BACKGROUND:Long-term alcohol consumption contributes to the development of alcohol use disorder (AUD), a complex disorder with multifaceted neurobiological underpinnings. One of these is appetite-regulatory peptides, such as amylin, where activation of the amylin receptor (AMYR) suppresses alcohol-related behaviours in rodents. Earlier research has pinpointed AMYR in the nucleus accumbens (NAc) as central for this interaction, where other brain regions most likely participate. One of these might be the middle part of the paraventricular thalamus (mid-PVT), a critical node in reward-related processes. We therefore accessed this interaction through a combination of behavioural, neurochemical, and molecular experiments. METHODS:Western Blot, immunohistochemistry, and RNAscope were utilized to identify the calcitonin receptor (CTR), the main component of AMYR, in mid-PVT. To investigate the effects of salmon calcitonin (sCT), a CTR and AMYR agonist, locally infused in the mid-PVT on alcohol-related behaviours in rodents, the intermittent alcohol drinking paradigm, locomotor stimulation test, and microdialysis setup were employed. FINDINGS:CTR was detected in the thalamus in male NMRI mice and in mid-PVT of Wistar and Sprague Dawley (SD) rats. Locally infused sCT into mid-PVT decreased alcohol intake in males (P = 0.0048), but not in female (P = 0.8982) Wistar rats. A pilot experiment indicated that CTR was co-localized with glutamatergic projections from mid-PVT to NAc in males, but not female SD rats. Moreover, in male NMRI mice, sCT into mid-PVT attenuated alcohol-induced locomotor stimulation and dopamine release in NAc. INTERPRETATION:In summary, sCT into mid-PVT suppressed alcohol-related behaviours in male rodents, potentially through CTR on glutamatergic projections to NAc.

OBJECTIVE:One in nine Americans will undergo a surgical procedure during their lifetime and, for some, the treatment of postoperative pain represents their first prolonged exposure to an opioid. New persistent opioid use (NPOU) refers to continued opioid use beyond the typical surgical recovery period (3 months) in opioid-naïve patients and has been linked to increased morbidity, mortality, and opioid-related complications. This systematic review with meta-analysis synthesized the recent evidence on patient-related risk factors for NPOU among opioid-naïve postsurgical adults in the United States to derive a pooled effect size for evaluable factors using a random-effects model (PROSPERO: CRD420250651059). METHODS:We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement and checklist. The level of evidence and methodological quality were assessed using the Joanna Briggs Institute checklist. Estimates of associations and CIs were extracted. Risk factors were categorized as either sociodemographic, clinical, or opioid exposure factors using a narrative synthesis. A random effects meta-analysis of estimates of association was performed. RESULTS:A comprehensive literature search resulted in 27 articles; all were retrospective cohort studies and 89% were deemed of good quality. Among the various risk factors identified through narrative synthesis, mood disorders, anxiety, Medicaid enrollment, and preoperative benzodiazepine use were the most predictive of NPOU. The pooled odds ratios for these risk factors from meta-analysis were 1.24 (95% CI, 1.17-1.32), 1.17 (1.11-1.23), 1.77 (1.46-2.15), and 1.77 (1.53-2.05), respectively. CONCLUSION:Opioid-naïve persons insured by Medicaid or with preoperative anxiety, depression, or benzodiazepine use, are associated with a higher risk for NPOU.

Psychostimulant use disorder (PSUD) and nicotine use disorder (NUD) affect tens of millions of people worldwide, yet no clinically approved medications exist for PSUD, and existing NUD treatments have limited long-term efficacy. Recent preclinical evidence suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists could be repurposed for treating PSUD and NUD. This review summarizes the current literature investigating the efficacy of GLP-1R agonists to reduce psychostimulant and nicotine-mediated behaviors in animal models of PSUD and NUD, respectively. The neural mechanisms underlying the suppressive effects of GLP-1R agonists on drug-mediated behaviors as well as the role of central endogenous GLP-1 neural circuits in voluntary drug-taking and drug-seeking behaviors are also discussed. Overall, a growing preclinical literature and emerging clinical studies support the translational potential of GLP-1R agonists as novel pharmacotherapies for treating substance use disorders including PSUD and NUD.

