Accumbens Research Articles

Trans-synaptic modulation of cholinergic circuits tunes opioid reinforcement

Opioids trigger structural and functional neural adaptations of the reward circuit that lead to dependence. Synaptic cell adhesion molecules (CAMs) play a pivotal role in circuit organization and present prime candidates for orchestrating remodeling of neural connections in response to drug exposure. However, the contribution of CAMs to opioid-induced rewiring of the reward circuit has not been explored. Here, we used unbiased molecular profiling to identify CAMs in the nucleus accumbens (NAc) modulated by morphine administration. We found that opioid exposure induces the expression of ELFN1, a CAM selectively expressed in cholinergic interneurons in the NAc. We determined that ELFN1 acts trans-synaptically to modulate the strength and plasticity of the glutamatergic inputs onto cholinergic neurons via the recruitment of presynaptic metabotropic glutamate receptor 4 (mGlu4). Disruption of Elfn1 diminished morphine reward and intake in self-administering mice. Together, our findings identify a key molecular factor responsible for adjusting the strength of opioid effects by modulating the configuration of striatal circuitry in an experience-dependent fashion and unveil potential therapeutic target for combating opioid abuse.

Unveiling the Potential Abuse Liability of α-D2PV: A novel α-Carbon Phenyl-Substituted Synthetic Cathinone.

Unveiling the Potential Abuse Liability of α-D2PV: A novel α-Carbon Phenyl-Substituted Synthetic Cathinone.

Cognitive impairment in neurodegenerative diseases: A trans-diagnostic approach using a lesion-symptom mapping analysis.

Cognitive impairment in neurodegenerative diseases: A trans-diagnostic approach using a lesion-symptom mapping analysis.

Ketamine rescues anhedonia by cell-type- and input-specific adaptations in the nucleus accumbens.

Ketamine is recognized as a rapid and sustained antidepressant, particularly for major depression unresponsive to conventional treatments. Anhedonia is a common symptom of depression for which ketamine is highly efficacious, but the underlying circuits and synaptic changes are not well understood. Here, we show that the nucleus accumbens (NAc) is essential for ketamine's effect in rescuing anhedonia in mice subjected to chronic stress. Specifically, a single exposure to ketamine rescues stress-induced decreased strength of excitatory synapses on NAc-D1 dopamine receptor-expressing medium spiny neurons (D1-MSNs). Using a cell-specific pharmacology method, we establish the necessity of this synaptic restoration for the sustained therapeutic effects of ketamine on anhedonia. Examining causal sufficiency, artificially increasing excitatory synaptic strength onto D1-MSNs recapitulates the behavioral amelioration induced by ketamine. Finally, we used opto- and chemogenetic approaches to determine the presynaptic origin of the relevant synapses, implicating monosynaptic inputs from the medial prefrontal cortex and ventral hippocampus.

Polygalae Radix Attenuates Methamphetamine-Induced Behavioral Sensitization Through the TrkB/ERK Pathway in the Caudate Putamen of Mice.

Methamphetamine (METH) addiction is a chronic brain disorder characterized by intense drug cravings and high relapse rates. Traditional Chinese medicines (TCM) have shown efficacy in treating METH addiction via TrkB/ERK signaling. However, the role of Polygalae Radix (PR), a neuropharmacological active TCM, in METH addiction remains unclear. This study examined the effects of PR (25, 50, and 100mg/kg) on locomotor activity in mice and its impact on METH-induced behavioral sensitization (BS) at different stages. Western blotting (WB) assessed TrkB and ERK expression across brain regions. PR (25 and 50mg/kg) alone had no effect on locomotor activity in mice, whereas 100mg/kg significantly reduced locomotor activity. PR (25 and 50mg/kg) administered during the development phase inhibited METH-induced locomotor activity, but its administration during the expression phase had no impact. Continuous PR (25 and 50mg/kg) administration throughout the entire process prevented METH-induced BS in mice. WB analysis revealed that PR alone elevated ERK in the prefrontal cortex, nucleus accumbens (NAc), caudate putamen (CPu), and TrkB in the CPu. During the development phase, PR inhibited METH-induced TrkB/ERK increases in the CPu, whereas, during the expression phase, ERK elevation in the CPu was mitigated. Continuous PR administration blocked METH-induced TrkB/ERK increases in the CPu and ERK levels in the NAc. These findings indicate that PR attenuates METH-induced BS and locomotor activity during the developmental phase through the TrkB/ERK pathway in the CPu, highlighting its therapeutic potential for METH addiction.

