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We examined DA activity in the medial prefrontal cortex (mPFC) and nucleus accumbens core (NAcc) in two Different Rat Models of Attention-Deficit/Hyperactivity Disorder: Spontaneously Hypertensive Rats (SHR) Versus Lphn3 Knockout Rats. We examined baseline stimulation-evoked phasic DA release, half-life, and DA autoreceptor (DAR) functioning in the mPFC and NAcc, as well as the response to nomifensine (10 mg/kg, IP), a DA transporter (DAT) blocker, on these measures in the NAcc. Both rat models were hypodopaminergic, with notable regional and mechanistic differences. The SHRs displayed decreased DA release in the NAcc compared to their control strain (i.e., WKY rats), with no differences in the mPFC, leading a much lower NAcc-to-PFC DA release ratio in SHRs compared to controls suggesting an imbalance in DA transmission between these regions. The Lphn3 KO rats were considered hypodopaminergic based on the reduced summed DA release in the mPFC and NAcc compared to WT controls, although differences were not observed when examining each site independently. Lphn3 KOs displayed increased DA half-life in the mPFC compared with Lphn3 WT rats, an indication of decreased DAT reuptake, with no differences in the NAcc. DAT blockade by nomifensine had a similar effect on DA release in the NAcc of SHRs and WKYs, but increased DA release in the NAcc of Lphn3 KOs to a greater extent than in WTs. These results suggest that the efficacy of pharmacotherapies used to treat externalizing disorders such as ADHD and/or SUD, likely differ between SHRs and Lphn3 KO rats., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Research on nicotine's neurobiological effects has rarely focused on aerosols, despite their primary role in tobacco product consumption. Here, we utilized in vivo electrophysiology to examine brain activity in mice exposed to nicotine aerosols, both alone and with flavor additives (citric acid and menthol). Local field potential (LFP) recordings from the nucleus accumbens (NAc), basolateral amygdala (BLA), ventral tegmental area (VTA), and ventral posteromedial nucleus (VPM) were analyzed under saline, nicotine, nicotine with citric acid(CA + NIC), and nicotine with menthol(MENT + NIC) conditions. Nicotine exposure significantly reduced power spectral density (PSD) in the NAc-Alpha, NAc-Beta, and BLA-Beta bands, unaffected by flavor additives. Coherence between key brain regions (e.g., VPM-VTA in Beta, VPM-BLA in Alpha) also decreased with nicotine but was restored with citric acid or menthol, suggesting their role in mitigating nicotine's disruptive effects on neural synchronization. Our findings show that LFPs can effectively capture nicotine's neural effects and highlight the modulatory role of flavor additives, offering new insights into nicotine exposure management and tobacco product design., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Reactive oxygen species (ROS) have been implicated in behaviors induced by acute or repeated cocaine or methamphetamine administration in rodents. In the present study, we investigated the involvement of ROS in behavioral changes induced by nicotine administration and dopamine (DA) transmission changes in the nucleus accumbens (NAc) of rats. Rats were given repeated saline or nicotine (0.4 mg/kg) administration once daily for seven days, and the induction of hyperlocomotor activity, and oxidative stress marker expression induced by the increase in ROS production in the NAc were measured on day 7. We also tested the effect of ROS scavengers on repeated nicotine-induced hyperlocomotor activity and nicotine self-administration, and DA levels in the NAc. Repeated nicotine administration induced hyperlocomotor activity and decreased the expression of oxidative stress markers, such as superoxide dismutase-1 and glutathione peroxidase 1/2, by elevating ROS production in the NAc. Pretreatment with the nonspecific ROS scavenger PBN and the superoxide-selective scavenger TEMPOL significantly attenuated nicotine-induced hyperlocomotor activity without impairing motor function in nicotine-naïve rats on day 7. In addition, in intravenous nicotine self-administration study, TEMPOL significantly reduced nicotine-taking behavior without affecting food intake in nicotine-naïve rats. Furthermore, TEMPOL pretreatment prevented nicotine effects on stimulated DA release in the NAc, which was associated with nicotine-induced behavioral changes. Taken together, these findings suggest that increased ROS production in the NAc contributes to the neuropharmacological properties of nicotine., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All procedures regarding the handling and use of animals in the present study were conducted as approved by the Institutional Animal Care and Use Committee (IACUC) of the Korea Institute of Toxicology (KIT; No. 2112–0049 and 2112–0055)., (© 2025. The Author(s).)

Research has extensively explored the role of the dopaminergic system in the reward circuit, while the contribution of the noradrenergic system remains less understood. This study aims to fill this gap by employing computational modeling to examine how the medial prefrontal cortex (mPFC) influences cocaine-induced norepinephrine (NE) release in the nucleus accumbens shell (NAcc), with mediation by the nucleus of the tractus solitarius (NTS) and the locus coeruleus (LC). The model replicates previously reported data on NE release in the mPFC following cocaine administration. Additionally, it predicts that NE depletion in the mPFC affects NE release in the NAcc through interactions with the NTS and LC. This work proposes a system-level hypothesis, suggesting that the mPFC regulates NE release in the NAcc by modulating the LC and NTS. These findings enhance our understanding of the neurochemical response to cocaine and offer potential directions for future addiction treatments., Competing Interests: Declarations. Conflict of interest: The authors declare no competing financial interests. On behalf of all authors, the corresponding author states that there is no Conflict of interest., (© 2025. The Author(s).)

Alcohol use disorder is a severe mental health condition causing medical consequences and preterm death. Alcohol activates the mesolimbic dopamine system leading to an increase of extracellular dopamine (DA) in the nucleus accumbens, an event that is associated with the reinforcing effects of alcohol. Cholinergic interneurons (CIN) are important modulators of accumbal DA signalling, and depletion of accumbal CIN attenuates the alcohol-induced increase in extracellular DA. The aim of this study was to explore the functional role of accumbal CIN in alcohol-related behaviour. To this end, ablation of CIN was induced by local administration of anticholine acetyltransferase-saporin bilaterally into the nucleus accumbens of male Wistar rats. Alcohol consumption in ablated and sham-treated rats was studied using a two-bottle-choice intermittent alcohol consumption paradigm. Rats with depleted CIN consumed significantly less alcohol than sham-treated controls. No differences in sucrose preference, motor activity, water intake or weight gain were noted between treatment groups, suggesting that the ablation selectively affected alcohol-related behaviour. In conclusion, this study further supports a role for accumbal CIN in regulating alcohol-consummatory behaviour., (© 2025 The Author(s). Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Dopamine is a neurotransmitter that plays a significant role in reward and motivation. Dysfunction in the mesolimbic dopamine pathway has been linked to a variety of psychiatric disorders, including addiction. Low-intensity focused ultrasound (LIFU) has demonstrated effects on brain activity, but how LIFU affects dopamine neurotransmission is not known. Here, we applied three different intensities (6.5, 13, and 26 W/cm 2 I SPPA ) of 2-min LIFU to the prelimbic cortex (PLC) and measured dopamine in the nucleus accumbens (NAc) core using fast-scan cyclic voltammetry. Two minutes of LIFU sonication at 13 W/cm 2 to the PLC significantly reduced dopamine release by ~50% for up to 2 h. However, double the intensity (26 W/cm 2 ) resulted in less inhibition (~30%), and half the intensity (6.5 W/cm 2 ) did not result in any inhibition of dopamine. Anatomical controls applying LIFU to the primary somatosensory cortex did not change NAc core dopamine, and applying LIFU to the PLC did not affect dopamine release in the caudate or NAc shell. Histological evaluations showed no evidence of cell damage or death. Modeling temperature rise demonstrates a maximum temperature change of 0.5°C with 13 W/cm 2 , suggesting that modulation is not due to thermal mechanisms. These studies show that LIFU at a moderate intensity provides a noninvasive, high spatial resolution means to modulate specific mesolimbic circuits that could be used in future studies to target and repair pathways that are dysfunctional in addiction and other psychiatric diseases., (© 2025 The Author(s). Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Neuropathic pain presents a significant challenge, with its underlying mechanisms still not fully understood. Here, we investigated the role of GluN2C- and GluN2D-containing NMDA receptors in the development of neuropathic pain induced by cisplatin, a widely used chemotherapeutic agent. Through genetic and pharmacological strategies, we found that GluN2D-containing NMDA receptors play a targeted role in regulating cisplatin-induced neuropathic pain (CINP), while sparing inflammatory or acute pain responses. Specifically, both GluN2D knockout (KO) mice and pharmacological blockade of GluN2D-containing receptors produced robust reduction in mechanical nocifensive response in CINP. In contrast, GluN2C KO mice behaved similar to wildtype mice in CINP but showed reduced mechanical hypersensitivity in inflammatory pain. Using conditional KO strategy, we addressed the region- and cell-type involved in GluN2D-mediated changes in CINP. Animals with conditional deletion of GluN2D receptors from parvalbumin interneurons (PVIs) or local ablation of GluN2D from nucleus accumbens (NAc) displayed reduced mechanical hypersensitivity in CINP, underscoring the pivotal role of accumbal GluN2D in PVIs in neuropathic pain. Furthermore, CINP increased excitatory neurotransmission in the NAc in wildtype mice and this effect is dampened in PV-GluN2D KO mice. Other changes in CINP in NAc included an increase in vGluT1 and c-fos labeled neurons in wildtype which were absent in PV-GluN2D KO mice. G i DREADD-induced inhibition of PVIs in the NAc produced reduction in mechanical hypersensitivity in CINP. These findings unveil a novel cell-type and region-specific role of GluN2D-containing NMDA receptors in neuropathic pain and identify PVIs in NAc as a novel mediator of pain behaviors., Competing Interests: Declaration of competing interest SMD has patent pending on GluD1-Cbln1 signaling in pain. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shashank M. Dravid reports financial support was provided by National Institutes of Health. Shashank M. Dravid reports financial support was provided by National Science Foundation. Shashank M. Dravid reports a relationship with None that includes:. Shashank M. Dravid has patent pending to Creighton University. None If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Recreational use of nitrous oxide (N 2 O) has risen dramatically over the past decades. This study aimed to examine its rewarding effect and the underlying mechanisms. The exposure of mice to a subanesthetic concentration (20%) of N 2 O for 30 min for 4 consecutive days paired with N 2 O in the morning and paired with the air in the afternoon produced apparent rewarding behavior in the conditioned place preference (CPP) paradigm. This was abrogated by microinjection into the nucleus accumbens (NAc) of the dopamine (DA) D1 receptor antagonist SCH23390, but not the D2 antagonist haloperidol. N 2 O robustly enhanced DAergic neuronal activity of the ventral tegmental area (VTA) and the concentration of DA in the NAc. The repeated N 2 O exposure also upregulated the expression of brain-derived neurotrophic factor (BDNF) in the VTA and its multiple downstream mediators in the NAc. Conversely, VTA focal knockdown of BDNF and the inhibition of the downstream mediators suppressed the N 2 O-induced rewarding effect and the DAergic neuronal activity of the VTA. Further, the combined intervention of BDNF knockdown and D1 antagonist significantly inhibited the N 2 O-induced rewarding effect in mice, which was greater than that of BDNF knockdown alone, but was not significantly different from that of D1 antagonist alone. These results indicate that the rewarding properties of N 2 O at subanesthetic concentration are associated with its upregulation of the VTA-NAc DA reward pathway probably via mediation of D1 receptor and BDNF/TrkB signaling. Among them, the modulation of BDNF may be the upstream of D1 receptor involved in N 2 O rewarding effect., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All animal experiments were performed following the approved protocol according to the guidelines of the Committee on the Use of Live Animals in Teaching and Research of the University of Hong Kong (CULATR ref: 22–121). All animal procedures were performed in strict accordance with the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines., (© 2025. The Author(s).)