Background Cocaine use disorder (CUD) remains among the most treatment-resistant addictions, characterised by high relapse rates even following extended abstinence periods. Dopamine signalling in mesocorticolimbic circuits contributes to cocaine's reinforcing effects and remains an important target for therapeutic intervention. Growing evidence suggests appetite-regulating peptides may influence central dopamine transmission. Whether recently approved incretin polyagonists can modulate cocaine-related behaviours through their capacity to simultaneously engage multiple appetite-regulating peptide receptor pathways remains unexplored. Methods Here we investigated whether tirzepatide, a clinically approved long-acting dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide 1 (GLP-1) receptor agonist, alters cocaine-related behavioural and neurochemical responses in male rodents. Findings We found that tirzepatide produced dose-dependent reductions in cocaine self-administration (P < 0.001) and diminished cocaine-evoked dopamine responses, as evidenced by attenuated locomotor stimulation (P < 0.001), conditioned place preference (P < 0.001), and accumbal dopamine levels (P < 0.01) across two cocaine doses. Tirzepatide also reduced the motivation to self-administer cocaine (P < 0.05) and attenuated the reinstatement of cocaine-seeking behaviour in animal models of relapse (P < 0.001). Beyond these effects, tirzepatide prevented the expression of cocaine-induced locomotor sensitisation (P < 0.001), suggesting it may have broader neuroadaptive effects. Neurochemical analyses revealed that tirzepatide normalised cocaine-induced dopamine elevations in mesocorticolimbic circuits (P < 0.001) and the lateral septum (P < 0.001), consistent with the behavioural attenuation and our accumbal microdialysis data. We also observed effects on GABA (P < 0.01) and glutamate (P < 0.01) signalling in these regions, suggesting possible multi-neurotransmitter mechanisms. Principal component analysis indicated that tirzepatide affects neural substrates regulating mesocorticolimbic function, potentially contributing to the observed effects on accumbal dopamine release. Interpretation When considering our findings alongside tirzepatide's clinical availability, the evidence suggests this incretin polyagonist merits investigation as a potential treatment approach for CUD. Funding The study is supported by grants (EJ) from the Swedish Research Council (2023-2600 and 2025-07154), LUA/ALF (grant no. 723941) from the Sahlgrenska University Hospital, Alcohol Research Council of the Swedish Alcohol Retailing Monopoly (FO2024-0048), Adlerbertska Research Foundation (2024-791), Wilhelm & Martina Lundgren’s Research Foundation (2024-SA-4698) and Mary von Sydow Foundation (2024-36). This work was also supported by the following grants from the National Institutes of Health (NIH): R01 DA037897 and R01 DA061799 (H.D.S.) Thaynnam A Emous held an international internship scholarship from the São Paulo Research Foundation (FAPESP), Process Number #2023/18470-5, while conducting research at the University of Gothenburg.

As obesity rates continue to rise globally, combination therapies are being developed for their pronounced and sustained weight loss effects. CagriSema is a fixed-ratio combination of the long-acting GLP-1R agonist semaglutide and the calcitonin (CTR)/amylin receptor (AMYR) agonist cagrilintide that shows greater efficacy for weight loss compared to GLP-1R and CTR/AMYR mono-agonists alone. However, knowledge of the neural sites capable of producing potentiated effects as a result of GLP-1R/CTR/AMY co-agonism remains incomplete. In this study, we investigate the laterodorsal tegmental nucleus (LDTg) as a central site of integration for GLP-1R and CTR/AMYR signaling, and explore the effect of co-agonism in this nucleus on feeding behavior. We first performed fluorescence in situ hybridization (FISH) to show that glp-1r- and ctr-expressing neurons comprise largely distinct populations within the LDTg, supporting a model where LDTg GLP-1R and CTR/AMYR agonists reduce feeding via engagement of distinct complementary cells in the LDTg. We also showed that co-administration of GLP-1R and CTR/AMYR agonists into the LDTg resulted in a greater suppression of food intake and reduction in body weight compared to either treatment alone. Finally, using an operant model, we found that this combinatorial treatment significantly reduced motivation to self-administer a highly palatable food reward. Overall, intra-LDTg co-agonism of GLP-1Rs and CTR/AMYRs produced a greater suppressive effect on homeostatic and motivational aspects of feeding behavior than monotherapy alone. These results highlight the LDTg as a previously undescribed central site with potential clinical relevance for the development of dual GLP-1R and CTR/AMYR pharmacotherapies to combat obesity.