Striatal dopamine represents valence on dynamic regional scales.

Adaptive decision making relies on dynamic updating of learned associations where environmental cues come to predict valenced stimuli, such as food or threat. Cue-guided behavior depends on a network of brain systems, including dopaminergic projections to the striatum. Critically, it remains unclear how dopamine signaling across the striatum encodes multi-valent, dynamic learning contexts, where positive and negative associations must be rapidly disambiguated. To understand this, we employed a Pavlovian discrimination paradigm, where cues predicting food or threat were intermingled during conditioning sessions, and their meaning was serially reversed across training. We found that male and female rats readily distinguished these cues and updated their behavior rapidly upon valence reversal. Using fiber photometry, we recorded dopamine signaling in three major striatal subregions - the dorsolateral striatum (DLS), the nucleus accumbens (NAc) core, and the nucleus accumbens medial shell - finding that valence was represented uniquely across all three regions, indicative of local signals biased for value and salience. Further, ambiguity introduced by cue reversals reshaped striatal dopamine on different timelines: nucleus accumbens signals updated more readily than those in the DLS. Together, these results indicate that striatal dopamine flexibly encodes stimulus valence according to region-specific rules, and these signals are dynamically modulated by changing contingencies in the resolution of ambiguity about the meaning of environmental cues.Significance Statement Adaptive decision making relies on updating learned associations to disambiguate predictions of reward or threat. This cue-guided behavior depends on striatal dopamine, but it remains unclear how dopamine signaling encodes multi-valent, dynamic learning contexts. Here, we employed a paradigm where cues predicting positive and negative outcomes were intermingled, and their meaning was serially reversed across time. We recorded dopamine signaling, finding heterogeneous patterns of valence encoding across striatal subregions, and cue reversal reshaped subregional signals on different timelines. Our results suggest that dopamine flexibly encodes dynamic learning contexts to resolve ambiguity about the meaning of environmental cues.

Oxytocin signaling in the ventral tegmental area mediates social isolation-induced craving for social interaction.

Social interaction is crucial for mental health across animal species. Social experiences, especially in early-life stages, strongly influence brain function and social behavior later in life. Acute social isolation (SI) increases motivation to seek social interaction, but little is known about its underlying neuronal and circuitry mechanisms. Here, we focus on oxytocin signaling in the ventral tegmental area (VTA), a vital node of the brain's reward network, as a potential mechanism for SI-induced craving for social interaction. Adolescent (4-week-old) or adult (14-week-old) male C57BL/6J mice underwent a 1-week SI. Free interaction, object exploration, three-chamber social approach, and habituation tests were used to assess social and non-social behavior changes. Viral vectors were used to decipher the underlying neural circuitry, and chemogenetic techniques were applied to modify neuronal activity. We found that in male C57BL/6J mice, SI during adolescence, but not adulthood, leads to increased craving for social interaction and object exploration, accompanied by impaired social habituation, social novelty preference, and social recognition memory (SRM). SI-induced craving for social interaction and SRM deficit is still observed upon regrouping. Through cell-type-specific manipulations with designer receptors exclusively activated by designer drugs (DREADD), we show that oxytocin neurons in the paraventricular nucleus of the hypothalamus (PVN) are crucial for SI-induced social behavior changes. Chemogenetic activation of PVN oxytocin neurons recapitulates social behavior changes observed in SI mice, whereas chemogenetic inhibition of oxytocin neurons prevents social behavior changes caused by SI. Moreover, we found that dopaminergic neurons in the VTA mediate SI-induced craving for social interaction through their projections to the medial prefrontal cortex (mPFC), but not to the nucleus accumbens. Injection of a specific oxytocin receptor antagonist L368,899 into the VTA or chemical lesions of dopaminergic axon terminals in the mPFC with local application of 6-hydroxydopamine ameliorates SI-induced social behavior changes. These findings suggest that adolescent SI has enduring effects on social behaviors in male mice through an oxytocinergic modulation of the VTA-to-mPFC dopaminergic circuit activity.

