Glu− via a phosphate-activated glutaminase (PAG) reaction to replenish their vesicular Glu− stores.
Understanding EAATs helps in designing drugs or therapies that could regulate glutamate levels more effectively and prevent or treat these conditions2.
Mental Health and EAATs
Studies have also linked EAAT dysregulation to mood disorders like depression and anxiety. In fact, some antidepressants may act (in part) by modulating glutamate levels or transporter function3. A healthy glutamate balance ensures stable mood, cognition, and neural resilience.
Future Therapies and Personalized Medicine
The public should care because EAATs are potential therapeutic targets. Research in this field is paving the way for precision medicine that could help people based on their specific transporter function, especially those with genetic mutationsaffecting EAAT expression4.
Why This Topic Deserves Public Attention
Neurodegeneration affects millions and leads to costly healthcare burdens.
Mental health disorders are rising, and glutamate imbalance plays a role in many of them.
Increased public understanding can lead to support for neuroscience research and better health policy.
Families affected by diseases like ALS, Alzheimer’s, or epilepsy stand to benefit from breakthroughs in EAAT-targeted treatments.
Rothstein, J. D., Dykes-Hoberg, M., Pardo, C. A., et al. (1996). Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron, 16(3), 675–686. https://doi.org/10.1016/S0896-6273(00)80086-0
Sanacora, G., Zarate, C. A., Krystal, J. H., & Manji, H. K. (2008). Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nature Reviews Drug Discovery, 7(5), 426–437. https://doi.org/10.1038/nrd2462
Choudary, P. V., Molnar, M., Evans, S. J., et al. (2005). Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. PNAS, 102(43), 15653–15658. https://doi.org/10.1073/pnas.0507901102
Imagine you’re at a concert. The air is buzzing, the bass is thumping, and the crowd is alive. The excitement of anticipation builds as the lights dim and the first chords strike. Every beat pulses through your body, connecting you to the thousands around you. In your brain, a similar concert is happening every time you feel joy, excitement, or even the rush of a risky decision. The headliners? Dopamine and Glutamate — the dynamic duo behind your brain’s greatest hits.
The Beat
Dopamineis like the lead singer of the band, basking in the spotlight. It’s the neurotransmitter responsible for that euphoric feeling when you accomplish something or indulge in a pleasurable experience. Whether it’s a bite of chocolate cake or a victory dance after scoring a goal, dopamine is right there, dropping the beat.
But no concert is complete without the hype-man hyping. Enter Glutamate— the brain’s primary excitatory neurotransmitter. While dopamine signals pleasure, glutamate amplifies the experience, strengthening connections between neurons. It’s the reason you remember the way that cake tasted or the thrill of that winning moment. Glutamate makes sure those memories stick, playing a key role in learning and reinforcement.
The interplay between dopamine and glutamate is most evident in the brain’s reward circuitry. At the heart of this circuit is the nucleus accumbens, often referred to as the brain’s “pleasure center.” When you engage in a rewarding activity, dopamine floods this region, signaling a positive experience. Meanwhile, glutamate, originating from areas like the prefrontal cortex and amygdala, reinforces the memory of the experience and the associated cues. This coordination ensures that behaviors linked to pleasure are remembered and likely repeated. However, addictive substances can hijack this process, leading to overstimulation of the nucleus accumbens and creating strong, maladaptive memories that drive compulsive drug-seeking behaviors [1].
The Catch: When the Beat Gets Twisted
An abstract by Venesa Angau
But here’s the twist. Just like an over-amped concert can get chaotic, an imbalance between dopamine and glutamate can throw the brain into disarray. This is exactly what happens with addictive substances like nicotine, cocaine, or methamphetamine. These drugs hijack the soundboard, cranking up dopamine to extreme levels while distorting glutamate’s role.
Instead of a balanced duet, dopamine takes over, blaring constant reward signals. Glutamate, meanwhile, reinforces those memories, creating strong neural pathways that scream, “More, more, more!” This combination rewires the brain, making cravings feel impossible to resist.
The longer this cycle continues, the more difficult it becomes to restore balance. Over time, the brain’s natural dopamine production may dwindle, leaving individuals feeling joyless without the substance. Meanwhile, the heightened glutamate signaling remains like a haunting encore, pushing the desire to use again. This explains why even after quitting, people often experience intense cravings and a heightened sensitivity to triggers.
Additionally, the prefrontal cortex, responsible for decision-making and self-control, weakens under the constant strain. It’s like the sound engineer abandoning their post, leaving the music to spiral out of control. Without the brain’s natural ability to regulate impulses, resisting cravings becomes a monumental challenge.
A New Track: Restoring the Harmony
Figure 1. Diagram showing the interaction of dopamine & glutamate
Therefore, researchers are tuning into ways to restore this balance. Metabotropic glutamate receptors (mGluRs), especially those in Group II, act like sound engineers, turning down the volume of excessive glutamate release. By targeting these receptors with medications, scientists hope to weaken the overpowering neural pathways that drive addiction [2].
Drugs like LY379268 are showing promise in preclinical trials. They calm the overstimulated circuits, reducing cravings and preventing relapse. Think of it as a gentle fade-out of that relentless craving track, making space for healthier rhythms to emerge [3].
