Parkinson’s disease (PD) is a progressive neurodegenerative disorder clinically defined by motor instability, bradykinesia, and resting tremors. The clinical symptomatology is seen alongside pathologic changes, most notably the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of α-synuclein and neuromelanin aggregates throughout numerous neural circuits. Traumatic brain injury (TBI) has been implicated as a risk factor for developing various neurodegenerative diseases, with the most compelling argument for the development of PD. Dopaminergic abnormalities, the accumulation of α-synuclein, and disruptions in neural homeostatic mechanisms, including but not limited to the release of pro-inflammatory mediators and the production of reactive oxygen species (ROS), are all present following TBI and are closely related to the pathologic changes seen in PD. Neuronal iron accumulation is discernable in degenerative and injured brain states, as is aquaporin-4 (APQ4). APQ4 is an essential mediator of synaptic plasticity in PD and regulates edematous states in the brain after TBI. Whether the cellular and parenchymal changes seen post-TBI directly cause neurodegenerative diseases such as PD is a point of considerable interest and debate; this review explores the vast array of neuroimmunological interactions and subsequent analogous changes that occur in TBI and PD. There is significant interest in exploring the validity of the relationship between TBI and PD, which is a focus of this review.

Alcohol Use Disorder (AUD) profoundly impacts individuals and society, driven by neurobiological adaptations that sustain chronicity and relapse. Emerging research highlights neuroinflammation, particularly microglial activation, as a central mechanism in AUD pathology. Ethanol engages microglia—the brain’s immune cells—through key signaling pathways such as Toll-like receptor 4 (TLR4) and the NLRP3 inflammasome, triggering the release of proinflammatory cytokines (IL-1β, TNF-α, IL-6). These mediators alter synaptic plasticity in addiction-related brain regions, including the ventral tegmental area, nucleus accumbens, amygdala, and lateral habenula, thereby exacerbating cravings, withdrawal symptoms, and relapse risk. Rodent models reveal that microglial priming disrupts dopamine signaling, heightening impulsivity and anxiety-like behaviors. Human studies corroborate these findings, demonstrating increased microglial activation markers in postmortem AUD brains and neuroimaging analyses. Notably, sex differences influence microglial reactivity, complicating AUD’s neuroimmune landscape and necessitating sex-specific research approaches. Microglia-targeted therapies—including minocycline, ibudilast, GLP-1 receptor agonists, and P2X7 receptor antagonists—promise to mitigate neuroinflammation and reduce alcohol intake, yet clinical validation remains limited. Addressing gaps such as biomarker identification, longitudinal human studies, and developmental mechanisms is critical. Leveraging multi-omics tools and advanced neuroimaging can refine microglia-based therapeutic strategies, offering innovative avenues to break the self-sustaining cycle of AUD.

Depressive disorders and alcohol use disorders are widespread among the general population and are significant public health and economic burdens. Alcohol use disorders often co-occur with other psychiatric conditions and this dual diagnosis is called comorbidity. Depressive disorders invariably contribute to the development and worsening of alcohol use disorders, and vice versa. The mechanisms underlying these disorders and their comorbidities remain unclear. Recently, interest in the lateral habenula, a small epithalamic brain structure, has increased because it becomes hyperactive in depression and alcohol use disorders, and can inhibit dopamine and serotonin neurons in the midbrain reward center, the hypofunction of which is believed to be a critical contributor to the etiology of depressive disorders and alcohol use disorders as well as their comorbidities. Additionally, calcium/calmodulin-dependent protein kinase II (CaMKII) in the lateral habenula has emerged as a critical player in the etiology of these comorbidities. This review analyzes the interplay of CaMKII signaling in the lateral habenula associated with depressive disorders and alcohol use disorders, in addition to the often-comorbid nature of these disorders. Although most of the CaMKII signaling pathway’s core components have been discovered, much remains to be learned about the biochemical events that propagate and link between depression and alcohol abuse. As the field rapidly advances, it is expected that further understanding of the pathology involved will allow for targeted treatments.