Investigating the effect of Arvcf reveals an essential role on regulating the mesolimbic dopamine signaling-mediated nicotine reward

The mesolimbic dopamine system is crucial for drug reinforcement and reward learning, leading to addiction. We previously demonstrated that Arvcf was associated significantly with nicotine and alcohol addiction through genome-wide association studies. However, the role and mechanisms of Arvcf in dopamine-mediated drug reward processes were largely unknown. In this study, we first showed that Arvcf mediates nicotine-induced reward behavior by using conditioned place preference (CPP) model on Arvcf-knockout (Arvcf-KO) animal model. Then, we revealed that Arvcf was mainly expressed in VTA dopaminergic neurons whose expression could be upregulated by nicotine treatment. Subsequently, our SnRNA-seq analysis revealed that Arvcf was directly involved in dopamine biosynthesis in VTA dopaminergic neurons. Furthermore, we found that Arvcf-KO led to a significant reduction in both the dopamine synthesis and release in the nucleus accumbens (NAc) on nicotine stimulation. Specifically, we demonstrated that inhibition of Arvcf in VTA dopaminergic neurons decreased dopamine release within VTA-NAc circuit and suppressed nicotine reward-related behavior, while overexpression of Arvcf led to the opposite results. Taken together, these findings highlight the role of Arvcf in regulating dopamine signaling and reward learning, and its enhancement of dopamine release in the VTA-NAc circuit as a novel mechanism for nicotine reward.

The neural basis of dialectical thinking: recent advances and future prospects.

Dialectical thinking represents a cognitive style emphasizing change, contradiction, and holism. Cross-cultural studies reveal a stark contrast of dialectical thinking between East Asian and Western cultures, highlighting East Asians' superior ability to embrace contradictions and foresee transformation, fostering psychological resilience through emotional complexity and tolerance for contradictions. Despite its importance, the neural basis of dialectical thinking remains underexplored. This review synthesizes current neuroscientific findings and introduces the dialectical-integration network (DIN) hypothesis, which identifies key brain regions such as the dorsal anterior cingulate cortex (dACC), medial prefrontal cortex (mPFC), dorsal lateral prefrontal cortex (DLPFC), nucleus accumbens, basal ganglia, and amygdala. These regions, along with networks like the default mode network (DMN) and frontoparietal network (FPN), facilitate holistic reasoning, conflict resolution, and sensory-emotional integration. The psychological benefits of dialectical thinking include enhanced cognitive flexibility, reduced emotional extremes, and improved conflict resolution. This review emphasizes the need for cross-cultural and neuroscientific research to explore the principle of change, a core aspect of dialectical cognition. By bridging cultural psychology and cognitive neuroscience, this work offers theoretical and methodological insights into culturally shaped cognitive styles, with practical applications in education, mental health, and intercultural communication. The DIN model provides a framework for future research on dynamic neural interactions supporting dialectical thinking.

Neuroimaging changes in major depression with brief computer-assisted cognitive behavioral therapy compared to waitlist.

The goals of the current study were to determine the efficacy in major depressive disorder (MDD) of a shortened, computer-augmented cognitive behavioral therapy (CCBT) protocol and to determine brain plasticity effects following CCBT. Seventy-two MDD participants were randomized to CCBT or waitlist control groups and compared to 40 healthy controls (HCs). Functional MRI data were collected for all participants and repeated for patients following CCBT (five therapist-administered manualized CBT sessions plus computer training exercises). Linear mixed-effects models evaluated changes in depression scores throughout treatment and in connectivity from pre- to post-CCBT. Linear regression models compared connectivity differences between groups (MDD vs. HC). Following CCBT, there were decreases in MADRS and BDI (ps < 0.001); there was more negative connectivity of dlPFC with sgACC and DMN with sgACC (ps < 0.002); and there was more positive connectivity of FPN with nucleus accumbens, bilateral amygdalae, bilateral hippocampi, and sgACC and of DMN with ventral and dorsal bilateral anterior insulae (ps < 0.01). There were no associations between change in MADRS and change in connectivity; however, there was an association between change in BDI and change in FPN-sgACC connectivity (p = 0.01). A shortened CBT schedule coupled with home computer exercises was associated with decreased depression symptoms and augmented PFC connectivity with multiple subcortical regions. One possible mechanism of the CCBT intervention is modulating PFC connectivity with subcortical regions, influencing top-down control of affective processes dysregulated in MDD.

Feeling at home in a virtually amputated body; neural and phenomenological effects of illusory embodiment in body integrity dysphoria.

Feeling at home in a virtually amputated body; neural and phenomenological effects of illusory embodiment in body integrity dysphoria.