The Final Encore
So next time you savor a delicious meal or celebrate a win, remember dopamine and glutamate are behind the scenes, delivering a symphony of experience. And just like a perfectly balanced concert, when these neurotransmitters play in harmony, the brain’s greatest hits keep on coming.
But when the balance goes awry, science is working on remixing the track. Because everyone deserves a standing ovation for the brain, and all the brilliance it contains.
Resources
[1] Scofield, M. D., Heinsbroek, J. A., Gipson, C. D., Kupchik, Y. M., Spencer, S., Smith, A. C. W., Roberts-Wolfe, D., & Kalivas, P. W. (2016). The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis. Pharmacological Reviews, 68(3), 816–871. https://doi.org/10.1124/pr.116.012484
[2] Taepavarapruk, P., Butts, K. A., & Phillips, A. G. (2014). Dopamine and Glutamate Interaction Mediates Reinstatement of Drug-Seeking Behavior by Stimulation of the Ventral Subiculum. International Journal of Neuropsychopharmacology, 18(1), pyu008–pyu008. https://doi.org/10.1093/ijnp/pyu008
[3] Cannella, N., Halbout, B., Uhrig, S., Evrard, L., Corsi, M., Corti, C., Deroche-Gamonet, V., Hansson, A. C., & Spanagel, R. (2013). The mGluR2/3 Agonist LY379268 Induced Anti-Reinstatement Effects in Rats Exhibiting Addiction-like Behavior. Neuropsychopharmacology, 38(10), 2048–2056. https://doi.org/10.1038/npp.2013.106
You may have heard that addiction is a disease, but this disease uniquely harms the body – it attacks learning.
Psychostimulant Use Disorder (PUD) is a chronic, relapsing condition characterized by compulsive drug-seeking behavior despite negative consequences[1]. Despite its prevalence, there are no FDA-approved medications specifically for treating PUD. Recent research, however, has pinpointed metabotropic glutamate receptors (mGluRs) as key players in the neuroplastic changes underlying addiction. “A review on the role of metabotropic glutamate receptors in neuroplasticity following psychostimulant use disorder”[2] delves into how these receptors modulate synaptic plasticity in brain reward circuits following psychostimulant use. This blog post will break down the science highlighted in the article and discuss possible therapeutic interventions for PUD.
Addiction hijacks the brain’s reward system, which includes the ventral tegmental area (VTA), nucleus accumbens (NAc), prefrontal cortex (PFC), and amygdala. Psychostimulants like cocaine, amphetamines, and nicotine disrupt glutamate signaling (the brain’s primary excitatory neurotransmitter) leading to long-term synaptic changes[2]. These synaptic changes are extremely similar to those observed in learning. Instead of learning a new word in Spanish, a mathematics formula, or a fun psychology fact, the brain is learning that psychostimulant use feels good. These positive feelings are due to the drugs increasing extracellular dopamine and glutamate, reinforcing drug-associated memories and cravings. Glutamate acts through two receptor families: ionotropic receptors (fast-acting ligand-gated channels) critical for synaptic plasticity, and metabotropic receptors (mGluRs, which are G-protein coupled receptors) that modulate synaptic strength over longer time periods. The review focuses on mGluRs, divided into three groups based on signaling pathways and localization.
Group I mGluRs (mGluR1/5): Synaptic Potentiation and Relapse
Group I mGluRs are located postsynaptically and are linked to Gq proteins. They activate phospholipase C (PLC) and PKC, which hydrolyze PIP2 into DAG and IP3. These intracellular events create various outcomes depending on the psychostimulant.
Role in PUD:
Cocaine: Enhances long-term potentiation in the NAc and PFC. Antagonists reduce drug-seeking, while agonists promote relapse.
Amphetamines: Increase mGluR5 expression in the PFC, correlating with conditioned place preference.
Nicotine: mGluR5 blockade via antagonists attenuates nicotine self-administration and reward[2].
Group II and III mGluRs (mGluR2/3/4/6/7/8): Presynaptic Inhibition
Group II and III mGluRs are located presynaptically. They are Gi/o-coupled, which function to inhibit glutamate release (dampening the effects of the drugs) by decreasing cAMP and adenylyl cyclase levels. As with Group I, the intracellular inhibition creates varying effects depending on the type of drug.
Role in PUD:
Cocaine: Agonists inhibit relapse by normalizing hyper-glutamatergic states in the NAc. mGluR7 activation inhibits relapse by reducing glutamate release in the NAc.
Methamphetamine: Downregulation of mGluR2/3 contributes to cravings, and agonists reduce reinstatement. mGluR8 expression changes may counteract drug-induced plasticity.
Nicotine: Activation in the VTA decreases nicotine-seeking behavior[2].
Figure 1. An illustration of mGluR localization in reward circuitry and synapses [2].Repeated drug use alters dendritic spine density and synaptic strength in reward circuits. For example, cocaine increases AMPA/NMDA ratios in VTA dopamine neurons, a hallmark of long-term potentiation (LTP; aka learning). Additionally, nicotine enhances hippocampal LTP via mGluR5[2]. These changes underlie the persistence of drug memories, making relapse a formidable challenge. Such changes are why addiction is a disease of learning.