Background: Methamphetamine (METH) is a potent psychostimulant that interferes the functionality of various brain regions and nervous connections, leading to addiction. The nucleus accumbens core (NAcC), primarily composed of gamma-aminobutyric acid (GABAergic) neurons, serves as a critical nucleus intimately related to addictive behavior. Previous research has indicated the involvement of cholecystokinin (CCK) receptors in drug addiction, yet the precise function of CCK receptors within the neural circuitry mediating METH-induced addiction remains elusive., Methods: METH-induced conditioned place preference (CPP) model was established in mice. In CCK receptor 1 conditional knockout (CCK1R flox/flox ) or CCK receptor 2 conditional knockout (CCK2R flox/flox ) mice, we then utilized the adeno-associated virus (AAV) transfection system to knock out the specific CCK receptor subtype and explore the function of the CCK receptors in the ventral tegmental area (VTA) to NAcC circuit during METH-induced CPP acquisition., Results: During the acquisition of METH-induced CPP, the expression of CCK1R, but not CCK2R, was upregulated specifically in NAcC. Genetic disruption of either CCK1R in the NAcC effectively hindered METH-induced CPP acquisition and prevented the hyper-excitability of neurons triggered by METH. Furthermore, CCK is released by dopaminergic neurons in the VTA, projecting to the NAcC. Notably, specifically knocking out CCK1R in the VTA DA  → NAcC GABA circuit blocked the presynaptic release and synaptic plasticity enhancement induced by METH., Conclusions: These discoveries highlight the critical effect of CCK1R in the VTA DA  → NAcC GABA circuit on METH-induced CPP acquisition and provide a more comprehensive understanding of the mechanisms underlying CCK receptors contributing to the METH-induced addictive behavior., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest and have approved the final version of the manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

2,5-dimethoxy-4-methylamphetamine (DOM) and lisuride are both 5-HT 2A receptor partial agonists. Lisuride exhibits a similar affinity to DOM but lacks hallucinogenic properties attributed to DOM. While extensive research has been conducted on their behavioral effects, a comparative analysis of their electrophysiological characteristics has not been documented. In this study, we employed multi-channel electrophysiological techniques to assess the effects of hallucinogen DOM and non-hallucinogen lisuride on neuronal activity in the Nucleus Accumbens (NAc) of freely moving rats. Our findings indicate that both DOM and lisuride increased the power of theta and High-Frequency Oscillations (HFO), reduced burst rates of putative medium spiny neurons (pMSNs), and enhanced correlations between pMSNs spiking and theta band activity. Additionally, DOM decreased low gamma power, whereas lisuride increased it. Furthermore, DOM decreased the spiking rate of putative fast-spiking interneurons (pFSIs) while lisuride increased it. DOM also reduced burst rates of pFSIs, whereas lisuride had no effect. Notably, DOM induced increased synchronous discharges between pFSIs and low gamma rhythm, a phenomenon not observed with lisuride. The consistent effects of both drugs on theta and HFO power, pMSNs firing patterns, and correlations between pMSNs spiking and theta rhythm suggest common mechanisms underlying their actions. Conversely, differences in low gamma power, pFSIs firing patterns, and correlations between pFSIs spiking and low gamma rhythm serve as key distinguishing factors. These differences in electrophysiological responses might contribute to the distinct behavioral effects associated with hallucinogenic and non-hallucinogenic properties of these compounds. The results will provide electrophysiological evidence for treatment of related psychotomimetic symptoms., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Substance Use Disorder (SUD) is a medical condition where an individual compulsively misuses drugs or alcohol despite knowing the negative consequences. The anterior cingulate cortex (ACC) has been implicated in various types of SUDs, including nicotine, heroin, and alcohol use disorders. Our research aimed to investigate the effects of deep brain stimulation (DBS) in the ACC as a potential therapeutic approach for morphine use disorder. Additionally, we measured c-Fos protein expression as an indicator of neural activity in the nucleus accumbens (NAc) and prefrontal cortex (PFC). Our findings indicate that high-frequency (130 Hz) DBS at different amperages, 150 µA and 200 µA in the ACC during the acquisition phase of morphine conditioned place preference (CPP) inhibited the rewarding properties of morphine. Furthermore, DBS at these intensities during the extinction phase facilitated the extinction and mitigated the reinstatement of morphine CPP triggered by drug priming. Morphine conditioning was associated with impaired novel object conditioning (NOR) and locomotor activity. While DBS in the acquisition and extinction phases at both intensities restored NOR memory, only DBS at 200 µA recovered locomotor activity in the open field test. Treatment with DBS at 200 µA decreased c-Fos protein expression in the NAc and PFC (compared to morphine-only group). In conclusion, our data indicate an intensity-dependent effect of ACC DBS on the acquisition, extinction, and reinstatement of morphine-induced CPP in rats. These findings suggest that ACC DBS could be a potential intervention for the treatment of morphine use disorder., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