Cocaine use disorder (CUD) remains a major public health concern with no FDA-approved pharmacotherapy, underscoring the need to define the cellular and molecular adaptations produced by voluntary cocaine taking. The nucleus accumbens (NAc) is a key substrate for cocaine reinforcement and drug-seeking behavior, but interpretation of the functional role of its cellular heterogeneity in these behaviors is limited by past bulk transcriptomic studies. Here, we used single-nucleus RNA sequencing to profile the NAc of male and female rats that self-administered intravenous cocaine for 10 consecutive days versus yoked saline controls. After quality control, we analyzed 36,766 nuclei spanning major neuronal, glial, and vascular cell populations. Pseudobulk differential-expression analyses identified 478 cocaine-associated cell type-specific transcriptional changes that were concentrated in discrete medium spiny neuron (MSN) subclasses and astrocytes. D1 Ebf1+ MSNs showed the largest transcriptomic response, accounting for ~40% of all differential-expression events, followed by D2 Stk32a+ MSNs, astrocytes, and D1 Ppm1e+ MSNs. These responses were largely cell type-specific, indicating that cocaine self-administration engages multiple molecular programs rather than a uniform accumbens-wide transcriptional signature. Immediate-early gene module-score analyses further revealed cocaine-associated activation states in select neuronal and non-neuronal cell populations, including D1 Ebf1+ MSNs, Drd3+ neurons, Sst+ interneurons, astrocytes, and oligodendrocytes. Gene-set, pathway, and upstream-regulator analyses nominated synaptic organization, axon guidance, RAS/MAPK signaling, NMDA receptor-associated signaling, and CREB-related transcriptional regulation as candidate mechanisms of cocaine-evoked plasticity. Together, these data provide a cell type-resolved resource for understanding how voluntary cocaine taking alters the rat NAc transcriptome and identifies discrete neuronal and glial cell populations for future mechanistic studies using preclinical CUD models.

Background and PurposeEmerging literature indicates that simultaneously targeting glucagon-like peptide-1 receptors (GLP-1Rs) and neuropeptide Y receptors (Y1/Y2) may represent a new pharmacotherapeutic approach to treating opioid use disorder (OUD). The overall goal of this study was to screen the efficacy of GEP12, a novel GLP-1R/Y1 receptor/Y2 receptor triple agonist, to reduce voluntary fentanyl taking and seeking.Experimental ApproachRats were allowed to self-administer fentanyl (2.5 mu g kg-1, i.v.) for 21 days. Rats were then pretreated with vehicle or GEP12 (1.57 or 12.53 mu g kg-1, i.p.) prior to fentanyl self-administration test sessions. Opioid taking was then extinguished and rats were pretreated with vehicle or GEP12 (1.57 or 12.53 mu g kg-1, i.p.) prior to subsequent reinstatement test sessions.Key ResultsGEP12 reduced fentanyl taking in both male and female rats and shifted the fentanyl self-administration dose-response curve downward. Importantly, we identified behaviourally selective doses of GEP12 that were well-tolerated in fentanyl-experienced rats. GEP12 also reduced fentanyl seeking during abstinence in both male and female rats at doses that did not alter food intake or produce adverse malaise-like effects. To identify a central mechanism underlying the efficacy of GLP-1R/Y1 receptor/Y2 receptor triple agonists, we showed that systemic GEP12 penetrated the brain and distributed to the mesolimbic reward system. Using in vivo fibre photometry, we discovered that GEP12 reduced fentanyl self-administration-evoked dopamine release in the nucleus accumbens.Conclusions and ImplicationsTogether, these findings support the continued development of GLP-1R/Y1 receptor/Y2 receptor triple agonists as a novel class of pharmacotherapies for treating OUD.

Currently, no pharmaceutical treatments exist for cocaine use disorder, which is characterized by dysregulated motivation, intense drug craving, compulsive drug-seeking behavior, and relapse during abstinence. While shortacting glucagon-like peptide-1 receptor (GLP-1R) reduces cocaine-related behaviors, its impact is limited by low affinity towards GLP-1R. Semaglutide may be beneficial in this context as it is long-acting with greater potency and affinity for the GLP-1R. Its superiority is substantiated in studies on alcohol and alcohol use disorder (AUD) as it profoundly reduces alcohol intake in animals and patients with AUD, whereas exendin-4 (Ex4) slightly reduces alcohol intake in rats, whereas it does not alter alcohol intake in AUD patients. However, it remains to be explored whether its beneficial effects extend to more complex cocaine-related behaviors, the aim of the present study. Using the cocaine self-administration paradigm in male rats, we tested the efficacy of different doses of semaglutide to reduce voluntary cocaine taking, the motivation to consume cocaine, and the reinstatement of cocaine-seeking behavior. Furthermore, we explored the effects of semaglutide on cocaine-evoked dopamine levels in the nucleus accumbens (NAc). Semaglutide decreased cocaine self-administration, the motivation to consume cocaine, and cocaine reinstatement in male rats. Moreover, semaglutide attenuated cocaine-induced elevation of dopamine levels in mice and rats. Additionally, neither of the tested doses altered kaolin intake, a measurement of malaise, in cocaine-experienced rats. These findings further support the role of GLP-1R in cocaine taking and imply that semaglutide should be tested as a candidate for treating cocaine use disorder.