Just as we are able to learn, we are able to unlearn. Viewing addiction as a problem with learning, association, and rewards provides possible promising therapeutic implications for something that is currently untreatable by medication. Targeting mGluRs offers a nuanced approach, and the article notes that Group I antagonists may prevent cue-induced cravings, Group II agonists could restore glutamate homeostasis, and Group III modulation might disrupt drug-associated memories[2]. Taken together, targeting mGluRs may have promising therapeutic benefits.
Figure 2. An illustration of long-term potentiation at the synapses. Synaptic plasticity can cause an increase in the amount of neurotransmitters released or the number of post-synaptic receptors available [3].
The review highlights mGluRs as critical mediators of addiction-related neuroplasticity. While recent research is promising, translating these findings into treatments requires further research, especially given the complexity of glutamate signaling across brain regions and its importance in a variety of normal brain functions. For now, mGluRs remain a hopeful future direction in curing PUD.
Addiction rewires the brain and creates a learned dependence on and craving for drugs, but by hacking glutamate’s mGluRs, researchers may just reset the system. Therefore, researching the therapeutic effects of mGluR agonists and antagonists is essential for combating PUD.
The article we have covered in a previous week, “A role on the metabotropic glutamate receptors in neuroplasticity” by Roghayeh Mozafari, Saeidah Karimi-Haghighi, Mojdeh Fattahi, Peter Kalivas, and Abbas Haghparast was an article about the basics on psychostimulant use disorder as an addiction disorder. Basically, it is a growing public problem attached with both physical and mental handicaps. However, the article warns that there is currently very little we can really do for psychostimulant use disorder, so it is essential to obtain all micro-scale information we can gather on all related topics from reward to many others.The topic today is why people should care about this topic and what the people must know, so without further ado let’s get reading!
The article informs us of some of the distinguishable characteristics of psychostimulant use disorder connected to the micro-scale levels of small. Though, the article specifically focuses mainly on neuron circuitry and glutamate receptors.^1 As a result of this connection, we can now classify correlation here.
Figure one from the article mentioned above is especially excellent at explaining this where it was needed (excellently timed, or in other words placed well). That piece is simultaneously even an absolutely massive diagram which shows even a seemingly full diagram of the journey of glutamate in the brain going off of glutamate receptors activation. Although, one slight problem could be that it could feel a large bunch overwhelming if you’re not too familiar with the applied terms of figure two in the Neuroscience field. This was an excellent piece to me for it is maximized simplicity because, for clear reasons, that kind of thing strongly helps. The figure may also benefit people uninvolved in Neuroscience as well because figure one works similarly like speech bubbles in comic books with all the brief, yet descriptive, labeling, and I find that effective myself in general because it’s easy on the eyes to track or logicate.
Now, at this point, one, such as yourself, may wonder why people really should care about all the above information. Well, let’s answer with essential basics to answer ourselves by quickly asking ourselves something simpler first; what really is a stimulant disorder? Well, the answer is absolutely nothing short of a true tragedy. According to the U.S. Department of Veterans Affairs, stimulant use is known as the situation where a person is addicted to a drug for an innate reward (think cocaine, methamphetamine, amd even ritalin) with a consequence of serious health risks with the worst listed being, “heart attack, stroke,…”^2 that in turn becomes medical emergencies. Considering that we know about these symptoms as a consequence, it’s no shock to pretty much anyone that such a scenario can turn serious fast. Let us put this into perspective with another topic.
In my class, I personally examined the neurodiverse populations adapting to addictions. Unsurprisingly, I learned from Help 4 Addiction that neurodiverse populations get whole new different symptom addictions compared to the common neurotypical (such as lower functioning symptoms, long term executive functioning struggles, and so on)^3. However, it gets far worse than that; you may recall what I call “reinforcement culture” where people often magnetize towards others with similar addictions (think coffee, sugar, and especially alcohol) which makes it harder to make friends if you do not share an addiction (nor at least part takes). Well, neurodiverse populations such as autistic populations have an increased risk to addictions compared to neurotypicals.
References:
1.) “A role on the metabotropic glutamate receptors in neuroplasticity” by Roghayeh Mozafari, Saeidah Karimi-Haghighi, Mojdeh Fattahi, Peter Kalivas, and Abbas Haghparast
2.) https://www.mentalhealth.va.gov/substance-use/stimulants.asp
3.) https://www.help4addiction.co.uk/addiction-and-neurodiversity/
HIJACKED HAPPINESS: HOW ADDICTION REWIRES THE BRAINS REWARD SYSTEM
Addiction hijacks the brain’s reward circuits, reshaping the very wiring that governs pleasure and motivation. Key areas such as the ventral tegmental area (VTA), nucleus accumbens (NAc), prefrontal cortex (PFC), and amygdala—which are normally involved in reinforcing survival behaviors like eating or socializing—are overtaken by psychostimulants. These drugs flood the brain with dopamine, causing compulsive drug-seeking behaviors and diminishing the sensitivity to natural rewards. Glutamate, another neurotransmitter crucial for synaptic plasticity, is disrupted, leading to long-lasting changes that reinforce addiction and heighten vulnerability to relapse. By targeting neurotransmitter systems, innovative treatments can help restore balance in the reward circuitry, offering hope for those suffering from psychostimulant use disorder. [1]
WHAT IS PUD?