Peripheral nerve injury–induced neuronal hyperactivity in the dorsal root ganglion (DRG) participates in neuropathic pain. The calcium-activated potassium channel subfamily N member 1 (KCNN1) mediates action potential afterhyperpolarization (AHP) and gates neuronal excitability. However, the specific contribution of DRG KCNN1 to neuropathic pain is not yet clear. We report that chronic constriction injury (CCI) of the unilateral sciatic nerve or unilateral ligation of the fourth lumbar nerve produced the downregulation of Kcnn1 mRNA and KCNN1 protein in the injured DRG. This downregulation was partially attributed to a decrease in DRG estrogen-related receptor gamma (ESRRG), a transcription factor, which led to reduced binding to the Kcnn1 promoter. Rescuing this downregulation prevented CCI-induced decreases in total potassium voltage currents and AHP currents, reduced excitability in the injured DRG neurons, and alleviated CCI-induced development and maintenance of nociceptive hypersensitivities, without affecting locomotor function and acute pain. Mimicking the CCI-induced DRG KCNN1 downregulation resulted in augmented responses to mechanical, heat, and cold stimuli in naive mice. Our findings indicate that ESRRG-controlled downregulation of DRG KCNN1 is likely essential for the development and maintenance of neuropathic pain. Thus, KCNN1 may serve as a potential target for managing this disorder.

Subanesthetic ketamine offers promising potential for reducing harm in individuals with cocaine use disorder (CUD). Research indicates that even a single dose can lessen cravings and decrease drug-seeking behaviors, though achieving long-term abstinence remains challenging. However, reduced cocaine consumption itself is a meaningful outcome. Ketamine’s potential in reducing the harm of CUD is also supported by its mechanism of action in the dopaminergic system, as it counters cocaine’s effect by interacting with dopamine receptors, stabilizing brain-derived neurotrophic factor levels, and modulating lateral habenula neuron bursting. In addition, concerns about ketamine’s abuse potential are minimized when it is administered in a clinical setting under professional supervision. This is supported by its success as a treatment for depression, indicating that, with appropriate safeguards, ketamine could be a valuable pharmacological strategy for harm reduction in CUD. When developing ketamine as a CUD harm-reduction strategy, it is also important to account for sex differences, which may affect patients’ sensitivity to ketamine and the potential for misuse. Although the promising effects of ketamine in treating depression support its use for CUD, most studies have focused on depression models, and additional research is needed to confirm safety and understand its specific mechanisms in CUD. Nonetheless, subanesthetic ketamine is a promising CUD intervention and should be further explored to provide an efficient and safe solution for patients in need. This narrative review mainly elucidates the ongoing research regarding ketamine’s mechanisms of action, pharmacology, and clinical application potential in CUD.

Alcohol use disorder involves persistent changes in motivation that a uniform increase or decrease in dopamine activity cannot explain. This narrative review examines how alcohol alters ventral tegmental dopamine circuits through membrane conductances, excitatory and inhibitory inputs, and synaptic plasticity. We propose that repeated exposure can reduce baseline dopamine output while preserving or enhancing responses to alcohol and its cues. Baseline output is defined as a prespecified measurement before an event; recruitment is the event-evoked increment above that baseline. Evidence for individual adaptations is distinguished from the unproven prediction that their joint change within a defined projection contributes to renewed seeking. Withdrawal-related reward deficits, stress recruitment, receptor-specific inhibitory signaling, and selective synaptic recovery provide complementary mechanisms. Projection identity, sex, hormonal state, and dopamine release and clearance at terminals help explain differences across studies. Regional rescue experiments strengthen causal inference, but most mechanisms have not been linked selectively to relief-driven drinking or recurrence. For prevention research, these findings identify candidate processes that may support progression to persistent use and vulnerability after cessation; they do not establish clinical preventive efficacy. Priorities include longitudinal measurements within defined circuits, independent tests of reward and relief motivation, and selective physiological rescue with appropriate behavioral controls. The practical contribution is a framework for evaluating when a dopamine adaptation is a cause of vulnerability, a compensatory response, or a marker of exposure.