There are no approved therapeutics for psychostimulant use and recurrence of psychostimulant use. However, in preclinical rodent models environmental enrichment can decrease psychostimulant self-administration of low unit doses and cue-induced amphetamine seeking. We have previously demonstrated that glutamate-dependent therapeutics are able to alter amphetamine seeking to amphetamine-associated cues only in enriched rats. In the current experiment, we will determine if enrichment can attenuate responding and cue-induced amphetamine seeking during extended access to a high dose of intravenous amphetamine. We will also determine if N-acetylcysteine (NAC), a glutamate dependent therapeutic, can attenuate amphetamine seeking in differentially reared rats. Female and male Sprague-Dawley rats were reared in enriched, isolated, or standard conditions from postnatal day 21-51. Rats were trained to self-administer intravenous amphetamine (0.1 mg/kg/infusion) during twelve 6-hour sessions. During the abstinence period, NAC (100 mg/kg) or saline was administered daily. Following a cue-induced amphetamine-seeking test, astrocyte densities within regions of the medial prefrontal cortex (mPFC) and nucleus accumbens (ACb) were quantified using immunohistochemistry. Environmental enrichment decreased responding for amphetamine and during the cue-induced amphetamine-seeking test. NAC did not attenuate cue-induced amphetamine seeking or alter astrocyte density. Across all groups, female rats self-administered less amphetamine but responded more during cue-induced amphetamine seeking than male rats. While amphetamine increased astrocyte densities within the ACb and mPFC, it did not alter mPFC astrocyte densities in female rats. The results suggest that enrichment can attenuate responding during extended access to a high dose of amphetamine and the associated cues. Sex alters amphetamine-induced changes to astrocyte densities in a regionally specific matter., Competing Interests: Declaration of Competing Interest On behalf of all authors, the corresponding author states that there is no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Protein/protein interactions (PPI) play crucial roles in neuronal functions. Yet, their potential as drug targets for brain disorders remains underexplored. The fibroblast growth factor 14 (FGF14)/voltage-gated Na + channel 1.6 (Na v 1.6) complex regulates excitability of medium spiny neurons (MSN) of the nucleus accumbens (NAc), a central hub of reward circuitry that controls motivated behaviors. Here, we identified compound 1028 (IUPAC: ethyl 3-(2-(3-(hydroxymethyl)-1H-indol-1-yl)acetamido)benzoate), a brain-permeable small molecule that targets FGF14 R117 , a critical residue located within a druggable pocket at the FGF14/Na v 1.6 PPI interface. We found that 1028 modulates FGF14/Na v 1.6 complex assembly and depolarizes the voltage-dependence of Na v 1.6 channel inactivation with nanomolar potency by modulating the intramolecular interaction between the III-IV linker and C-terminal domain of the Na v 1.6 channel. Consistent with the compound's effects on Na v 1.6 channel inactivation, 1028 enhances MSN excitability ex vivo and accumbal neuron firing rate in vivo in murine models. Systemic administration of 1028 maintains behavioral motivation preferentially during motivationally deficient conditions in murine models. These behavioral effects were abrogated by in vivo gene silencing of Fgf14 in the NAc and were accompanied by a selective reduction in accumbal dopamine levels during reward consumption in murine models. These findings underscore the potential to selectively regulate complex behaviors associated with neuropsychiatric disorders through targeting of PPIs in neurons., Competing Interests: Competing interests: The corresponding author, F.L., is the founder and president of IonTx Inc., a start-up company focusing on developing regulators of voltage-gated Na+ channels. The following patent is related to the present study: LAEZ-F-22A: TMB-0170000. Additional information related to the patent is as follows: Patent Int’l Application No: PCT/US24/32688; Title: Non-Peptide Small Molecule FGF14:Nav1.6 Channel Complex Protein-Protein Interaction Modulators; Tech ID: LAEZ-F-22A; Patent Applicant: The Board of Regents of the University of Texas System; Name of the Inventors: Drs. Jia Zhou, Fernanda Laezza, Pingyuan Wang, Nolan M. Dvorak, Paul A. Wadsworth; Status of the Application: Pending; Specific Aspect of the manuscript covered in the patent application: the synthetic route and chemical structure of 1028 is covered in the patent application. All other authors declare that they have no competing interests., (© 2024. The Author(s).)

The long-term influence of early-life stress on brain neurophysiology has been extensively investigated using different animal models. Among these, repeated maternal separation (RMS) in rodents is one of the most commonly adopted. In this study, we elucidated the long-lasting effects of exposure to postnatal RMS in C57BL/6J adult mice on voluntary alcohol consumption and nucleus accumbens (NAc) neurophysiology. Mice were separated from their dam for 360 min daily from postnatal day 2 (PND2) to PND17, and experiments were then performed in adult (PND60) animals. In addition, as recent evidence showed that circulating estrogens may play a protective role against stress effects on brain function, including the organization and activation of neuronal structures, we also evaluated the effect of a single injection of β-estradiol 3-benzoate (EB) at PND2, which is known to disrupt male sex differentiation, in male RMS mice. The RMS exposure was associated with an increased voluntary alcohol consumption and preference in male mice, but not in female mice or male mice treated with a single injection of EB. Patch clamp experiments conducted in NAc medium spiny neurons (MSNs) revealed that excitatory but not inhibitory synaptic transmission and long-term plasticity of glutamatergic synapses were significantly impaired in male but not in female mice exposed to the RMS protocol. This effect was again prevented in RMS male mice treated with EB. Our findings strengthen the idea of a sex-dependent influence of early-life stress on long-lasting modifications in synaptic transmission and plasticity in brain areas involved in goal-directed behavior and alcohol intake., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The dopamine D3 receptor (D3R), principally confined to the nucleus accumbens (NAc), is involved in regulating natural and drug rewards; however, the molecular mechanisms underlying the associated process remain unclear. Earlier research has reported the concurrent influence of D3R and miR-29c expressed in the NAc on methamphetamine (METH)-induced reward behaviors and microglial activation, hinting at regulatory roles in reward processing. Herein, we performed viral manipulation-mediating D3R/miR-29c overexpression and inhibition in the whole NAc in male D3R knockout and wild-type mice to investigate this potential relationship. Behavioral responses to the rewarding stimuli were assessed using sucrose preference score, METH-induced locomotor sensitization, and METH-induced conditioned place preference tests. Overall, we observed a notable decrease in the behavioral response to sucrose and METH in D3R-deficient mice, accompanied by the downregulation of miR-29c expression in the NAc. Diminished responses to those rewarding stimuli in D3R-deficient mice primarily stemmed from the reduction of GSK3β activity and subsequent down-regulation of miR-29c in the NAc. Microglial activation in the NAc mediates the effect of D3R-miR-29c deficiency on the reward effects of sucrose and METH. Pharmacological suppression of microglial activity rescued the reduced response in mice lacking D3R-miR-29c in the NAc. Overall, this study revealed the mechanism by which D3R regulates both natural and drug rewards via miR-29c in the murine NAc, highlighting the role of the NAc D3R-miR-29c pathway as a critical regulator of rewards, and providing new insights into the role of NAc D3R-miR-29c in encoding rewarding experiences., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Methadone and buprenorphine are commonly prescribed during pregnancy to maintain recovery and prevent symptoms of withdrawal in women with opioid use disorder. Infants prenatally exposed to medications for opioid use disorder (MOUD), however, commonly show signs of neonatal opioid withdrawal syndrome (NOWS), which can include feeding-related issues like hyperphagia. To investigate the effects of prenatal MOUD exposure on feeding behavior, female Sprague-Dawley rats were implanted with osmotic minipumps filled with methadone, buprenorphine, or saline and subsequently mated. On postnatal day (PND) 1, buprenorphine- and methadone-exposed offspring weighed less than saline-exposed subjects. Throughout early postnatal development (PND2, 7, and 12), this reduction in weight persisted in buprenorphine, but not methadone, offspring. RNAscope in situ hybridization was then used to measure expression of genes in the nucleus accumbens (NAc) previously associated with hyperphagia in NOWS infants, including proopiomelanocortin (Pomc), neuropeptide Y2 receptors (Npy2r), and dopamine type 2 receptors (Drd2). Distinct developmental expression patterns were noted across the postnatal period, with few effects of MOUD; however, significantly lower Pomc expression was observed in methadone-exposed but not buprenorphine-exposed offspring. These findings demonstrate differential effects of methadone and buprenorphine on offspring development and gene expression, highlighting differences in offspring outcomes associated with these two MOUDs., (© 2024 Wiley Periodicals LLC.)