Psychostimulant Use Disorder (PUD) is a chronic, relapsing condition characterized by an uncontrollable drive to consume psychostimulants, even in the face of negative emotional and physical consequences. It causes profound neuroadaptations within the glutamatergic circuitry responsible for reinforcement and reward processing, resulting in physical and mental impairments. Psychostimulants include a range of substances such as nicotine, cocaine, methamphetamine, MDMA, dextroamphetamine, and methylphenidate—all of which trigger extensive changes in glutamate transmission and receptor function, playing a pivotal role in both the development and persistence of PUD.
Fig.1 image of pills
THE ROLE OF THE REWARD CIRCUIT
The brain’s reward system comprises interconnected regions—the VTA, NAc, PFC, hippocampus (HPC), and amygdala (AMY)—that work together to encourage survival behaviors like eating and socializing to give us feelings of pleasure and motivation. However, psychostimulants exploit these circuits, driving the transition from initial drug use to addiction. Dopaminergic neurons in the VTA regulate glutamate and GABA neurotransmission, ensuring balance in the brain’s signaling. When this balance is disrupted, addictive behaviors become deeply ingrained.[2] The interactions among various parts of this circuit and neuroadaptations in these areas mainly contribute in the rewarding impact of drugs and to the progression from initial drug use to PUD’s.
Fig.2 cocaines response in the brain, involving glutamate and GABAminergic neurons.
GLUTAMATE: THE MAIN NEUROTRANSMITTER
Glutamate is the brain’s most abundant excitatory neurotransmitter, making up about 70–90% of the brain’s synaptic communication. Glutamate helps neurons “talk” to each other quickly, which is essential for processes like learning, memory, and overall brain function.
Its role in addiction is profound, as glutamate projections from the prefrontal cortex (mPFC) and amygdala to the NAc directly influence GABAergic activity, which regulates dopamine transmission. Different glutamate receptors—including NMDA, AMPA, kainate, and metabotropic receptors (mGluRs)—are involved in addiction-related neuroadaptations, highlighting the complexity of glutamatergic involvement in psychostimulant use disorder. This ability to rapidly transmit signals also plays a key role in synaptic plasticity, the brain’s way of adapting and changing based on experiences.
Metabotropic glutamate receptors (mGluRs)—classified I, II, and III—play a key role in synaptic plasticity within brain reward circuitry. These G-protein coupled receptors are distributed throughout the peripheral nervous system and interact with psychostimulants such as cocaine, amphetamines, methamphetamine, and nicotine.
Beyond addiction, glutamate is vital for learning and memory. Changes in glutamate function not only influence recall and cognitive adaptability but also contribute to the development of addictive behaviors. Among the crucial receptors involved in synaptic plasticity and addiction are:
NMDA and AMPA receptors: Facilitate fast excitatory signals.
Kainate and metabotropic glutamate receptors (mGluRs): Engage in more intricate signaling processes.
SYNAPTIC PLASTICTY– ADDICTION
Addiction is more than physical dependency—it’s deeply intertwined with memory and learning processes, particularly in the hippocampus (HPC), the brain’s center for memory. A key concept that explains addiction’s impact on the brain is synaptic plasticity, which refers to the brain’s ability to strengthen or weaken connections between neurons over time. This dynamic process shapes how we learn, remember, and even how addiction memories persist—playing a critical role in relapse.
Types of Synaptic Plasticity:
Structural Plasticity: This involves physical changes in the brain, like the formation or pruning of dendrites and synapses, which are the connections between neurons.
Functional Plasticity: The brain’s ability to shift functions from damaged areas to healthier regions, allowing it to adapt to new situations.
In the case of addiction, the brain’s natural adaptability is exploited, creating powerful neural circuits that are tied to drug-seeking behaviors. Over time, addiction essentially “rewires” the brain’s reward and memory systems to prioritize substance use.[3]
HOW SYNAPTIC PLASTICITY DRIVES ADDICTION
Repeated drug use reinforces synapses linked to drug-related cues, such as specific sights, smells, or environments. This process, largely driven by Long-Term Potentiation (LTP), occurs in key brain regions like the hippocampus (HPC), nucleus accumbens (NAc), and ventral tegmental area (VTA). Over time, these circuits become deeply ingrained, fueling compulsive drug-seeking behaviors.
Drugs overwhelm the brain with dopamine, dulling its responsiveness to everyday pleasures like eating or socializing. Long-Term Depression (LTD) affects neural circuits linked to natural rewards, effectively rewiring the brain to prioritize substance use over other activities.
Fig 3. Limbic reward pathway shown on brain
WHAT IS LTP? LONG TERM POTENTIATION
LTP is the process by which synaptic connections are strengthened after repeated stimulation. It’s crucial for learning and forming long-lasting memories. LTP helps solidify the connection between drug-related cues (like people, places, or paraphernalia) and the pleasurable high that comes with using substances. This means that even after a period of abstinence, these “reinforced” memories can quickly resurface when exposed to these triggers, increasing the risk of relapse.
