Open research questions in Neurotransmitter Receptor Influence on Behavior

What the literature leaves open

• Evidence for co-release of the NE precursor and neurotransmitter dopamine (DA) from LC neurons has been accumulating for years, yet definitive measures of DA release across regions, stimulus paradigms, and behaviors associated with the LC-NE system remain controversial.

  Stimulus-dependent dopamine dynamics from locus coeruleus axons · 2026 · DOI

• Impulsive-compulsive disorders (ICDs), including pathological gambling, hypersexuality, and compulsive buying, are frequently precipitated by dopamine D2/3 receptor agonists such as pramipexole (PPX), yet the molecular mechanisms that confer individual vulnerability remain poorly understood.

  miR-10a-5p as a critical molecular regulator of dopaminergic impulsivity in the nucleus accumbens · 2026 · DOI

• The results of this study align with prior evidence that aversion- induced decreases in dopamine and DRD2 receptor activity, specifi- cally, are an important regulator of aversion-learning. DRD2 receptor agonism attenuated escape, suggesting that this signal is necessary to maintain aversion-motivated behavior. These findings align with an opposing valence-encoding model of striatal signaling, but there is growing evidence that challenges this model. While it is clear that the complexity of D1 and D2 MSN activity in behavioral regulation is much greater than previously appreciated, clinical insights suggest that a valence-based model may provide therapeutic insight. Depleted dopamine due to Parkinson’s disease or experimental manipulation are associated with enhanced punishment learning but not reward learning, and this effect is reversed by DRD2-agonist medications (Frank et al., 2004; Robinson et al., 2010). A disruption to valence- free associative learning does not account for the absence of a reward- based learning effect observed in these clinical studies. Further, this demonstrates improved performance through enhanced aversion signaling, rather than reward-based motivation. In line with this, our lab has recently demonstrated that aversion-induced decreases in dopamine can precede both increased drug taking and escape in a negative reinforcement design (Grafelman et al., 2025). Importantly, increased performance does not directly imply reward-based motiva- tion, and it is important to consider that a similar mechanism may also be engaged to increase motivated behavior during optogenetic or chemogenetic manipulations. To rigorously test if or how D1 and D2 MSNs encode valence, future studies should continue to charac- terize the heterogeneous cell subpopulations, and careful behavioral designs should be employed to isolate the effects of valence encoding from other factors including learning and motivation.

  Nucleus accumbens DRD2 receptor agonism attenuates escape behavior · 2026 · DOI

• Background Dopaminergic neurons are vulnerable to injury from gliosis and have high density of ACE2 receptors, but the integrity of dopaminergic neurons has not been investigated in long COVID.

  Loss of vesicular monoamine transporter 2 in striatum of long COVID and relationship to neuropsychiatric symptoms · 2026 · DOI

• The dissociation between comparable circuit-level plasticity and sex-specific relapse vulnerability suggests that PVT-NAcSh strengthening represents a shared neuroadaptation to oxycodone abstinence, while mechanisms driving heightened relapse in females likely involve additional circuit elements that remain to be identified.

  Thalamo-accumbal circuit adaptations following extended oxycodone abstinence. · 2026 · DOI

• The ventral tegmental area (VTA) projects to both the nucleus accumbens (NAc) and prefrontal cortex (PFC), forming distinct pathways that are implicated in drug-cue associations, though their specific roles in fentanyl-context encoding are not well defined.

  Mesolimbic and mesocortical pathways differentially support fentanyl-context associations · 2026 · DOI

• Background Adolescent alcohol consumption is a known risk factor for developing alcohol use disorder (AUD) in adulthood, but individual susceptibility varies widely, contributed to by differences in factors that are not well-understood.