Dopamine activity encodes the changing valence of the same stimulus in conditioned taste aversion paradigms

Mesolimbic dopamine encoding of non-contingent rewards and reward-predictive cues has been well established. Considerable debate remains over how mesolimbic dopamine responds to aversion and in the context of aversive conditioning. Inconsistencies may arise from the use of aversive stimuli that are transduced along different neural paths relative to reward or the conflation of responses to avoidance and aversion. Here, we made intraoral infusions of sucrose and measured how dopamine and behavioral responses varied to the changing valence of sucrose. Pairing intraoral sucrose with malaise via injection of lithium chloride (LiCl) caused the development of a conditioned taste aversion (CTA), which rendered the typically rewarding taste of sucrose aversive upon subsequent re-exposure. Following CTA formation, intraoral sucrose suppressed the activity of ventral tegmental area dopamine neurons (VTADA) and nucleus accumbens (NAc) dopamine release. This pattern of dopamine signaling after CTA is similar to intraoral infusions of innately aversive quinine and contrasts with responses to sucrose when it was novel or not paired with LiCl. Dopamine responses were negatively correlated with behavioral reactivity to intraoral sucrose and predicted home cage sucrose preference. Further, dopamine responses scaled with the strength of the CTA, which was increased by repeated LiCl pairings and weakened through extinction. Thus, the findings demonstrate differential dopamine encoding of the same taste stimulus according to its valence, which is aligned to distinct behavioral responses.

Glucagon-like peptide-1 receptor agonists: a new pharmacological treatment option for psychiatric illnesses?

Albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, orforglipron and semaglutide are glucagon-like peptide‑1 (GLP-1) receptor agonists. Tirzepatide targets not only GLP‑1 but also glucose-dependent insulinotropic peptide (GIP) receptors and retatrutide is atriple GLP‑1, GIP and glucagon receptor agonist. The GLP‑1 receptor agonists increase insulin release but suppress glucagon release. They slow down the emptying of the stomach and thus prevent blood sugar spikes. They reduce appetite and food intake. In the brain GLP‑1 receptor agonists lead to abetter glycemic control and they appear to have anti-inflammatory and neuroprotective effects. It has been reported that GLP‑1 receptor agonists reduce oxidative stress and apoptosis, lower the risk of ischemia and promote neurogenesis. The GLP‑1 receptor agonists can also influence dopaminergic signal transduction in the nucleus accumbens. Therefore, they could modify the effect of cocaine, alcohol and nicotine. Preliminary investigations provide indications of the therapeutic benefits of GLP‑1 receptor agonists for people with dementia, eating disorders, psychopharmacologically induced weight gain, depression, anxiety and substance use disorders. Typical accompanying adverse reactions are gastrointestinal side effects, such as nausea, vomiting, diarrhea, eructation and gastroesophageal reflux. More severe side effects include pancreatitis, allergic reactions, renal function disorders and possibly an increased risk of thyroid cancer.

Dopamine activity encodes the changing valence of the same stimulus in conditioned taste aversion paradigms.

Mesolimbic dopamine encoding of non-contingent rewards and reward-predictive cues has been well established. Considerable debate remains over how mesolimbic dopamine responds to aversion and in the context of aversive conditioning. Inconsistencies may arise from the use of aversive stimuli that are transduced along different neural paths relative to reward or the conflation of responses to avoidance and aversion. Here, we made intraoral infusions of sucrose and measured how dopamine and behavioral responses varied to the changing valence of sucrose. Pairing intraoral sucrose with malaise via injection of lithium chloride (LiCl) caused the development of a conditioned taste aversion (CTA), which rendered the typically rewarding taste of sucrose aversive upon subsequent re-exposure. Following CTA formation, intraoral sucrose suppressed the activity of ventral tegmental area dopamine neurons (VTADA) and nucleus accumbens (NAc) dopamine release. This pattern of dopamine signaling after CTA is similar to intraoral infusions of innately aversive quinine and contrasts with responses to sucrose when it was novel or not paired with LiCl. Dopamine responses were negatively correlated with behavioral reactivity to intraoral sucrose and predicted home cage sucrose preference. Further, dopamine responses scaled with the strength of the CTA, which was increased by repeated LiCl pairings and weakened through extinction. Thus, the findings demonstrate differential dopamine encoding of the same taste stimulus according to its valence, which is aligned to distinct behavioral responses.

Melanin-Concentrating Hormone Projections to the Nucleus Accumbens Enhance the Reward Value of Food Consumption and Do Not Induce Feeding or REM Sleep.