The opioidergic and dopaminergic systems play an essential role in processing pain information in the nucleus accumbens (NAc). The present work examined the hypothesis that interaction between opioidergic and D1-like dopamine receptors in the NAc area may influence acute pain-related behaviors. One hundred sixty adult male Wistar rats unilaterally received different doses of the drug solution or vehicle. First, separate groups of animals received different doses of morphine (5, 10, and 25 mmol/0.5 μL) and various doses of SKF38393 (1.5, 3, 6, and 12 mmol/0.5 μL) as opioid and D1-like receptor agonists in the NAc region, respectively. In the second set of experiments, animals got different amounts (1.5, 3, 6, and 12 mmol/0.5 μL) of SCH23390, a D1-like receptor antagonist, before an effective dose of morphine (10 mmol/0.5 μL). In the last experiment, the animals were given naloxone (1.5, 5, and 15 mmol/0.5 μL) before they were given an effective dose of SKF38393 (3 mmol/0.5 μL). The tail-flick test was then used to measure their acute pain threshold. The main findings showed that intra-NAc injection of morphine and SKF38393 alone causes antinociceptive responses. However, the intra-accumbal injection of SCH23390 significantly reduced the antinociceptive responses elicited by intra-NAc morphine. Additionally, intra-NAc naloxone significantly reduced the antinociceptive effects elicited by intra-NAc SKF38393. Interestingly, SCH23390 was more effective in reversing the analgesic effects of morphine (η2 = 0.61) than naloxone in reversing the analgesic effects of SKF38393 (η2 = 0.49). The findings suggest that the opioidergic and dopamine systems in the NAc collaborate to produce pain-relieving effects. This insight could potentially enhance the effectiveness of lower doses of opioids for pain management, ultimately reducing their usage in clinical settings in the future., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Prolonged periods of opioid use have been shown to cause neuroadaptations in the brain's reward circuitry, contributing to addictive behaviors and drug dependence. Recently, considerable focus has been placed on the role of the endocannabinoid system (ECS) and its CB receptors in opioid-driven behaviors. However, opioid-induced neuroadaptations to the ECS remain understudied. In this study, we systematically assessed CB1 receptor (CB1R) protein expression within the cortico-mesolimbic-basal ganglia circuit in rats following chronic fentanyl exposure. Male and female Long Evans rats were administered increasing daily doses of fentanyl or saline for 14 days. During naloxone-precipitated withdrawal, fentanyl-treated rats exhibited significantly higher withdrawal symptoms than saline-treated controls. Using Western Blotting, we demonstrated that the fentanyl-treated rats had significantly higher CB1R expression in the insula and significantly lower CB1R expression in the nucleus accumbens and substantia nigra compared to saline-treated rats. No significant differences in CB1R expression were detected between saline and fentanyl-treated rats in the prefrontal cortex, dorsal striatum, medial septum, hypothalamus, amygdala, hippocampus, ventral tegmental area, periaqueductal gray area, pedunculopontine tegmentum, and laterodorsal tegmentum (LDT). These findings suggest that chronic fentanyl exposure leads to region-specific neuroadaptations of CB1R protein expression in motivation- and addiction-associated brain regions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The T-2 toxin is a frequent contaminant in the global environment and agricultural production. Existing evidence suggests that the ingested T-2 toxin can enter the brain and exhibit neurotoxicity. However, it is still unknown whether T-2 toxin causes the depression-like behaviors. In this study, the mice were orally administrated with 1.5 mg/kg T-2 toxin daily for 14 d, and the depression-like behaviors were assessed by the tail suspension test (TST) and sucrose preference test (SPT). Here, the results showed that T-2 toxin exposure induced depression-like behaviors, manifested as behavioral despair and anhedonia, without anxiety-like behaviors. In addition, the reduced dopamine (DA) level and elevated dopamine transporter (DAT) level were found in reward center nucleus accumbens (NAc) receiving DAergic projection from ventral tegmental area (VTA) in brain after T-2 toxin administration, while there was no significant alteration in DA synthesis-related tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) in VTA and DA storage-related vesicle monoamine transporter 2 (VMAT2) in NAc. The local administration of DAT inhibitor AHN 1-055 hydrochloride into NAc alleviated T-2 toxin caused the depression-like behaviors. Importantly, the chemogenetic activation of the VTA DA -NAc circuit increased the DA content in NAc and reversed the T-2 toxin-produced behavioral despair and anhedonia. Thus, our study for the first time illustrates DA dysregulation by upregulated DAT in NAc mediates T-2 toxin-triggered depression-like symptoms in mice. Meanwhile, this study establishes a novel causal relation between the neurotoxicant T-2 toxin exposure and the etiology of depression-like behaviors, and provides reference for the prevention and treatment for mycotoxin-induced depression-like symptoms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Mesolimbic dopamine (DA) plays a critical role in behavioral activation and exertion of effort in motivated behaviors. DA antagonism and depletion in nucleus accumbens (Nacb) induces anergia in effort-based decision-making tasks. Exercise improves motor function in Parkinson's disease (PD). However, the beneficial effects of physical exercise on anergia, a symptom present in many psychiatric and neurological pathologies needs to be studied. During 9 weeks, young CD1 male mice were trained to run at a moderate speed in automatically turning running wheels (RW) (forced exercise group) or locked in static RWs (control group) in 1 h daily sessions. Both groups were tested in a 3-choice-T-maze task developed for the assessment of preference between active (RW) vs. sedentary reinforcers, and vulnerability to DA depletion-induced anergia was studied after tetrabenazine administration (TBZ; VMAT-2 blocker). Exercise did not change spontaneous preferences, did not affect body weight, plasma corticosterone levels or measures of anxiety, but it increased the cerebral DA neurotrophic factor (CDNF) in Nacb core, suggesting a neuroprotective effect in this nucleus. After TBZ administration, only the non-trained group showed a shift in relative preferences from active to sedentary options, reducing time running but increasing consumption of pellets, thus showing a typical anergic but not anhedonic effect. Moreover, only in the non-trained group, phosphorylation of DARPP-32(Thr34) increased after TBZ administration. These results are the first to show that mild forced exercise carried out from a young age to adulthood could act on Nacb-related functions, and prevent the anergia-inducing effects of DA depletion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The last two decades have witnessed substantial advances in identifying synaptic plasticity responsible for behavioral changes in animal models of substance use disorder. We have learned the most about cocaine-induced plasticity in the nucleus accumbens and its relationship to cocaine seeking, so that is the focus in this review. Synaptic plasticity pointing to potential therapeutic targets has been identified mainly using two drug self-administration models: extinction-reinstatement and abstinence models. A relationship between cocaine seeking and potentiated AMPAR transmission in nucleus accumbens is indicated by both models. In particular, an atypical subpopulation-Ca2+-permeable or CP-AMPARs-mediates cue-induced seeking that persists even after long periods of abstinence, modeling the persistent vulnerability to relapse that represents a major challenge in treating substance use disorder. We review strategies to reverse CP-AMPAR plasticity; strategies targeting other components of excitatory synapses, including dysregulated glutamate uptake and release; and behavioral interventions that can be augmented by harnessing synaptic plasticity.

Chronic cocaine use triggers inflammatory and oxidative processes in the central nervous system, resulting in impaired microglia. Mesenchymal stem cells, known for their immunomodulatory properties, have shown promise in reducing inflammation and enhancing neuronal survival. The study employed the cocaine self-administration model, focusing on ionized calcium-binding adaptor protein 1 (Iba-1) and cell morphology as markers for microglial impairment and PLX-PAD cells as a treatment for attenuating cocaine craving. The results revealed an addiction-stage and region-specific impairment in microglia following chronic cocaine exposure, with deficits observed in the Nucleus Accumbens (NAc) during the maintenance stage and in both the NAc and Dentate Gyrus (DG) during the extinction and reinstatement stages. Furthermore, PLX-PAD cell therapy demonstrated a significant reduction in cocaine craving and seeking behavior, interestingly accompanied by the prevention of Iba-1 level decrease and restoration of microglial activity in the NAc and DG. These findings highlight the unique role of microglia in modulating cocaine addiction behaviors through their influence on synaptic plasticity and neuronal remodeling associated with memory formation. They also suggest that PLX-PAD therapy may mitigate the detrimental effects of chronic cocaine exposure on microglia, underscoring the importance of incorporating microglia in comprehensive addiction rehabilitation strategies.

Background: Understanding drug addiction as a disorder of maladaptive learning, where drug-associated or environmental cues trigger drug cravings and seeking, is crucial for developing effective treatments. Actin polymerization, a biochemical process, plays a crucial role in drug-related memory formation, particularly evident in conditioned place preference paradigms involving drugs like morphine and methamphetamine. However, the role of actin polymerization in the reconsolidation of heroin-associated memories remains understudied., Methods: This study employed a rodent model of self-administered heroin to investigate the involvement of actin polymerization in the reconsolidation of heroin-associated memories. Rats underwent ten days of intravenous heroin self-administration paired with conditioned cues. Subsequently, a 10-day extinction phase aimed to reduce heroin-seeking behaviors. Following this, rats participated in a 15-minute retrieval trial with or without cues. Immediately post-retrieval, rats received bilateral injections of the actin polymerization inhibitor Latrunculin A (Lat A) into the nucleus accumbens core (NACc), a critical brain region for memory reconsolidation., Results: Immediate administration of Lat A into the NACc post-retrieval significantly reduced cue-induced and heroin-primed reinstatement of heroin-seeking behavior for at least 28 days. However, administering Lat A 6-hour post-retrieval or without a retrieval trial, as well as administering Jasplakionlide prior to memory reactivation did not affect heroin-seeking behaviors., Conclusions: Inhibiting actin polymerization during the reconsolidation window disrupts heroin-associated memory reconsolidation, leading to decreased heroin-seeking behavior and prevention of relapse. These effects are contingent upon the presence of a retrieval trial and exhibit temporal specificity, shedding light on addiction mechanisms and potential therapeutic interventions., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

Amphetamine abuse is a global health epidemic that is difficult to treat due to individual differences in response to environmental factors, including stress reactivity and anxiety levels, as well as individual neuronal differences, which may result in increased/decreased vulnerability to addiction. In the present study, we investigated whether the Wistar rats behavioral traits of high (HR) and low (LR) locomotor activity to novelty influence motivational behavior (induced feeding model; iFR by electrical stimulation of the ventral tegmental area; Es-VTA) supported by amphetamine injection into the nucleus accumbens shell (AcbSh) (HR Amph , n = 5; LR Amph , n = 5). A correlation was found between the novelty test's locomotor activity score and the frequency threshold percentage change ( p < 0.001, Rs = -0.867). In HR Amph , there was a shortening (-24.16%), while in LR Amph , there was a lengthening (+51.84%) of iFR latency. Immunofluorescence studies showed differential neuronal density (activity of tyrosine hydroxylase, choline acetyltransferase, and cFos protein) in the selected brain structures in HR Amph and LR Amph animals as well as in comparison to a control group (HR ACSF , n = 5; LR ACSF , n = 5). These results contribute to expanding the state of knowledge of the behavioral and neuronal propensity to take drug abuse.