  Evaluating machine learning algorithms at predicting developmental trajectories using sequential dataset truncation of voluntary alcohol consumption in adolescent mice · 2026 · DOI

• The field needs direct measurements of mitochondrial res- piration, membrane potential, ROS load, calcium buffering, and mitophagy in adolescent NAcc microcircuits, ideally distinguishing dopaminergic terminals, interneurons, astro- cytes, and microglia. The MFN2 in the NAcc demonstrates that mitochondrial dynamics are behaviorally consequential [20], but it does not yet resolve which cellular compartments are primary in adolescent anhedonia. A decisive next step would be developmental single-cell or spatial multi-omics combined with functional mitochondrial assays in stress- sensitive adolescent models. Mitophagy is a particularly Neurosci. Bull. strong candidate because it sits at the intersection of stress adaptation, ROS control, and synaptic endurance. The core experimental question is whether defective removal of dam- aged mitochondria in adolescent dopaminergic terminals or accumbal neurons precedes blunted reward behavior, or merely follows it. Longitudinal studies should manipulate PINK1/Parkin-linked pathways, fusion-fission balance, and mitochondrial trafficking during adolescence while meas- uring NAcc dopamine release, effort-based decision mak- ing, and anhedonia-like behavior. Adolescent depression is biologically heterogeneous. Mechanism-based trials should enrich for adolescents with prominent anhedonia, evidence of inflammatory activation, and reward-circuit impairment, then test whether mitochondrial-directed interventions normalize both symptoms and circuit function. This is the necessary translational bridge: not simply asking whether a metabolic adjunct reduces total depression scores [6], but whether it rescues the specific motivational computations most dependent on NAcc dopamine.

  The Dopaminergic Energy Crisis of Adolescent Depression: Mitochondrial Bioenergetics Control of Nucleus Accumbens Signaling · 2026 · DOI

• Among previously established vulnerability factors for AUD – including age, sex, genetic/family history, environmental, health, and psychological conditions [11, 13] – reduced central 5-HT tone may represent an additional risk factor. Serotonergic deficits are linked to behavioral traits that often precede problematic alcohol use and overlap with AUD risk, including depression, heightened stress reactivity, aggression, impulsivity, and early-onset drinking (Fig. 2). Accordingly, alcohol use may serve as a form of selfmedication not only in depression, but also in individuals with impaired stress coping and other negative affective states. Importantly, stress represents a key factor linking negative affect to AUD, with women being more vulnerable to drinking to cope than men. Social anxiety disorder represents another relevant risk factor, and has been associated with increased 5-HT synthesis in specific limbic regions and the basal ganglia, as measured by [11C]5-HTP accumulation Beyond behavioral and clinical indicators, research evidence points to potential serotonergic biomarkers of AUD risk (Fig. 1). For example, reduced CSF 5-HIAA levels, reflecting decreased central 5-HT turnover, have been associated with vulnerability to AUD. Another candidate marker is reduced prefrontal 5-HT2A receptor binding, measured by quantitative autoradiography and proposed as an inherited feature linked to AUD risk. Notably, 5-HT signaling can be shaped by multiple interacting factors, including diet (i.e., TRP availability), environmental stressors, pain, and genetic variation in 5-HTrelated genes such as DDC, SLC6A4, and HTR1A (Fig. 2). These factors may underlie distinct behavioral profiles that may contribute to AUD risk and modulate its severity, withdrawal symptoms, and treatment response. Exposure to ethanol per se also leads to 5-HT dysregulation, primarily through alterations in TPH2 activity, changes in SERT density (in the prefrontal cortex and nucleus accumbens), reduced 5-HT function, and increased 5-HT turnover (Fig. 1). A potential marker of excessive alcohol consumption may be increased activity in the raphe nuclei and decreased activity in the prefrontal cortex. Although the co-occurrence of these changes within the same individual remains unclear, their possible overlap may suggest that serotonergic DR raphe projections to the prefrontal cortex and nucleus accumbens are particularly relevant to AUD risk and maintenance, however, further confirmation is required. Consistent with AUD heterogeneity, the efficacy of SSRIs in AUD is highly subtype-dependent. More favorable responses to SSRIs are observed in individuals with lesssevere, later-onset type A alcohol dependence and in alcohol-dependent patients with comorbid depression.