WHAT IS LTD? LONG TERM DEPRESSION
LTP is the weakening of synaptic connections after low-frequency stimulation. It allows the brain to “forget” less relevant information over time. Addiction shows that LTD can suppress memories tied to natural rewards, like the joy of spending time with loved ones. Over time, this creates an imbalance where drug-related rewards take precedence, further cementing the addictive behavior and making it harder to return to normal, healthy reward patterns. [4]
NEUROPLASTICITY FOR RECOVERY
The psychostimulant-induced behavioral and neurological plasticity could potentially explore circuit and molecular targets with the potential to contribute to the treatment of PUD. To date, there are no FDA-confirmed medicines for the treatment of psychostimulant abuse; therefore, clarification of the cellular and molecular alterations participating in PUD is crucial for developing beneficial medications.
Short- and long-term adaptive changes in dopamine transmission and brain circuitry have been extensively studied as mediators of PUD and its associated neuropsychiatric impairments. These studies underline the importance of neurotransmitter synthesis and release in various parts of the reward circuit, which are significantly altered by prolonged drug use. Such disruptions are primary contributors to the cognitive and behavioral impairments seen in individuals with PUD.
Innovative treatments targeting glutamate receptors or excitatory amino acid transporters (EAATs) offer promising pathways to normalize synaptic transmission and reduce cravings. By restoring balance within the reward circuitry and addressing neuroplastic changes, these therapeutic approaches could play a critical role in reshaping the future of addiction recovery.
Fig 4. Drawing of man and pills
REFERENCES
Cooper, S., Robison, A. J., & Mazei-Robison, M. S. (2017). Reward Circuitry in Addiction. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 14(3), 687–697. https://doi.org/10.1007/s13311-017-0525-z
Kalivas, P. W., Lalumiere, R. T., Knackstedt, L., & Shen, H. (2009). Glutamate transmission in addiction. Neuropharmacology, 56 Suppl 1(Suppl 1), 169–173. https://doi.org/10.1016/j.neuropharm.2008.07.011
Mozafari, R. et al, (2023) A review on the role of metabotropic glutamate receptors in neuroplasticity following psychostimulant use disorder, Progress in Neuro-Psychopharmacology and Biological Psychiatry,Volume 124. https://doi.org/10.1016/j.pnpbp.2023.110735
Puderbaugh, M. (2023, May 1). Neuroplasticity. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK557811/
FOOTNOTES
[1] Kalivas, P. W., Lalumiere, R. T., Knackstedt, L., & Shen, H. (2009). Glutamate transmission in addiction. Neuropharmacology, 56 Suppl 1(Suppl 1), 169–173. https://doi.org/10.1016/j.neuropharm.2008.07.011
[2] Cooper, S., Robison, A. J., & Mazei-Robison, M. S. (2017). Reward Circuitry in Addiction. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 14(3), 687–697. https://doi.org/10.1007/s13311-017-0525-z
[3] Puderbaugh, M. (2023, May 1). Neuroplasticity. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK557811/
[4] Mozafari, R. et al, (2023) A review on the role of metabotropic glutamate receptors in neuroplasticity following psychostimulant use disorder,Progress in Neuro-Psychopharmacology and Biological Psychiatry,Volume 124.https://doi.org/10.1016/j.pnpbp.2023.110735
Picture this: you’re at a party, feeling great, laughing with friends. Someone hands you a drink—or something stronger—and says, “Just try it. You’ll feel amazing.” You do. And in that moment, your brain lights up like a Christmas tree. You don’t realize it, but your brain is quietly rewiring itself. Not for pleasure—though that’s how it starts—but for need. For survival. That’s how addiction begins.
This week in Cobbers on the Brain, we explore the compelling science behind this transformation in our brains, through Nora Volkow’s groundbreaking review on the neuroscience of drug reward and addiction. Addiction isn’t simply about poor decisions or “bad habits.” It’s about a fundamental hijacking of our brain’s reward system. And once that system is altered, the line between want and need blurs into something far more dangerous.
Let’s start with the basics. Our brains are built to seek out things that ensure our survival—food, water, connection. These activities trigger the release of dopamine, a feel-good neurotransmitter that acts like a chemical “thumbs up,” reinforcing behavior so we repeat it. This loop is vital: dopamine helps us learn what’s worth doing again.
But drugs like cocaine, opioids, nicotine, and alcohol flood the brain with dopamine in ways that natural rewards simply can’t match. The ventral tegmental area (VTA) and nucleus accumbens (NAc)—two key regions of the brain’s mesolimbic reward pathway—light up like fireworks when drugs are introduced. Over time, this hyperstimulation starts to reshape the brain’s wiring, creating strong associations between the drug, the environment, and the experience of reward.
Here’s the paradox: the more someone uses a drug, the less pleasure they feel from it. Over time, dopamine levels don’t rise as dramatically with drug use—but the cues that remind someone of the drug (a lighter, a party, a memory) still do. These cues trigger craving, not satisfaction. And that craving becomes unbearable. It’s not about getting high anymore—it’s about not feeling miserable.
Addiction shifts from pleasure-seeking to survival-seeking, not because people are weak, but because their brains are operating on a new set of rules. The prefrontal cortex, the area responsible for judgment, impulse control, and decision-making, loses its regulatory grip. And so, even when someone desperately wants to quit, their brain is shouting louder: “You need this. Now.”
This explains why addiction is a chronic relapsing disease—not a moral failing. It’s a neurobiological condition that demands compassion, science-based treatment, and long-term care strategies.