Recent progress in psychiatric research has highlighted neuroinflammation in the pathophysiology of opioid use disorder (OUD), suggesting that heightened immune responses in the brain may exacerbate opioid-related mechanisms. However, the molecular mechanisms resulting from neuroinflammation that impact opioid-induced behaviors and transcriptional pathways remain poorly understood. In this study, we have begun to address this critical knowledge gap by exploring the intersection between neuroinflammation and exposure to the opioid heroin, utilizing lipopolysaccharide (LPS)-induced neuroinflammation, to investigate transcriptional changes in the nucleus accumbens (NAc), an essential region in the mesolimbic dopamine system that mediates opioid reward. By integrating RNA sequencing with bioinformatic and statistical analyses, we observed significant transcriptional overlaps between neuroinflammation and experimenter-administered heroin exposure in the NAc. Furthermore, we identified a subset of NAc genes synergistically regulated by LPS and heroin, suggesting that LPS history may exacerbate some heroin-induced molecular neuroadaptations. We extended our findings to examine the impact of neuroinflammatory history on responsiveness to heroin in a locomotor sensitization assay and observed LPS-induced exacerbation of heroin sensitization, indicating that neuroinflammation may increase sensitivity to opioids' behavioral effects. Lastly, we performed comparative analysis of the NAc transcriptional profiles of LPS-heroin rats with those obtained from voluntary heroin intake in a rat model of heroin self-administration (SA) and published human OUD datasets. We observed significant convergence of the three datasets and identified transcriptional patterns in the preclinical models that recapitulated human OUD neuropathology, highlighting the utility of preclinical models to further investigate molecular mechanisms of OUD pathology. Overall, our study elucidates transcriptional interconnections between neuroinflammation and heroin exposure, and also provides evidence of the behavioral ramifications of such interactions. By bridging the gap between neuroinflammation and heroin exposure at the transcriptional level, our work provides valuable insights for future research aimed at mitigating the influence of inflammatory pathways in OUD., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All methods were performed in accordance with the relevant guidelines and regulations. All procedures were compliant with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals and approved by Temple University’s Institutional Animal Care and Use Committee (IACUC Approval # 4880)., (© 2024. The Author(s).)

Targeted intracranial delivery of molecularly-specific therapies within intricate brain structures poses a formidable challenge due to the heterogeneity of neuronal phenotypes and functions. Here we report the use of an implantable, miniaturized neural drug delivery system permitting dynamic adjustment of pharmacotherapies. Specifically, we exploit the spatial accuracy afforded by this method for targeting modulation of neuronal microstructures. Kappa opioid receptors (KOR) within the dorsal medial nucleus accumbens shell (NASh) are selectively activated through micro infusions of the KOR agonist, U-50488. Remarkably, we demonstrate that micro infusions of U-50488 into the dorsal NASh induces reward-like conditioned place preferences, whereas a mere 1 mm shift ventrally results in conditioned place aversions. The striking precision afforded by this method may prove useful in other neurotherapeutic interventions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Rodents have a strong motivation for wheel running; however, the neural mechanisms that regulate their motivation remain unknown. We investigated the possible involvement of serotonin (5-HT) systems in regulating motivation for wheel running in male mice. Systemic administration of a 5-HT 1A receptor antagonist (WAY100635) increased the number of wheel rotations, whereas administration of a 5-HT 2A or 5-HT 2C receptor antagonist (volinanserin or SB242084, respectively) decreased it. In the open field test, neither WAY100635 nor volinanserin affected locomotor activity, whereas SB242084 increased locomotor activity. To identify the brain regions on which these antagonists act, we locally injected these into the motivational circuitry, including the nucleus accumbens (NAc), dorsomedial striatum (DM-Str), and medial prefrontal cortex (mPFC). Injection of SB242084 into the NAc, but not the DM-Str or mPFC, reduced the number of wheel rotations without altering locomotor activity. The local administration of WAY100635 or volinanserin to these brain regions did not affect the number of wheel rotations. Immunohistochemical analyses revealed that wheel running increased the number of c-Fos-positive cells in the NAc medial shell (NAc-MS), which was reduced by systemic SB242084 administration. In vitro slice whole-cell recordings showed that bath application of the 5-HT 2C receptor agonist lorcaserin increased the frequency of spontaneous excitatory and inhibitory postsynaptic currents in the ventral tegmental area (VTA)-projecting neurons, whereas it only increased the frequency of spontaneous excitatory postsynaptic currents in ventral pallidum (VP)-projecting neurons in the NAc-MS. These findings suggest that the activation of VP-projecting NAc-MS neurons via 5-HT 2C receptor stimulation regulates motivation for wheel running., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The opioid system plays crucial roles in modulating social behaviors in both humans and animals. However, the pharmacological profiles of opioids regarding social behavior and their therapeutic potential remain unclear. Multiple pharmacological, behavioral, and immunohistological c-Fos mapping approaches were used to characterize the effects of μ-opioid receptor agonists on social behavior and investigate the mechanisms in naive mice and autism spectrum disorder-like (ASD-like) mouse models, such as prenatally valproic acid-treated mice and Fmr1-KO mice. Here, we report that low-dose morphine, a μ-opioid receptor agonist, promoted social behavior by selectively activating neurons in prosocial brain regions, including the nucleus accumbens, but not those in the dorsomedial periaqueductal gray (dmPAG), which are only activated by analgesic high-dose morphine. Critically, intra-dmPAG morphine injection counteracted the prosocial effect of low-dose morphine, suggesting that dmPAG neural activation suppresses social behavior. Moreover, buprenorphine, a μ-opioid receptor partial agonist with less abuse liability and a well-established safety profile, ameliorated social behavior deficits in two mouse models recapitulating ASD symptoms by selectively activating prosocial brain regions without dmPAG neural activation. Our findings highlight the therapeutic potential of brain region-specific neural activation induced by low-dose opioids for social behavior deficits in ASD.

Though μ and δ opioid receptors are reported to regulate energy homeostasis, any role for κ opioid receptors in these processes remains unclear. The present study investigated the role of κ opioid receptors in regulation of feeding behavior and plasma glucose levels using nalfurafine, a κ opioid receptor agonist used clinically. Systemic injection of nalfurafine increased food intake under non-fasted conditions, but not after food deprivation, and this effect was inhibited by the κ opioid receptor antagonist norbinaltorphimine. In contrast, nalfurafine did not affect plasma glucose levels. I.c.v. injection of nalfurafine increased food intake, whereas systemic injection of nalfurafine methiodide, which does not penetrate the blood brain barrier, was without effect. In addition, nalfurafine tended to increase preproorexin mRNA in the hypothalamus. However, neither the orexin OX1 receptor antagonist YNT-1310 nor the non-selective orexin receptor antagonist suvorexant inhibited the increase in food intake induced by nalfurafine. While nalfurafine injected into the lateral hypothalamus did not affect food intake, nalfurafine injected into the nucleus accumbens increased food intake, which was inhibited by norbinaltorphimine. Finally, we examined the effect of nalfurafine on anorexia induced by the anti-cancer agent 5-fluorouracil. Reduced food intake at 2 days following 5-fluorouracil administration was alleviated across the first 3 h following daily injection of nalfurafine, though daily food intake was not influenced. These results indicate that nalfurafine promotes feeding behavior through stimulation of κ opioid receptors in the nucleus accumbens and may be a candidate for reducing anorexia due to anti-cancer agents., Competing Interests: Declaration of competing interest HI has received research support from Toray Industries. All other authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Behavioral sensitization is defined as the heightened and persistent behavioral response to repeated drug exposure as a manifestation of drug craving. Psychomotor stimulants such as cocaine can induce strong behavioral sensitization. In this study, we explored the effects of optogenetic stimulation of the prelimbic (PL) to the nucleus accumbnes (NAc) core on the expression of cocaine-induced behavioral sensitization. Using wireless optogenetics, we selectively stimulated the PL-NAc core circuit, and assessed the effects of this treatment on cocaine-induced locomotor activity and accompanying changes in neuronal activation and dendritic spine density. Our findings revealed that optogenetic stimulation of the PL-NAc core circuit effectively suppressed the cocaine-induced locomotor sensitization, accompanied by a reduction in c-Fos expression within the NAc core. Moreover, optogenetic stimulation led to reduction in dendritic spine density, particularly thin and mushroom spine densities, in the NAc core. This study demonstrates that cocaine-induced locomotor sensitization can be regulated by optogenetic stimulation of the PL-NAc core circuit, providing insights into the crucial role of this circuit in psychomotor stimulant addiction., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The hypocretin (Hcrt) system modulates arousal and anxiety-related behaviors and has been considered as a novel treatment target for stress-related affective disorders. We examined the effects of Hcrt acting in the nucleus accumbens shell (NAcSh) and anterodorsal bed nucleus of the stria terminalis (adBNST) on social behavior in male and female California mice (Peromyscus californicus). In female but not male California mice, infusion of Hcrt1 into NAcSh decreased social approach. Weak effects of Hcrt1 on social vigilance were observed in both females and males. No behavioral effects of Hcrt1 infused into the adBNST were observed. Analyses of sequencing data from California mice and Mus musculus NAc showed that Hcrtr2 was more abundant than Hcrtr1, so we infused the selective Hcrt receptor 2 antagonist into the NAcSh, which increased social approach in females previously exposed to social defeat. A calcium imaging study in the NAcSh of females before and after stress exposure showed that neural activity increased immediately following the expression of social avoidance but not during freezing behavior. This observation is consistent with previous studies that identified populations of neurons in the NAc that drive avoidance. Intriguingly, calcium transients were not affected by stress. These data suggest that hypocretin acting in the NAcSh plays a key role in modulating stress-induced social avoidance., (© 2024. The Author(s).)