  Decoding the serotonin–alcohol crosstalk: the role of central serotonergic dysregulation in alcohol use disorder · 2026 · DOI

• In these studies dependence on psychostimulants such as methamphetamine, cocaine, MDMA is linked with inhibitory control deficits, whereas such evidence is lacking in case of cannabis dependence.

  Neurocognitive Impulsivity in Addiction: Mechanisms, Manifestations, and Clinical Implications · 2026 · DOI

• Substantial efforts have been made towards understanding the neurobiology of DYN / KOR dysregulation; however, the role of dynorphinergic islands of Calleja within the ventral striatum remain poorly understood.

  Dynorphinergic neuroadaptations in the islands of Calleja: implications for alcohol use disorder · 2026 · DOI

• The transition from controlled to escalated drug intake is a core feature of cocaine use disorder (CUD), yet the molecular mechanisms underlying this behavioral escalation remain poorly defined.

  ANKS1B in the Nucleus Accumbens controls escalated cocaine self-administration via regulating CBP-FoxO3 complex · 2026 · DOI

• Aldehyde dehydrogenase 1A1-positive (ALDH1A1+) dopaminergic neurons (DANs) are preferentially vulnerable in Parkinsons disease (PD), yet how their activity is modulated by presynaptic inputs remains poorly defined.

  Sex-Dependent Effects of Glutamatergic Disruption on Dopaminergic Neuron Subtype Vulnerable in Parkinson's Disease · 2026 · DOI

• Converging evidence implicates the frontoparietal network (FPN) in actively regulating alcohol approach-avoidance behavior, but whether its constituent nodes make dissociable causal contributions remains unclear.

  Dissociable Causal Roles of Right Frontoparietal Nodes in Automatic Alcohol Approach-Avoidance Tendencies · 2026 · DOI

• A major limitation of the current literature is the absence of longitudinal, multimodal studies directly linking LC-NE dynamics to stable personality traits, which contain the ability to distinguish trait effects from adaptive state responses.

  The role of norepinephrine in personality traits: alertness, anxiety, and adaptability—a comprehensive study · 2026 · DOI

• inherent to single-camera video recordings. In particular, its frame-by-frame interface enables users to detect subtle preparatory or proximal movements (e.g., shoulder or trunk contractions) that may precede overt limb movements, even when distal body parts are occluded from view. This capability can improve scoring reliability compared to conventional realtime or coarse video-based approaches. Because it relies on human interpretation, it is also inherently robust to variations in lighting and other artifacts that can confound automated systems. This makes iMOSS-MV a powerful standalone tool that is not only highly eÿcient, with a 6-min session typically scored in approximately 8 min, but is also flexible enough to be applied to other binary behaviors, such as freezing or grooming. Critically, iMOSS-MV provides a practical approach to improving inter-rater and inter- laboratory reliability. Its ability to reload and review prior annotations creates an eective platform for observer training, allowing labs to build and maintain a consistent scoring standard. Our validation demonstrates the power of this approach: after just a single 30-min training session, new observers achieved a high consistency with an expert scorer, even when analyzing videos strategically selected for diverse immobility patten and drug treatments (Figures 2C–F). The single instance of divergence we observed underscores the system’s sensitivity for identifying where targeted training may be beneficial. These findings support iMOSS-MV as a robust solution for improving reproducibility. Future studies could further build upon this by creating curated training libraries from larger, more diverse video cohorts (e.g., dierent lighting conditions and mouse strains), which would further help minimize inter-rater and inter-laboratory variability. Having established this highly accurate reference with iMOSS- MV, we then developed iMOSS-AS, a sensor-based platform comprising a hardware add-on module and automated scoring software, to serve as the “high-throughput workhorse.” The superior performance of iMOSS-AS is therefore not an incidental finding, but stems from two key advantages: First, as a sensorbased system, it measures force change directly and is therefore immune to the inherent limitations of video analysis. Second, it was optimized against the superior, human-curated ground truth from iMOSS-MV. Importantly, iMOSS-AS is not “trained” on observer annotations in the conventional machine-learning sense; rather, its performance is calibrated by adjusting a single parameter (the “Global Best Threshold”) to align immobility detection with human scoring. This relatively simple calibration step improves temporal correspondence with observer-defined immobility, but does not involve fitting complex features to a specific observer. This two-step validation ensures iMOSS-AS is exceptionally accurate, outperforming widely used video-based systems like DBscorer and EthoVision. In addition, iMOSS-AS oers substantially higher temporal resolution (80 Hz) than videobased systems, including iMOSS-MV and EthoVision (30 Hz, limited by camera frame rate) and DBscorer (which operates at an eective resolution of 1 Hz). This enhanced sampling rate allows iMOSS-AS to capture rapid behavioral transitions that may be missed by lower-frequency methods. To illustrate its eÿciency, iMOSS-AS can analyze 16 TST sessions in under 4 min, a task that would take over 2 h to manually annotate using the video recordings. This rigorous development process also ensures the robust generalizability of the GBT used by iMOSS-AS. First, our system is designed to minimize variability arising from factors such as animal weight or baseline drift. The load cell signal is calibrated to standardized force units (mg) during setup, and the baseline is tared before each session. Importantly, the threshold is defined based on changes in force during movement rather than absolute body weight.