Background Chronic substance abuse is a significant global health problem. This issue is exacerbated by polysubstance use, such as the combination of fentanyl, a potent opioid, and xylazine, an animal tranquilizer which is not approved for human use. This combination enhances the sedative and respiratory depressant effects of fentanyl in a manner resistant to rescue pharmacotherapy and leads to severe health consequences, like necrotic wounds that frequently result in limb amputation. Despite these known dangers, fentanyl+xylazine polysubstance use rates are increasing. Thus, it is imperative that additional efforts are dedicated to understanding the neurobiological mechanisms underlying the effect of fentanyl+xylazine on reward circuitry. This study aims to generate foundational knowledge of the molecular effects of fentanyl, xylazine, or fentanyl+xylazine on the nucleus accumbens (NAc) of male and female rats using isoform resolved transcriptomics. Methods Adult male and female Sprague Dawley rats received twice-daily intraperitoneal injections of fentanyl (45 µg/kg), xylazine (2.5 mg/kg), fentanyl+xylazine, or saline (n=4/sex/treatment) for 14 consecutive days. RNA purified from the NAc was used for Oxford Nanopore Technologies long-read sequencing. Results Our findings reveal alterations in shared and sex-specific gene and isoform level expression in the NAc when comparing fentanyl, xylazine, and fentanyl+xylzine groups. We identified several biological pathways and regulatory mechanisms that were disrupted by the fentanyl and xylazine combination. Discussion These results highlight the unique molecular underpinnings of fentanyl+xylazine polysubstance exposure and the need for continued research that examines the neurogenetic basis of substance abuse using splice variant aware approaches

Background The central amygdala (CeA) has been shown to play a critical role in cocaine craving, one of the primary drivers of relapse in individuals with cocaine use disorder. Our knowledge of the specific pathways and cell types involved in cocaine craving is still limited but new single cell technologies provide an opportunity to examine the effects of cocaine on individual cellular populations in the CeA. Methods We used single nucleus ATAC-seq (assay for transposase-accessible chromatin with sequencing) to characterize chromatin accessibility changes in the CeA of rats self-administering cocaine. A cohort of Sprague Dawley rats (n=6; 3 males, 3 females) was allowed to self-administer intravenous cocaine for ten consecutive days. Each cocaine-experienced rat was paired to a sex-matched, yoked saline control rat. 10x Genomics ATAC-seq libraries were generated from nuclei isolated from CeA punches. ATAC-seq data were analyzed with the R package Signac. Results All expected glial and neuronal populations were identified. Cell type-specific differentially accessible regions (DAPs) were observed in cocaine-experience animals compared to the saline controls in both glia and neuronal subtypes, suggesting that cocaine-induced alterations in transcription in the CeA are mediated by chromatin conformation changes. Bioinformatic analyses identified upstream regulatory mechanisms and downstream signaling pathways associated with these cell type-specific DAPs. Discussion These results indicate that repeated, daily cocaine self-administration is associated with distinct cell type-specific chromatin accessibility changes in the rat CeA. These findings highlight specific amygdalar cell populations and novel molecular substrates that could be targeted to reduce compulsive cocaine taking.