This brings us to the second article, a fascinating review on metabotropic glutamate receptors (mGluRs)and their role in neuroplasticity following psychostimulant use disorder (PUD). These receptors help modulate glutamate, the brain’s main excitatory neurotransmitter, and play a crucial role in learning, memory, and motivation.
While dopamine gets most of the attention, glutamate is the hidden architect of addiction—laying down the long-term wiring changes that make addiction so persistent. mGluRs act like dimmer switches for glutamate transmission and are found throughout the brain’s reward system, including the prefrontal cortex, amygdala, and hippocampus.
Research shows that activating or inhibiting specific mGluRs can reduce drug-seeking behavior, block relapse triggers, and even enhance the brain’s ability to unlearn the powerful conditioning that ties drugs to environmental cues. Drugs that modulate these receptors—called positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs)—are being explored as promising treatment options for cocaine, methamphetamine, and nicotine addictions.
Addiction isn’t something that happens to “other people.” It’s affecting our neighbors, our classmates, our families. The opioid epidemic alone has claimed hundreds of thousands of lives in the U.S. alone. And yet, shame and stigma often silence those struggling, even as their brains scream for help.
Understanding the neuroscience of addiction humanizes the condition. It tells us that this isn’t about “just saying no.” It’s about unlocking the mechanisms of craving, relapse, and recovery—and using that knowledge to create treatments that actually work.
So what should you take away from all this?
Addiction is preventable. It’s treatable. And it’s not about being strong or weak—it’s about the brain’s incredible, but vulnerable, capacity to adapt. With continued research into dopamine, glutamate, and beyond, we can shift the narrative—from blame to biology, from punishment to progress.And maybe, just maybe, we can build a world where people have a better chance of getting their lives back.
Addiction is a chronic dependence on a substance. The condition involves compulsive seeking and persistent use despite the negative contributions it provides to their life[1]. The disorder is classified as a disease and falls under the category of chronic brain disorders. Individuals can be addicted to substances and behaviors[1]. Common substances are caffeine, nicotine, alcohol, and opioids[1]. Typical behavior additions revolve around phone use, Gambling, and pornography[1].
These G-protein-coupled receptors modulate synaptic activity and affect long-term changes in neuronal activity.[2]
Group I mGluRs (mGluR1 and mGluR5) are postsynaptic and enhance excitatory signaling. They are involved in synaptic plasticity and are highly expressed in brain regions important for cognition and reward, such as the hippocampus, thalamus, and striatum.[2]
Group II mGluRs (mGluR2, mGluR3) are presynaptic and help modulate neurotransmitter release. mGluR2 is primarily presynaptic, while mGluR3 is found both presynaptically and postsynaptically and in glial cells.[2]
Group III mGluRs ( mGluR7, mGluR8) have a more specialized distribution, affecting areas like the cerebellum, hippocampus, and olfactory bulb.[2]
How Addiction Affects Receptors
Group 1 mGluRs
Amphetamine, methamphetamine, and nicotine modulate glutamate signaling via group I mGluRs[2]. Amphetamine upregulates in the mPFC, influencing synaptic plasticity and reward[2]. Methamphetamine enhances glutamate release and mGluR1-induced long-term synaptic depresion in the NAc, while mGluR antagonists reduce drug-seeking behavior[2].
Group 2 mGluRs
Amphetamine, methamphetamine, and nicotine affect the brain’s reward system by changing how glutamate works. Amphetamine increases certain glutamate receptors (mGluR1/5) in the brain, which influences addiction and reward[2]. Methamphetamine boosts glutamate levels and strengthens certain brain connections, but blocking these receptors can reduce cravings[2]. Nicotine raises mGluR1 levels and helps with memory formation, reinforcing addiction[2].
Group 3 mGluRs
Group 3 mGluRs (mGluR7 and mGluR8) help regulate drug-seeking behavior by controlling glutamate release[2]. Activating mGluR7 reduces cocaine-seeking, while mGluR8 levels rise after chronic drug use, possibly to counteract its effects[2]. In the hypothalamus, stimulating these receptors decreases cocaine-seeking after withdrawal, making them potential targets for addiction treatment[2].
Medications
Quitting a substance is a very painful and physically taxing process. To help ease the process, medication have been developed, but they mostly focus on opioid withdrawal. Several medications target opioid and glutamate receptors to help manage opioid dependence and withdrawal [3]. These drugs modulate neurotransmission, reducing cravings and withdrawal symptoms while also influencing pain perception [3]. Buprenorphine, a partial opioid receptor agonist [4], and methadone, a full opioid receptor agonist [5], both interact with glutamate receptors, contributing to their effectiveness in addiction treatment.
Buprenorphine
Figure 2 [6]. Mu, Kappa, and delta opioid receptors.Buprenorphine is used for patients going through opioid withdrawal. The drug partially activates mu-opiod metabatropic receptors, making it a partial agonist [4]. It also weakly blocks metabotropic kappa receptors and activates ionotropic glutamate delta receptors [4]. As a strong pain reliever affecting the central nervous system, its interactions with the mu receptors give it unique properties [4].
Methadone
Methadone is a synthetic opioid that fully activates mu-opioid receptors to relieve pain [4]. It also affects kappa and sigma opioid receptors in the nervous system [5]. Methadone also blocks the glutamate receptor NMDA and strongly inhibits serotonin and norepinephrine reuptake, causing pain relief [5].