  iMOSS: an integrated open-source tail suspension test platform for high-resolution immobility scoring and synchronization with neural activity · 2026 · DOI

• Repeated testing can affect novelty driven behaviors through habituation or one trial tolerance (File and Wardill, 1975; Carobrez and Bertoglio, 2005; Walf and Frye, 2007), the long inter-test interval (30 days) and the inclusion of age and sex matched control groups tested at identical time points likely minimized these effects (Schrader et al., 2018). Moreover, repeated gavage administration may also have induced mild procedural stress, potentially reducing baseline sex differences, in females (Luine et al., 2007), and engaging particularly monoaminergic circuits in stress related allostatic adaptations (Koob and Le Moal, 2001; Koob, 2008). involved The behavioral correlates of the polydrug protocol observed here are subtle. One possible explanation is that they are not readily detectable using conventional quantitative analyses, thus requiring more sensitive multivariate approaches.

  Sex-specific behavioral and monoaminergic network alterations following adolescent binge-like ethanol and WIN55,212-2 exposure under chronic nicotine in rats · 2026 · DOI

• Affecting approximately 1% of the population, its etiology remains unclear, but it is believed to arise from the interaction of genetic and environmental factors, primarily impacting the frontal and temporal lobes.

  Molecular Evidence Underlying the Dopamine Hypothesis of Schizophrenia · 2025 · DOI

• Yet, the idea of SNS addiction remains controversial and more theory-driven research is required to understand the mechanisms of excessive and compulsive SNS use and to facilitate the development of targeted interventions helping affected users.

  A reward and incentive-sensitization perspective on compulsive use of social networking sites – Wanting but not liking predicts checking frequency and problematic use behavior · 2020 · DOI

• Overall, we propose that while computational models capture some aspects of addiction and have advanced our thinking, most have focused on the effects of drug use rather than addiction per se, most have not been tested on and/or supported by human data, and few capture multiple stages and symptoms of addiction.

  Computational models of drug use and addiction: A review. · 2020 · DOI

• Serotonin (5-HT), dopamine (DA), and noradrenaline (NA) levels are controlled by various brain structures and these levels are related to motor activity; however, the concentration of these neurotransmitters during the postictal process remains unknown.

  Effect of postictal process in motor deficit and monoaminergic concentration in hippocampus, cerebellum, and cortex · 2019 · DOI

• The capacity for cholinergic neuromodulation in STs is limited by a neuronal choline transporter (CHT) that fails to support increases in cholinergic activity.

  The neuroscience of cognitive-motivational styles: Sign- and goal-trackers as animal models. · 2018 · DOI

• We conclude that the unidimensional view of the BAS is overly oversimplified; and we suggest that it should be studied as a multidimensional construct and, by implication, so too should the reward system.