AIMS:Opioid use disorder (OUD) remains a serious public health problem. Opioid maintenance treatment is effective but under-utilized, hard to access under existing federal regulations, and, once patients achieve OUD stability, challenging to discontinue. Fewer than 2% of persons with OUD stop using opioids completely. There have been calls from public advocacy groups, governmental agencies, and public health officials for new treatments for OUD. Dezocine, a non-scheduled opioid previously used in the United States and currently widely prescribed in China for pain management, could be a candidate for a novel OUD treatment medication in the U.S. Nonetheless, to date, there have been no reviews of the clinical and preclinical literature detailing dezocine's abuse potential, a key consideration in assessing its clinical utility. DISCUSSION:There are no English language reports of human abuse, dependence, or overdose of dezocine, despite years of extensive clinical use. There are a few case reports of dezocine abuse in the Chinese literature, but there are no reports of overdose deaths. Dezocine is perceived as an opioid and is "liked" by opioid-experienced human and non-human primates, properties that are not dose-dependent and are mitigated by ceiling effects-higher doses do not result in more "liking." There is little withdrawal, spontaneous or precipitated, in humans, monkeys, rats, or mice treated chronically with dezocine alone. However, at some doses, dezocine can precipitate withdrawal in humans and monkeys dependent on other opioids. In rodents, dezocine reduces the severity of morphine withdrawal and the rewarding properties of other opioids. CONCLUSIONS:Although dezocine is reinforcing in humans and monkeys with prior or concurrent opioid use within a restricted dose range, there are only a few anecdotal reports of dezocine abuse despite of the long history of use in humans. Given the evidence of dezocine's limited abuse potential, it could be useful both as a treatment for OUD. However, in-depth studies would be required for dezocine to be re-considered for clinical use.

Neural processing of rewarding stimuli involves several distinct regions, including the nucleus accumbens (NAc). The majority of NAc neurons are GABAergic projection neurons known as medium spiny neurons (MSNs). MSNs are broadly defined by dopamine receptor expression, but evidence suggests that a wider array of subtypes exist. To study MSN heterogeneity, we analyzed single-nucleus RNA sequencing data from the largest available rat NAc dataset. Analysis of 48,040 NAc MSN nuclei identified major populations belonging to the striosome and matrix compartments. Integration with mouse and human data indicated consistency across species and disease-relevance scoring using genome-wide association study results revealed potentially differential roles for MSN populations in substance use disorders. Additional high-resolution clustering identified 34 transcriptomically distinct subtypes of MSNs definable by a limited number of marker genes. Together, these data demonstrate the diversity of MSNs in the NAc and provide a basis for more targeted genetic manipulation of specific populations.

Nicotine use disorder (NUD) remains a leading cause of preventable death in the U.S. Unfortunately, current FDA-approved pharmacotherapies for smoking cessation have limited efficacy and are associated with high rates of relapse. One major barrier to long-term smoking abstinence is body weight gain during withdrawal. Nicotine withdrawal-induced body weight gain can also lead to development of chronic disease states like obesity and type II diabetes mellitus. Therefore, it is critical to identify novel pharmacotherapies for NUD that decrease relapse and nicotine withdrawal symptoms including body weight gain. Recent studies demonstrate that glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate voluntary nicotine taking and seeking and prevent withdrawal-induced hyperphagia and body weight gain. Emerging evidence also suggests that GLP-1R agonists improve cognitive deficits, as well as depressive- and anxiety-like behaviors, which contribute to smoking relapse during withdrawal. While further studies are necessary to fully characterize the effects of GLP-1R agonists on NUD and understand the mechanisms by which GLP-1R agonists decrease nicotine withdrawal-mediated behaviors, the current literature supports GLP-1R-based approaches to treating NUD.

Recent studies show that systemic administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist is sufficient to attenuate the reinstatement of cocaine-seeking behavior, an animal model of relapse. However, the neural mechanisms mediating these effects and the role of endogenous central GLP-1 signaling in cocaine seeking remain unknown. Here, we show that voluntary cocaine taking decreased plasma GLP-1 levels in rats and that chemogenetic activation of GLP-1-producing neurons in the nucleus tractus solitarius (NTS) that project to the ventral tegmental area (VTA) decreased cocaine reinstatement. Single nuclei transcriptomics and FISH studies revealed GLP-1Rs are expressed primarily on GABA neurons in the VTA. Using in vivo fiber photometry, we found that the efficacy of a systemic GLP-1R agonist to attenuate cocaine seeking was associated with increased activity of VTA GABA neurons and decreased activity of VTA dopamine neurons. Together, these findings suggest that targeting central GLP-1 circuits may be an effective strategy toward reducing cocaine relapse and highlight a novel functional role of GABAergic GLP-1R-expressing midbrain neurons in drug seeking.