Conclusion
Addiction is a chronic brain disorder driven by compulsive substance use and influenced by neurotransmitters like glutamate. It affects synaptic transmission, learning, and reward pathways. Medications like buprenorphine and methadone can help manage opioid withdrawal by targeting opioid and glutamate receptors. Understanding these mechanisms is key to improving addiction treatments.
[1]Cleveland Clinic. (2025, March 16). Addiction. https://my.clevelandclinic.org/health/diseases/6407-addiction
[2] Mozafari R, Karimi-Haghighi S, Fattahi M, Kalivas P, Haghparast A. A review on the role of metabotropic glutamate receptors in neuroplasticity following psychostimulant use disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2023 Jun 8;124:110735. doi: 10.1016/j.pnpbp.2023.110735. Epub 2023 Feb 20. PMID: 36813105.
[3]Geoffrion, L. (2023, November 2). Common medications used for drug detox: Recovery first. Recovery First Treatment Center. https://recoveryfirst.org/detox/medications/
[4]Kumar, R. (2024, June 8). Buprenorphine. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK459126/#:~:text=Mechanism%20of%20Action,-Buprenorphine%20is%20a&text=Buprenorphine%20exhibits%20high%2Daffinity%20binding,withdrawal%20symptoms%20for%20the%20patient.
[5] DrugBank. (2025). DrugBank online | Database for Drug and Drug Target Info. https://go.drugbank.com/
[6] Lec, P. M., Lenis, A. T., Golla, V., Brisbane, W., Shuch, B., Garraway, I. P., … Chamie, K. (2020). The Role of Opioids and Their Receptors in Urological Malignancy: A Review. Journal of Urology, 204(6), 1150–1159. https://doi.org/10.1097/JU.0000000000001156 (Original work published December 1, 2020)
In the article “A Review on the Role of Metabotropic Glutamate Receptors in Neuroplasticity Following Psychostimulant Use Disorder” by Roghayeh Mozafari et al., the authors look at the neurobiological mechanisms behind addiction. They specifically focus on metabotropic glutamate receptors (mGluRs) and their role in neuroplasticity. The review talks about the changes in brain structure and function in response to psychostimulant use. This suggests that mGluRs (which regulate synaptic plasticity) could be a target for treating addiction. The research mentions that drug use can affect the brain’s ability to adapt and heal, which brings forth the need for new approaches to treating addiction. These new ideas would need to be based on the neural pathways that are altered by repeated drug use [1]. In this blog post, we will look at the similarities and differences of addiction to both legal substances (sugar) and illicit (hard drugs).
Addiction Beyond Hard Drugs
Addiction is an increasingly common issue, but not all addictions are created equal. Most people think of addiction in the context of hard drugs (like cocaine, heroin, and methamphetamine), but there’s another type of addiction that is often under the radar: sugar addiction. The question is- is just as dangerous or damaging as addiction to harder substances? How do these addictions compare on a biological level? What do the latest findings in addiction research say about the brain’s response to substances, both legal and illicit?
Why Are These Addictions So Hard to Break?
Addiction to both sugar and psychostimulants alters the brain’s reward system, which causes changes in behavior and cognition. Research has shown that chronic use of both sugar and hard drugs can result in similar neuroplastic changes [2]. These are alterations in the brain’s neural pathways that make it harder for the individual to resist the substance. This neuroplasticity is regulated by metabotropic glutamate receptors (mGluRs), which are involved in both learning and memory [1]. The review by Mozafari et al. shows how these receptors could play a large role in addiction and neuroplasticity by mediating the long-term changes in brain function following repeated psychostimulant use.
This schematic shows the effect of sugar vs. cocaine on a rat study done.
Sugar and Hard Drugs
What Mozafari and colleagues’ findings about addiction in a general sense show is the similarity between sugar addiction and addiction to psychostimulants on a neurological level. Both types of addiction appear to use the same brain systems, while both have neuroplastic changes leading to the development of compulsive behaviors [1]. This suggests that our understanding of addiction should not be limited to illegal drugs but must also include substances like sugar that can trigger similar neural pathways and behavioral outcomes.
What does this mean for future research? Firstly, it opens up new opportunities for studying addiction in a broader context. If sugar addiction involves the same receptors and pathways as hard drugs, then treatments designed for one may be applicable to the other. This could lead to newer therapies for individuals struggling with sugar addiction, such as patients with obesity or type 2 diabetes.
What Does This Mean for You?
The implications of these findings are far-reaching. Beyond the lab and clinic, this research challenges how we think about addiction and its treatment in everyday-life. If addiction to sugar works similarly to hard drugs in terms of its impact on the brain, then it’s very important to reconsider how we approach nutrition and public health. This could spark conversations about food regulations and marketing practices, especially when it comes to dangerously sugary foods and beverages that are normalized in our culture.
It’s beyond time to think about addiction recovery in a more holistic way. Perhaps we need to expand our focus beyond just illicit substances and start viewing sugar as a more widespread and dangerous addiction- one that has long-term impacts for health and society.
This schematic shows the hidden amounts of sugar in foods you many normally eat without question.
Rethinking Our Approach to Addiction
The main takeaway is clear: addiction is not confined to illegal drugs alone. Substances like sugar can hijack the brain in similar ways. This leads to lasting changes in behavior and cognition similarly to hard drugs. The research into metabotropic glutamate receptors offers a new way to view addiction, which suggests new possibilities for treatments.