Cue-elicited drug-seeking behavior intensifies with the passage of time during withdrawal from drug taking and this "incubation of cocaine-craving" involves alterations in nucleus accumbens (NA) glutamate transmission. Here, we employed a combination of in vivo microdialysis and immunoblotting approaches to further examine changes in biochemical indices of glutamate transmission within NA subregions that accompany the incubation of cocaine-craving exhibited by male rats with a 10-day history of 6-h access to intravenous cocaine (0.25 mg/infusion). Immunoblotting on whole cell lysates from the core subregion (NAc core) revealed interactions between cocaine self-administration history, withdrawal and drug cue re-exposure for Homer2a/b, mGlu1, and GluN2b expression, as well as indices of Akt and ERK activity. With the exception of PKCε phosphorylation, most protein changes within the shell subregion (NAc shell) depended on drug cue re-exposure and cocaine history rather than varying in a consistent time-dependent manner. Reduced basal extracellular glutamate content was apparent only in the NAc core of cocaine-experienced rats during protracted (30 days) withdrawal and this was accompanied by a markedly blunted capacity of the mGlu1/5 agonist DHPG to elevate glutamate levels within this subregion. Finally, over-expressing neither Homer1c nor Homer2b within the NAc core during protracted cocaine withdrawal altered the magnitude of cue-elicited responding, its extinction or cocaine-primed reinstatement of drug-seeking behavior. The present findings are consistent with the extant literature implicating changes in Group 1 mGlu receptor function within the NAc core subregion as central to incubated cocaine-craving and provide further evidence against a major role for Homer proteins in gating incubated cocaine-craving. Further, our results provide novel correlational evidence implicating elevated Akt and blunted ERK activity within the NAc core as potential contributors to the expression of incubated cocaine-craving, worthy of future investigation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Relapse represents a consistent clinical problem for individuals with substance use disorder. In the incubation of craving model of persistent craving and relapse, cue-induced drug seeking progressively intensifies or "incubates" during the first weeks of abstinence from drug self-administration and then remains high for months. Previously, we and others have demonstrated that expression of incubated cocaine craving requires strengthening of excitatory synaptic transmission in the nucleus accumbens core (NAcc). However, despite the importance of dopaminergic signaling in the NAcc for motivated behavior, little is known about the role that dopamine (DA) plays in the incubation of cocaine craving. Here we used fiber photometry to measure DA transients in the NAcc of male and female rats during cue-induced seeking tests conducted in early abstinence from cocaine self-administration, prior to incubation, and late abstinence, after incubation of craving has plateaued. We observed DA transients time-locked to cue-induced responding but their magnitude did not differ significantly when measured during early versus late abstinence seeking tests. Next, we tested for a functional role of these DA transients by injecting DA receptor antagonists into the NAcc just before the cue-induced seeking test. Blockade of either D1 or D2 DA receptors reduced cue-induced cocaine seeking after but not before incubation. We found no main effect of sex or significant interaction of sex with other factors in our experiments. These results suggest that DA contributes to incubated cocaine seeking but the emergence of this role reflects changes in postsynaptic responsiveness to DA rather than presynaptic alterations., Competing Interests: Competing interests: MEW and OHSU have a financial interest in Eleutheria Pharmaceuticals LLC, a company that may have a commercial interest in results related to the research described herein. This potential conflict of interest has been reviewed and managed by OHSU. Wolf also serves as a Consultant for the University of Texas-Austin and has received compensation. The other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Although alcohol and nicotine are two of the most commonly co-used drugs with upwards of 90% of adults with an alcohol use disorder (AUD) in the US also smoking, we don't tend to study alcohol and nicotine use this way. The current studies sought to develop and assess a novel alcohol + nicotine co-access self-administration (SA) model in adult male and female Long-Evans rats. Further, both drugs are implicated in neuroimmune function, albeit in largely opposing ways. Chronic alcohol use increases neuroinflammation via toll-like receptors (TLRs) which in turn increases alcohol intake. By contrast, nicotine produces anti-inflammatory effects, in part, through the monomeric alpha7 receptor (ChRNa7). Following long-term co-access (6 months), rats reliably administered both drugs during daily sessions, however males generally responded for more alcohol and females for nicotine. This was reflected in plasma analysis with translationally relevant intake levels of both alcohol and nicotine, making it invaluable in studying the effects of co-use on behavior and CNS function. Moreover, male rats show sensitivity to alterations in alcohol concentration whereas females show sensitivity to alterations in nicotine concentration. Rats trained on this procedure also developed an anxiogenic phenotype. Finally, we assessed alterations in neuroimmune-related gene expression in the medial prefrontal cortex - prelimbic, (mPFC-PL), nucleus accumbens core (AcbC), and ventral tegmental area (VTA). In the AcbC, where α7 expression was increased and β2 was decreased, markers of pro-inflammatory activity were decreased, despite increases in TLR gene expression suggesting that co-use with nicotine modulates inflammatory state downstream from the receptor level. By contrast, in mPFC-PL where α7 was not increased, both TLRs and downstream proinflammatory markers were increased. Taken together, these findings support that there are brain regional and sex differences with co-use of alcohol + nicotine SA and suggest that targeting nicotinic α7 may represent a novel strategy for treating alcohol + nicotine co-dependence., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Nicotine addiction is a concern worldwide. Most mechanistic investigations are on nicotine substance dependence properties based on its pharmacological effects. However, no effective therapeutic treatment has been established. Nicotine addiction is reinforced by environments or habits. We demonstrate the neurobiological basis of the behavioural aspect of nicotine addiction. We utilized the conditioned place preference to establish nicotine-associated behavioural preferences (NABP) in rats. Brain-wide neuroimaging analysis revealed that the medial prefrontal cortex (mPFC) was activated and contributed to NABP. Chemogenetic manipulation of µ-opioid receptor positive (MOR + ) neurons in the mPFC or the excitatory outflow to the nucleus accumbens shell (NAcShell) modulated the NABP. Electrophysiological recording confirmed that the MOR + neurons directly regulate the mPFC-NAcShell circuit via GABA A receptors. Thus, the MOR + neurons in the mPFC modulate the formation of behavioural aspects of nicotine addiction via direct excitatory innervation to the NAcShell, which may provide new insight for the development of effective therapeutic strategies., Competing Interests: Conflict of interest: The authors declare no competing interests., (© 2024. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.)

Objectives: Substance use disorders (SUDs) represent a significant global health concern, demanding the development of effective pharmacological treatments. To address this, an investigation was conducted to examine the anti-addictive properties of two compounds, (S)-T1 and (S)-T2, which specifically target the α3β4 nicotinic acetylcholine receptor (nAChR)., Methods: The effects of (S)-T1 and (S)-T2 on nicotine-induced conditioned place preference (CPP), locomotor activity and dopamine levels in particular brain regions associated to addiction were investigated and compared in male C57BL/6N mice., Results: The results demonstrate that neither (S)-T1 nor (S)-T2 induced place conditioning or conditioned place aversion (CPA), suggesting the absence of rewarding or aversive effects. Both compounds significantly attenuated nicotine-induced CPP, with (S)-T1 exhibiting a dose-dependent effect. Furthermore, the co-administration of (S)-T2 (10 mg/kg) with nicotine markedly reduced locomotor activity compared to nicotine treatment alone. Additionally, dopamine analysis revealed that nicotine increased dopamine levels in the nucleus accumbens (NAc) and dorsal striatum, whereas the co-administration of (S)-T1 (1, 3, and 10 mg/kg) and (S)-T2 (10 mg/kg) significantly decreased dopamine levels in these brain regions. No significant effects were observed in the prefrontal cortex (PFC)., Conclusions: These findings suggest that (S)-T1 and (S)-T2 hold promise for treating nicotine addiction by attenuating nicotine-induced CPP and modulating dopamine release in key reward-related brain regions. Further research is needed to gain insights into the underlying mechanisms behind their anti-addictive effects and substantiate their potential for treating nicotine addiction., Competing Interests: Declarations Completing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Melanin-concentrating hormone (MCH) activity in the nucleus accumbens (Acb) has been shown to influence feeding behavior, yet this has not been characterized in terms of homeostatic vs. hedonic feeding processes. Hedonic feeding, driven by palatability rather than energy deficit, can be modeled through intra-Acb administration of the selective μ-opioid receptor agonist d-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO), which preferentially increases consumption and incentive motivation to obtain preferred palatable food. Pharmacological activation of MCH 1 receptors (MCHR1) within Acb has been shown to promote general feeding of chow in males, but not females. However, the effects of MCH on the incentive motivation to obtain preferred palatable food have not been explored. Here, we investigated the role of MCHR1 within the Acb in DAMGO-induced incentive motivation to obtain a sucrose pellet reward. Female Sprague Dawley rats were trained and tested for operant responding under a progressive ratio (PR) breakpoint in response to concurrent intra-Acb administration of DAMGO (0 μg and 0.025 μg/.5 μl/side) immediately following intra-Acb administration of the MCHR1 antagonist (N-(3-{1-[4-(3,4-difluoro-phenoxy)-benzyl]-piperdin-4-yl}-4-methyl-phenyl)-isobutyramide (SNAP-94847; 0 μg, 1.5 μg, and 15 μg/.5 μl/side), in a counterbalanced fashion. As expected, DAMGO significantly increased PR breakpoint and overall active lever presses. SNAP-94847 did not influence PR breakpoint by itself, compared to vehicle; however, both 1.5 and 15 μg doses of SNAP-94847 significantly blocked the increased PR breakpoint produced by intra-Acb DAMGO. The results of the study demonstrate that Acb MCHR1 may play a specific role in the hedonically-driven motivation for palatable food in females., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: Preclinical and clinical work has demonstrated altered plasticity and activity in the nucleus accumbens (NAc) under chronic pain states, highlighting critical therapeutic avenues for the management of chronic pain conditions. In this study, we demonstrate that myocyte enhancer factor 2C (MEF2C), a master regulator of neuronal activity and plasticity, is repressed in NAc neurons after prolonged spared nerve injury (SNI). Viral-mediated overexpression of Mef2c in NAc neurons partially ameliorated sensory hypersensitivity and emotional behaviors in mice with SNI, while also altering transcriptional pathways associated with synaptic signaling. Mef2c overexpression also reversed SNI-induced potentiation of phasic dopamine release and neuronal hyperexcitability in the NAc. Transcriptional changes induced by Mef2c overexpression were different than those observed after desipramine treatment, suggesting a mechanism of action different from antidepressants. Overall, we show that interventions in MEF2C-regulated mechanisms in the NAc are sufficient to disrupt the maintenance of chronic pain states, providing potential new treatment avenues for neuropathic pain., (Copyright © 2024 International Association for the Study of Pain.)