Background and PurposeThe limited effectiveness of current pharmacological treatments for alcohol use disorder (AUD) highlights the need for novel therapies. These may involve the glucagon-like peptide-1 receptor or the amylin receptor, as treatment with agonists targeting either of these receptors lowers alcohol intake. The complexity of the mechanisms underlying AUD indicates that combining agents could enhance treatment efficacy. While a combination of amylin receptor and GLP-1 receptor agonists reduced food intake and body weight synergistic-like, its influence on alcohol intake is unknown.Experimental ApproachEffects of a range of dose-combinations of GLP-1 receptor (dulaglutide) and amylin receptor (salmon calcitonin; sCT) agonists on alcohol intake were explored in male and female rats. We used dose combinations that either lowered alcohol intake as monotherapy (0.1 mgkg-1 + 5 mu gkg-1), or that did not affect alcohol consumption per se (0.075 mgkg-1 + 2 mu gkg-1).Key ResultsAcute administration of dulaglutide and sCT (0.1 mgkg-1 + 5 mu gkg-1) reduced alcohol intake in males, but not in females. When higher doses were evaluated in female rats, a decrease in alcohol intake was observed. Furthermore, the low dose combination (0.075 mgkg-1 + 2 mu gkg-1) decreased, in in a synergistic-like manner, alcohol intake and prevented abstinence-induced drinking without affecting kaolin intake in males. However, tolerance developed during sub-chronic treatment.Conclusion and ImplicationsCollectively, these findings show that the combination of dulaglutide and sCT decreased, in in a synergistic-like manner, alcohol consumption in male rats. Contrarily, higher doses are required for females.

More effective treatments for fentanyl use disorder are urgently needed. An emerging literature indicates that glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate voluntary opioid taking and seeking in rodents. However, GLP-1R agonists produce adverse malaise-like effects that may limit patient compliance. Recently, we developed a dual agonist of GLP-1Rs and neuropeptide Y2 receptors (Y2Rs) that attenuates fentanyl taking and seeking at doses that do not produce malaise-like effects in opioid-experienced rats. Whether activating Y2Rs alone is sufficient to reduce opioid taking and seeking, however, is not known. Here, we investigated the efficacy of the Y2R ligand PYY3-36 to reduce fentanyl self-administration and the reinstatement of fentanyl-seeking behavior, a model of relapse in humans. Male rats were allowed to self-administer fentanyl (2.5 μg/kg, i.v.) for 21 days on a fixed-ratio 5 (FR5) schedule of reinforcement. Rats were then pretreated with vehicle or PYY3-36 (50 μg/kg s.c.; 0.1 and 1.0 μg/100 nL intra-VTA) prior to fentanyl self-administration test sessions. There were no effects of systemic or intra-VTA PYY3-36 on intravenous fentanyl self-administration. Opioid taking was then extinguished. Prior to subsequent reinstatement test sessions, rats were pretreated with vehicle or PYY3-36 (50 μg/kg s.c.; 0.1 and 1.0 μg/100 nL intra-VTA). Both systemic and intra-VTA administration of PYY3-36 attenuated fentanyl reinstatement in male rats at doses that did not affect food intake or produce adverse malaise-like effects. These findings indicate that Y2R agonism alone is sufficient to decrease fentanyl-seeking behavior during abstinence in opioid-experienced rats and further support strategies aimed at targeting Y2Rs for treating opioid use disorders.

The high rates of relapse associated with current medications used to treat opioid use disorder (OUD) necessitate research that expands our understanding of the neural mechanisms regulating opioid taking to identify molecular substrates that could be targeted by novel pharmacotherapies to treat OUD. Recent studies show that activation of calcitonin receptors (CTRs) is sufficient to reduce the rewarding effects of addictive drugs in rodents. However, the role of central CTR signaling in opioid-mediated behaviors has not been studied. Here, we used single nuclei RNA sequencing (snRNA-seq), fluorescent in situ hybridization (FISH), and immunohistochemistry (IHC) to characterize cell type-specific patterns of CTR expression in the nucleus accumbens (NAc), a brain region that plays a critical role in voluntary drug taking. Using these approaches, we identified CTRs expressed on D1R- and D2R-expressing medium spiny neurons (MSNs) in the medial shell subregion of the NAc. Interestingly, Calcr transcripts were expressed at higher levels in D2R- versus D1R-expressing MSNs. Cre-dependent viral-mediated miRNA knockdown of CTRs in transgenic male rats was then used to determine the functional significance of endogenous CTR signaling in opioid taking. We discovered that reduced CTR expression specifically in D1R-expressing MSNs potentiated/augmented opioid self-administration. In contrast, reduced CTR expression specifically in D2R-expressing MSNs attenuated opioid self-administration. These findings highlight a novel cell type-specific mechanism by which CTR signaling in the ventral striatum bidirectionally modulates voluntary opioid taking and support future studies aimed at targeting central CTR-expressing circuits to treat OUD.