Regulation of food intake and energy balance is critical to survival. Hunger develops as a response to energy deficit and drives food-seeking and consumption. However, motivations to eat are varied in nature and promoted by factors other than energy deficit. When dysregulated, nonhomeostatic drives to consume can contribute to disorders of food intake, adding to the increasing prevalence of restrictive eating disorders and obesity. Melanin-concentrating hormone (MCH) neurons have been implicated in the regulation of feeding behavior, in addition to a number of other fundamental behaviors including sleep, anxiety, and maternal behavior. Several studies suggest that MCH peptide increases food consumption, while studies of MCH neurons show effects only on cued feeding, and others show no effect of MCH neuron manipulation on feeding. MCH neurons have widespread projections to diverse downstream brain regions, yet few studies have investigated the function of specific projections or differentiated the behaviors they regulate. Here we use optogenetics, in combination with different behavioral paradigms, to elucidate the role of MCH projections to the nucleus accumbens (NAc) in sleep and feeding behavior. We show that MCH neurons projecting to the NAc do not induce changes in baseline feeding or REM sleep but do enhance the preference for a food paired with optogenetic stimulation. Furthermore, this effect is diminished in female mice relative to males, in line with previous results suggesting sex differences in the functional role of MCH neurons. These results suggest that MCH projections to the NAc can enhance the rewarding value of consumed food.

α-Conotoxin TxIB Reversed Nicotine-Induced Locomotor Sensitization and Nicotine-Enhanced Dopaminergic Activity in Mice

Nicotine addiction is a serious global public health problem, so there is an urgent necessity to develop novel effective smoking cessation treatments with fewer adverse effects. Spontaneous behavioral sensitization induced by repeated intermittent exposure to the addictive substance represents a classical animal model of addiction research. A significant contributor to nicotine addiction is its interaction with α6β2* nAChRs located on midbrain dopaminergic neurons, which leads to an increase in dopamine (DA) release. α-Conotoxin (α-CTx) TxIB is a novel potent antagonist of the α6/α3β2β3* nAChRs, with an IC50 value of 28.4 nM developed by our group. In this study, we aimed to investigate the effectiveness of α-CTx TxIB in countering nicotine-induced behavioral sensitization and moderating the impact of nicotine on dopamine accumulation in the midbrain. Our results demonstrated that repeated nicotine administration remarkably elevated the locomotor activity of mice, including the number of entries, average speed, and total distance traveled, which could be effectively attenuated by α-CTx TxIB intervention in a dose-dependent manner (1 nmol and 5 nmol TxIB per mouse). Furthermore, 5 nmol α-CTx TxIB significantly reduced the nicotine-elevated DA and norepinephrine (NE) levels in the ventral tegmental area (VTA) and nucleus accumbens (NAc) of mice. 5 nmol α-CTx TxIB also markedly decreased the expression of critical proteins such as the dopamine transporter (DAT), N-methyl-D-aspartic acid receptor (NMDAR), and c-Fos in the NAc and prefrontal cortex (PFC) of the nicotine-exposed mice. This research provided the first compelling evidence that α-CTx TxIB attenuated nicotine-induced locomotor sensitization and inhibited the nicotine-induced dopamine elevation in mice. These results open up new avenues for exploring the therapeutic potential of α-CTx TxIB in the treatment of nicotine addiction.

A2A-positive neurons in the nucleus accumbens core regulate effort exertion.

Previous work has implicated the nucleus accumbens (NAc) in the regulation of effort, defined as the amount of work an animal is willing to perform for a given reward, but little is known about the specific contributions of neuronal populations within the NAc to effort regulation. In this study, using male and female mice, we examined the contributions of direct pathway and indirect pathway neurons in the NAc core using an operant effort regulation task, in which the effort requirement is the number of lever presses needed for earning a food reward. Using optogenetics, we manipulated the activity of direct pathway spiny projection neurons (dSPNs, dopamine D1-like, D1+) and indirect pathway SPNs (iSPNs, adenosine 2A receptor, A2A+). Activating dSPNs reduced lever pressing regardless of the effort requirement, as it elicited gnawing, a competing consummatory behavior. On the other hand, activating iSPNs in the NAc core (but not in the shell) reduced lever pressing in an effort-dependent manner: stimulation-induced reduction in performance was greater at higher press-to-reward ratio requirements. In contrast, optogenetically inhibiting NAc core iSPN output resulted in increased levels of effort exertion. Our results show that the indirect pathway output from the NAc core can bidirectionally regulate effort exertion.Significance statement Using bidirectional optogenetic manipulation to manipulate direct and indirect pathway neurons in the nucleus accumbens core, we found that activating the direct pathway neurons reduced lever pressing regardless of the effort requirement, as it elicited competing consummatory behaviors like gnawing. On the other hand, activating the indirect pathway neurons in the NAc core reduced lever pressing in an effort-dependent manner: stimulation-inducted reduction in performance was greater at higher press-to-reward ratio requirements.