Alcohol use is widespread across many societies. While most people can control their alcohol use, a vulnerable sub-population develops alcohol use disorder, characterized by continued alcohol use despite negative consequences. We used a rat model of alcohol self-administration despite negative consequences to identify brain activity associated with this addiction-like behaviour. We and others have previously shown that response-contingent punishment of alcohol self-administration with mild footshock reliably identifies two sub-populations. One group substantially decreases alcohol self-administration in the face of punishment (punishment-sensitive, controlled) and another group continues alcohol self-administration despite negative consequences (punishment-resistant, addiction-like behaviour). In this study, we aimed to validate this model in females and identify associated brain regions. We trained Long-Evans outbred rats (n = 96) to self-administer 20% ethanol, and then introduced response-contingent footshock. We found that female rats consumed more alcohol in unpunished and punished sessions compared to male rats. In one group of rats (n = 24, m/f), we identified neuronal activity associated with punishment-resistant alcohol self-administration using the neurobiological marker of activity cFos. We found lower cFos expression in NAcSh associated with punishment-resistant alcohol self-administration. In another group of rats (n = 72, m/f), we used chemogenetic inhibition of NAcSh during punished alcohol self-administration. We found that chemogenetic NAcSh inhibition had no effect on unpunished alcohol self-administration but selectively increased punished alcohol self-administration in punishment-resistant female rats. These results indicate that more female rats develop punishment-resistant alcohol consumption, and that NAcSh hypofunction may underlie this phenotype., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Methamphetamine (METH) has well-documented long-term effects on the brain, including increased psychomotor activity and behavioral sensitization. However, its immediate effects on the brain's reward system following acute exposure, which may contribute to the development of addiction, are less understood. This study aimed to investigate the effects of acute METH on brain oscillations in the nucleus accumbens of C57BL/6 mice. Mice in the METH group received 5 mg/kg of METH for 5 days during the conditioning phase, followed by an 8-day abstinence period. Afterward, they underwent a 6-minute tail suspension test and were given a 1 mg/kg METH challenge. Local field potential (LFP) data were analyzed for percent total power, mean frequency indices, and phase-amplitude coupling (PAC) to assess the neural effects of METH exposure across these phases. A reduction in theta power was observed across the conditioning, abstinence, and challenge phases of METH exposure. The subsequent METH challenge enhanced gamma oscillations, and PAC analysis revealed a consistent theta-gamma coupling index during both the METH administration and challenge phases. It highlights the sensitivity of the reward system to intense, short-term drug exposure, providing new insights into how acute neural stimulation may contribute to the development of addictive behaviors, reinforcing the brain's vulnerability to drug-induced changes in neural circuitry., Competing Interests: Declarations. Competing interest: The authors state that there are no known conflicts of interest or personal relationships that could have influenced the work described in this paper., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Converging findings have established that the endocannabinoid (eCB) system serves as a possible target for the development of new treatments as a complement to opioid-based treatments. Here, we show in male and female mice that enhancing levels of the eCB, 2-arachidonoylglycerol (2-AG), through pharmacological inhibition of its catabolic enzyme, monoacylglycerol lipase (MAGL), either systemically or in the ventral tegmental area (VTA) with JZL184, leads to a substantial attenuation of the rewarding effects of opioids in mice using conditioned place preference and self-administration paradigms, without altering their analgesic properties. These effects are driven by cannabinoid receptor 1 (CB1R) within the VTA, as VTA CB1R conditional knockout counteracts JZL184's effects. Using fiber photometry with fluorescent sensors for calcium and dopamine (DA), we find that enhancing 2-AG levels diminishes opioid reward-related nucleus accumbens (NAc) activity and DA neurotransmission. Together, these findings reveal that 2-AG diminishes the rewarding properties of opioids and provides a potential adjunctive therapeutic strategy for opioid-related analgesic treatments.

Electronic nicotine delivery systems (ENDS) are unique from combustible cigarettes due to the availability of flavor options which make these devices popular among adolescents. However, there are no preclinical investigations into the impact of vaporized nicotine on late-developing brain regions such as the prefrontal cortex. Here, we investigated how neuronal function and drug self-administration differed between adult-exposed and adolescent-exposed mice. Male and female adolescent and adult C57BL/6J mice were used in a 20-session e-Vape® self-administration (EVSA) assay. Brains were then extracted and acute slices were used for either patch-clamp electrophysiology or fast-scan cyclic voltammetry. Adolescent-exposed males exhibited greater reinforcement-related behavior compared to their adult-exposed counterparts. However, adolescent-exposed and adult-exposed females exhibited similar levels of reinforcement-related behavior. Adolescent-exposed mice exhibited significant increases in intrinsic excitability of medial prefrontal cortex (mPFC) pyramidal neurons. Additionally, reinforcement-related behavior observed during EVSA assays correlated with adolescent-exposed mPFC neuronal excitability. This did not occur in adult-exposed mice. In the ventral tegmental area (VTA), we observed that upregulation of nicotinic acetylcholine receptors (nAChRs) only correlated with nicotine self-administration in adult and not adolescent-exposed mice. The relationship between self-administration and changes in neuronal excitability in adolescent mice indicates that the mPFC may be important for adolescent nicotine dependence., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Protein translation is essential for some forms of synaptic plasticity. Here we used fluorescent noncanonical amino acid tagging (FUNCAT) to examine whether dopamine modulates protein translation in cultured nucleus accumbens (NAc) medium spiny neurons (MSN). These neurons were co-cultured with cortical neurons to restore excitatory synapses. We measured translation in MSNs under basal conditions and after disinhibiting excitatory transmission using the GABA A receptor antagonist bicuculline (2 h). Under basal conditions, translation was not altered by the D1-class receptor (D1R) agonist SKF81297 or the D2-class receptor (D2R) agonist quinpirole. Bicuculline alone robustly increased translation. This was reversed by quinpirole but not SKF81297. It was also reversed by co-incubation with the D1R antagonist SCH23390, but not the D2R antagonist eticlopride, suggesting dopaminergic tone at D1Rs. This was surprising because no dopamine neurons are present. An alternative explanation is that bicuculline activates translation by increasing glutamate tone at NMDA receptors (NMDAR) within D1R/NMDAR heteromers. Supporting this, immunocytochemistry and proximity ligation assays revealed D1R/NMDAR heteromers on NAc cells both in vitro and in vivo, confirming previous results. Furthermore, bicuculline's effect was reversed to the same extent by SCH23390 alone, the NMDAR antagonist APV alone, or SCH23390 + APV. These results suggest that: (1) excitatory transmission stimulates translation in NAc MSNs, (2) this is opposed when glutamate activates D1R/NMDAR heteromers, even in the absence of dopamine, and (3) antagonist occupation of D1Rs within the heteromers prevents their activation. Our study is the first to suggest a role for D2 receptors and D1R/NMDAR heteromers in regulating protein translation., Competing Interests: Declarations. Ethics Approval: All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. Specifically, all procedures performed in studies involving animals were in accordance with the ethical standards of the Institutional Animal Care and Use Committees of Rosalind Franklin University of Medicine & Science and North Central College. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chronic exposure to methamphetamine (METH) has been suggested to cause METH use disorder and severe cognitive impairment. Paeoniflorin (PF) is a monoterpenoid glycoside with various beneficial effects, including anti-inflammatory, antioxidant and antidepressant. The current study was designed to investigate the effect of PF (30 mg/kg, i.p.) on the rewarding effect of METH (2.5 mg/kg, i.p.) and the associated cognitive impairment, using the animal model of conditioned place preference, new location reorganization test, new object reorganization test and Y-maze test. METH induced conditioned place preference, accompanied by increased expression of synapse-associated proteins in the ventral target areas (VTA) and nucleus accumbens (NAc). In addition, METH induced significant cognitive impairment and decreased the expression of synapse-associated proteins in the hippocampus (Hip). Administration of PF decreased the rewarding effect of METH and the expression of synapse-associated proteins in the VTA or NAc. PF was also effective to improve METH-induced cognitive impairment by upregulating the expression of synapse-associated proteins in the Hip. Therefore, PF could be a potential agent for the treatment of METH use disorder and the associated cognitive impairment., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Fentanyl, a potent analgesic and addictive substance, significantly impacts sleep-wakefulness (S-W). Acutely, it promotes wake, whereas chronic abuse leads to severe sleep disruptions, including insomnia, which contributes to opioid use disorders (OUD), a chronic brain disease characterized by compulsive opioid use and harmful consequences. Although the critical association between sleep disruptions and fentanyl addiction is acknowledged, the precise mechanisms through which fentanyl influences sleep remain elusive. Recent studies highlight the role of the dopaminergic system of the nucleus accumbens (NAc) in S-W regulation, but its specific involvement in mediating fentanyl's effects on S-W remains unexplored. We hypothesized that dopamine D2 receptors mediate fentanyl-induced effects on S-W. To test this hypothesis, male C57BL/6J mice, instrumented with sleep recording electrodes and bilateral guide cannulas above the accumbal core region (NAcC), were utilized in this study. At dark onset, animals were bilaterally administered sulpiride (D2 receptors antagonist; 250 ng/side) in the NAcC followed by an intraperitoneal injection of fentanyl (1.2 mg/Kg). S-W was examined for the next 12 h. We found that systemic administration of fentanyl significantly increased wakefulness during the first 6 h of the dark which was followed by a significant increase in NREM and REM sleep during the second 6 h of the dark period. D2-receptor blockade significantly reduced this effect as evidenced by a significant reduction in fentanyl-induced wakefulness during first 6 h of dark period and sleep rebound during the second 6 h. Our findings suggest that D2 receptors in the NAcC plays a vital role in mediating the fentanyl-induced changes in S-W., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). All rights reserved.)