So, what’s next? It’s important to think critically about our habits, diet, and the systems that support addictive behaviors. The challenge is real, but so is the opportunity to understand and fight addiction in new ways. Stay curious and keep pushing the boundaries of what we know to help create healthier, more informed lives.
Created by Rachel Cavaness, CHATGPT
[1] Mozafari, R., Karimi-Haghighi, S., Fattahi, M., Kalivas, P., & Haghparast, A. (2023). A review on the role of metabotropic glutamate receptors in neuroplasticity following psychostimulant use disorder. Progress in Neuropsychopharmacology & Biological Psychiatry, 124. https://doi.org/10.1016/j.pnpbp.2023.110735
[2] Avena NM, Rada P, Hoebel BG. Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci Biobehav Rev. 2008;32(1):20-39. doi: 10.1016/j.neubiorev.2007.04.019. Epub 2007 May 18. PMID: 17617461; PMCID: PMC2235907.
Society has stigmatized drug addiction, often blaming the person for going back to drugs. However, drugs alter the brain, so it’s harder to say no. Understanding the science behind addiction can help give a new understanding and greater empathy for those who are addicted to substances. Understanding the science may also help deter you from “just trying it once.” This article will specifically focus on psychostimulants: nicotine, methamphetamine, amphetamine, cocaine, NMDA, dextroamphetamine, and methylphenidate. We will also dive into some common treatment options for addiction.
Glutamate
Before we get into the science of how drug’s change the brain, let’s look at glutamate and its receptors at baseline, along with how drugs change their activity. Glutamate is one of the most influential neurotransmitters for drug addiction. Glutamate is the main excitatory neurotransmitter in the brain, in other words, it will elicit signals passing through neurons. It’s important for cognitive activities. [1]
Figure 1: Different Glutamate receptor types and their functioning at baseline. [2]Glutamate has 2 main groups of receptors that we’ll focus on for this article: Group 1 and Group 2.
Group 1 receptors will be on the postsynaptic neuron, and they are important for synaptic plasticity, or in other words, creating greater connections between neurons that will lead to stronger memory formation. When taking a drug, Group 1 glutamate receptors will activate drug-seeking behaviors, and an increased amount of glutamate will be released. [3] This will cause feelings associated with reward.
Group 2 glutamate receptors regulate glutamate release by decreasing the amount of glutamate released, so the feeling of reward is controlled. Group 2 can also decrease motivation for substance use. However, drugs decrease the activity of Group 2 receptors, so there is less regulation on glutamate, and therefore more feelings of reward and less motivation to stop drug use. [4] Drugs tamper the ability to stop using drug use.
A person addicted to drugs does not have a typical functioning brain, the drugs have removed protective measures in their brain that would help them stop drug use. This is why intervention and support are crucial for people addicted to substances.
Overview of Common Treatments
If someone you know, or you yourself, are struggling with drug addiction, there are resources for support. The most common form of treatment is various forms of therapy. [5] Initial medical detox is an important first step, and hospitalization or treatment facilities can help manage withdrawal symptoms and create a safe environment.
Common Forms of Treatments [6]After detox, therapy is recommended for dealing with cravings, drug behaviors, life changes, and preventing relapse. Cognitive Behavioral Therapy (CBT) is a standard practice for Substance Use Disorder (SUD). [7] This therapy method helps the client understand their drug behaviors and how it’s impacting their life. The client will work on different behaviors and changing their way of thinking.
Another common practice is Contingency Management. This practice is not a therapy option, but it is often used alongside other treatment options. The client will receive rewards, such as gift cards or vouchers, for attending treatment sessions and negative urine tests. This practice has been found to be effective at helping encourage drug abstinence. [8] It uses the reward circuit commonly associated with drug behaviors to reward non-drug behaviors.
Lastly, community reinforcement encourages the client to create new social networks, find different recreational activities, and create a meaningful life outside of drugs. These therapies are some of the most common, but there is many other forms of treatment that can help someone with addictions.
As we’ve established, drugs make it much harder to stop drug use once it’s began. It’s not entirely the person’s fault that their brain has made stopping harder, but it’s never impossible to stop addiction.
Resources
[1-4] Mozafari, R., Karimi-Haghighi, S., Fattahi, M., Kalivas, P., Haghparast, A. (2022). A review on the role of metabotropic glutamate receptors in neuroplasticity following psychostimulant use disorder. Progress in Neuropsychopharmacology & Biological Psychiatry, 124. https://doi.org/10.1016/j.pnpbp.2023.110735
[5] Volkow, N. D., & Blanco, C. (2023). Substance use disorders: a comprehensive update of classification, epidemiology, neurobiology, clinical aspects, treatment and prevention. World psychiatry : official journal of the World Psychiatric Association (WPA), 22(2), 203–229. https://doi.org/10.1002/wps.21073
[7, 8] Volkow, N. D., & Blanco, C. (2023). Substance use disorders: a comprehensive update of classification, epidemiology, neurobiology, clinical aspects, treatment and prevention. World psychiatry : official journal of the World Psychiatric Association (WPA), 22(2), 203–229. https://doi.org/10.1002/wps.21073