1H Nuclear Magnetic Resonance (NMR)-Based Metabolic Changes in Nucleus Accumbens and Medial Prefrontal Cortex Following Administration of Morphine in Mice

1H Nuclear Magnetic Resonance (NMR)-Based Metabolic Changes in Nucleus Accumbens and Medial Prefrontal Cortex Following Administration of Morphine in Mice

Mendelian randomization identifies proteins involved in neurodegenerative diseases.

Proteins are involved in multiple biological functions. High-throughput technologies have allowed the measurement of thousands of proteins in population biobanks. In this study, we aimed to identify proteins related to Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis by leveraging large-scale genetic and proteomic data. We performed a two-sample cis Mendelian randomization study by selecting instrumental variables for the abundance of >2700 proteins measured by either Olink or SomaScan platforms in plasma from the UK Biobank and the deCODE Health Study. We also used the latest publicly available genome-wide association studies for the neurodegenerative diseases of interest. The potentially causal effect of proteins on neurodegenerative diseases was estimated based on the Wald ratio. We tested 13 377 protein-disease associations, identifying 169 associations that were statistically significant (5% false discovery rate). Evidence of co-localization between plasma protein abundance and disease risk (posterior probability > 0.80) was identified for 61 protein-disease pairs, leading to 50 unique protein-disease associations. Notably, 23 of 50 protein-disease associations corresponded to genetic loci not previously reported by genome-wide association studies. The two-sample Mendelian randomization and co-localization analysis also showed that APOE abundance in plasma was associated with three subcortical volumes (hippocampus, amygdala and nucleus accumbens) and white matter hyper-intensities, whereas PILRA and PILRB abundance in plasma was associated with caudate nucleus volume. Our study provided a comprehensive assessment of the effect of the human proteome that is currently measurable through two different platforms on neurodegenerative diseases. The newly associated proteins indicated the involvement of complement (C1S and C1R), microglia (SIRPA, SIGLEC9 and PRSS8) and lysosomes (CLN5) in Alzheimer's disease; the interleukin-6 pathway (CTF1) in Parkinson's disease; lysosomes (TPP1), blood-brain barrier integrity (MFAP2) and astrocytes (TNFSF13) in amyotrophic lateral sclerosis; and blood-brain barrier integrity (VEGFB), oligodendrocytes (PARP1), node of Ranvier and dorsal root ganglion (NCS1, FLRT3 and CDH15) and the innate immune system (CR1, AHSG and WARS) in multiple sclerosis. Our study demonstrates how harnessing large-scale genomic and proteomic data can yield new insights into the role of the plasma proteome in the pathogenesis of neurodegenerative diseases.

Oxytocin and Dopamine Receptor Expression: Cellular Level Implications for Pair Bonding.

Oxytocin ( Oxtr ) and dopamine ( Drd1 , Drd2 ) receptors provide a canonical example for how differences in neuromodulatory receptors drive individual and species-level behavioral variation. These systems exhibit striking and functionally-relevant differences in nucleus accumbens (NAc) expression across monogamous prairie voles ( Microtus ochrogaster ) and promiscuous meadow voles ( Microtus pennsylvanicus ). However, their cellular organization remains largely unknown. Using multiplex in situ hybridization, we mapped Oxtr , Drd1 , and Drd2 expression in sexually naïve and mate-paired prairie and meadow voles. Prairie voles have more Oxtr+ cells than meadow voles, but Oxtr distribution across dopamine-receptor cell class was similar, indicating a general upregulation rather than cell class bias. Oxtr was enriched in cells that express both dopamine receptors ( Drd1+/Drd2+ ) in prairie voles, suggesting these cells may be particularly sensitive to oxytocin. We found no species or pairing-induced differences in Drd1+ or Drd2+ cell counts, suggesting prior reports of expression differences may reflect upregulation in cells already expressing these receptors. Finally, we used single-nucleus sequencing to provide the first comprehensive map of Oxtr and Drd1-5 across molecularly-defined NAc cell types in the prairie vole. These results provide a critical framework for understanding how nonapeptide and catecholamine systems may recruit distinct NAc cell types to shape social behavior.