  Moving Forward with the BAS · 2017 · DOI

• Although the habituation period to spatial contexts is a determinant variable for the spatial specificity of latent inhibition of CTA, the influence of contextual-temporal familiarity (time of day) on latent inhibition of CTA has not been explored through direct comparisons between different periods of habituation to the temporal context.

  Effects of temporal contexts and contextual habituation on latent inhibition · 2017 · DOI

• However, allelic variants of genes influencing dopaminergic and noradrenergic neurotransmitters have not been investigated with respect to the neural correlates of emotional and motivational states in PG.

  A Preliminary Study of DBH (Encoding Dopamine Beta-Hydroxylase) Genetic Variation and Neural Correlates of Emotional and Motivational Processing in Individuals With and Without Pathological Gambling · 2016 · DOI

Most-cited papers in Neurotransmitter Receptor Influence on Behavior

• Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants · Science · 2003 · 3,580 citations
• Introduction to Behavioral Addictions · The American Journal of Drug and Alcohol Abuse · 2010 · 943 citations
• Précis of<i>The neuropsychology of anxiety: An enquiry into the functions of the septo-hippocampal system</i> · Behavioral and Brain Sciences · 1982 · 859 citations
• Cue-Induced Cocaine Craving: Neuroanatomical Specificity for Drug Users and Drug Stimuli · American Journal of Psychiatry · 2000 · 759 citations
• Low Level of Brain Dopamine D₂ Receptors in Methamphetamine Abusers: Association With Metabolism in the Orbitofrontal Cortex · American Journal of Psychiatry · 2001 · 722 citations
• a neurobehavioral model of affiliative bonding: implications for conceptualizing a human trait of affiliation · Behavioral and Brain Sciences · 2005 · 624 citations
• Stress-Induced Cocaine Craving and Hypothalamic-Pituitary-Adrenal Responses Are Predictive of Cocaine Relapse Outcomes · Archives of General Psychiatry · 2006 · 436 citations
• Classical Conditioning in Drug‐Dependent Humansa · Annals of the New York Academy of Sciences · 1992 · 408 citations
• Dopamine and Addiction · Annual Review of Psychology · 2020 · 360 citations
• Mood Disturbances and Regional Cerebral Metabolic Abnormalities inRecently Abstinent Methamphetamine Abusers · Archives of General Psychiatry · 2004 · 335 citations

Most recent work

• Single-nucleus transcriptomics reveals cell type-specific and time-dependent effects of psilocybin and ketamine on gene expression · bioRxiv · 2026
• Novel Tricyclic Compounds as 5-HT2A Receptor Agonists for Treating Depression, Anxiety, Substance Abuse, and Headaches · ACS Medicinal Chemistry Letters · 2026
• Impact of Age on Heroin Intravenous Self-Administration in Wistar Rats · bioRxiv (Cold Spring Harbor Laboratory) · 2026
• Thalamus orchestrates local acetylcholine-dependent dopamine release in the learning striatum · bioRxiv · 2026
• Independent heritability of aversive learning influences on cocaine-seeking and punishment resistance in rats · eneuro · 2026
• Systemic administration of the mGluR2/3 antagonist LY341495 disrupts reward-related behaviors across ingestive and social domains in mice · bioRxiv · 2026
• Scopolamine-induced cholinergic disruption impairs temporal prediction in head-fixed mice · bioRxiv · 2026
• The Acetylcholine Esterase Inhibitor Donepezil Increases Dopamine Levels in the Nucleus Accumbens and Blocks the Alcohol Deprivation Effect in Rats · Addiction Biology · 2026
• Sex-specific behavioral and monoaminergic network alterations following adolescent binge-like ethanol and WIN55,212-2 exposure under chronic nicotine in rats · Frontiers in Pharmacology · 2026
• Effects of exposure to lisdexamfetamine dimesylate on hepatic parameters of pubertal rats · Naunyn-Schmiedeberg s Archives of Pharmacology · 2026

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