The increasing prevalence of cannabis use during pregnancy has raised medical concerns, primarily related to Δ9-tetrahydrocannabinol (THC), which readily crosses the placenta and affects fetal brain development. Previous research has identified dopaminergic alterations related to maternal THC consumption. However, the consequences that prenatal cannabis exposure (PCE) has on striatum-based processing during reward pursuit have not been determined. Here, we characterize PCE rats during food or opioid-maintained reward seeking. We find that the supramotivational phenotype of PCE rats is independent of value-based processing and is instead related to augmented reinforcing efficiency of opioid rewards. Our findings reveal that prenatal THC exposure leads to increased cue-evoked dopamine responses and an overrepresentation of effort-driven striatal encoding patterns. Recapitulating clinical findings, drug-related PCE adaptations were more pronounced in males, who showed increased vulnerability for relapse. Collectively, these findings indicate that prenatal THC exposure in male rats engenders a pronounced neurodevelopmental susceptibility to addiction-like disorders.

Widely prescribed for Attention-Deficit/Hyperactivity Disorder (ADHD), stimulants (e.g., methylphenidate) have been studied for their chronic effects on the brain in prospective designs controlling dosage and adherence. While controlled approaches are essential, they do not approximate real-world stimulant exposure contexts where medication interruptions, dosage non-compliance, and polypharmacy are common. Brain changes in real-world conditions are largely unexplored. To fill this gap, we capitalized on the observational design of the Adolescent Brain Cognitive Development (ABCD) study to examine effects of stimulants on large-scale bilateral cortical networks' resting-state functional connectivity (rs-FC) with 6 striatal regions (left and right caudate, putamen, and nucleus accumbens) across two years in children with ADHD. Bayesian hierarchical regressions revealed associations between stimulant exposure and change in rs-FC of multiple striatal-cortical networks, affiliated with executive and visuo-motor control, which were not driven by general psychotropic medication. Of these connections, three were selective to stimulants versus stimulant naive: reduced rs-FC between caudate and frontoparietal network, and between putamen and frontoparietal and visual networks. Comparison with typically developing children in the ABCD sample revealed stronger rs-FC reduction in stimulant-exposed children for putamen and frontoparietal and visual networks, suggesting a normalizing effect of stimulants. 14% of stimulant-exposed children demonstrated reliable reduction in ADHD symptoms, and were distinguished by stronger rs-FC reduction between right putamen and visual network. Thus, stimulant exposure for a two-year period under real-world conditions modulated striatal-cortical functional networks broadly, had a normalizing effect on a subset of networks, and was associated with potential therapeutic effects involving visual attentional control., (© 2024. The Author(s).)

The use of psilocybin to treat alcohol use disorder is very promising, but its mechanisms of action remain poorly understood. We combined behavioural, pharmacological and gene expression analyses to decipher the mechanisms of action of psilocybin, for the first time, when injected into the brain. Male Long Evans rats underwent chronic operant ethanol self-administration before testing the effect of intraperitoneal psilocybin or directly within the nucleus accumbens core or the ventral tegmental area. Transcripts from the dopaminergic system were quantified in the nucleus accumbens and prefrontal cortex. Psilocybin significantly reduced (by 50%) ethanol self-administration when injected 4 h before the session either intraperitoneally (1 mg/kg) or directly within the left nucleus accumbens (0.15 μg) but not the right nucleus accumbens or the left ventral tegmental area. The effect of intraperitoneal injection of psilocybin was prevented by intra-left nucleus accumbens injection of 0.3 μg of the 5-HT2A receptor antagonist ketanserin. In rats that self-administered ethanol but not in those self-administering saccharin, dopamine D2 receptor (D2R) mRNA was increased in both the nucleus accumbens and the prefrontal cortex by psilocybin, while dopamine D1 receptor mRNA was increased only in the prefrontal cortex. As in humans, psilocybin reduced ethanol self-administration in rats through the 5-HT2A receptor within the left nucleus accumbens, possibly through increased D2R expression. Our results open unexpected perspectives regarding the hemispheric lateralization of psychedelic effects., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Psychedelics produce lasting therapeutic responses in neuropsychiatric diseases suggesting they may disrupt entrenched associations and catalyze learning. Here, we examine psychedelic 5-HT 2A/2C agonist, DOI, effects on dopamine signaling in the nucleus accumbens (NAc) core, a region extensively linked to reward learning, motivation, and drug-seeking. We measure phasic dopamine transients following acute DOI administration in rats during well learned Pavlovian tasks in which sequential cues predict rewards. We find that DOI (0.0-1.2 mg/kg, i.p.) increases dopamine signals, photometrically measured using GRAB DA optical sensor, to rewards and proximal reward cues, but not to the distal cues that predict these events. We determine that the elevated dopamine produced by DOI to reward cues occurs independently of DOI-induced changes in reward value. The increased dopamine associated with predictable reward cues and rewards supports DOI-induced increases in prediction error signaling. These findings lay a foundation for developing psychedelic strategies aimed at engaging error-driven learning mechanisms to disrupt entrenched associations or produce new associations., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Background: Past research has illuminated pivotal roles of dopamine D 3 receptors (D 3 R) in the rewarding effects of cocaine and opioids. However, the cellular and neural circuit mechanisms that underlie these actions remain unclear., Methods: We employed Cre-LoxP techniques to selectively delete D 3 R from presynaptic dopamine neurons or postsynaptic dopamine D 1 receptor (D 1 R)-expressing neurons in male and female mice. We utilized RNAscope in situ hybridization, immunohistochemistry, real-time polymerase chain reaction, voltammetry, optogenetics, microdialysis, and behavioral assays (n ≥ 8 animals per group) to functionally characterize the roles of presynaptic versus postsynaptic D 3 R in cocaine and opioid actions., Results: Our results revealed D 3 R expression in ∼25% of midbrain dopamine neurons and ∼70% of D 1 R-expressing neurons in the nucleus accumbens. While dopamine D 2 receptors (D 2 R) were expressed in ∼80% dopamine neurons, we found no D 2 R and D 3 R colocalization among these cells. Selective deletion of D 3 R from dopamine neurons increased exploratory behavior in novel environments and enhanced pulse-evoked nucleus accumbens dopamine release. Conversely, deletion of D 3 R from D 1 R-expressing neurons attenuated locomotor responses to D 1 -like and D 2 -like agonists. Strikingly, deletion of D 3 R from either cell type reduced oxycodone self-administration and oxycodone-enhanced brain-stimulation reward. In contrast, neither of these D 3 R deletions impacted cocaine self-administration, cocaine-enhanced brain-stimulation reward, or cocaine-induced hyperlocomotion. Furthermore, D 3 R knockout in dopamine neurons reduced oxycodone-induced hyperactivity and analgesia, while deletion from D 1 R-expressing neurons potentiated opioid-induced hyperactivity without affecting analgesia., Conclusions: We dissected presynaptic versus postsynaptic D 3 R function in the mesolimbic dopamine system. D 2 R and D 3 R are expressed in different populations of midbrain dopamine neurons, regulating dopamine release. Mesolimbic D 3 R are critically involved in the actions of opioids but not cocaine., (Published by Elsevier Inc.)