Conditioned Place Preference Model Research Articles

Effect of Raha syrup on the motivational effects of morphine and CSF serotonin levels in rats

Opiates may influence motivational processes by a dysregulation of brain reward pathways that play a role in context-induced reinstatement of drug seeking. Raha syrup as herbal bioactive compounds with anti-anxiety/depressant effects may be prevented morphine-induced reward and motivation effects. Therefore, the aim of this study was to investigate the effect of Raha syrup on the rewarding effects of morphine and motivational aspects of morphine-seeking behavior in morphine-induced conditioned place preference (CPP) model and also the cerebrospinal fluid (CSF) serotonin levels following the extinction and reinstatement in rats. In this study, adult male Wistar rats received Raha syrup via oral gavage to assess of the acquisition, extinction and reinstatement of the morphine-induced CPP and as well as measurement of the CSF serotonin levels. Administration of Raha syrup during the conditioning period significantly attenuated the acquisition of morphine-induced CPP, and increased the CSF serotonin level, 6 days after cessation of treatment during extinction, while did not affect the duration of the extinction period. Also, Raha syrup during the extinction period did not affect the reinstatement of morphine-induced CPP and the CSF serotonin levels in rats. We conclude that Raha syrup attenuated the acquisition of morphine reward probably through an increase in CSF serotonin, while could not maintain the extinguished CPP and had no effect on the reinstatement. Therefore, Raha syrup as a useful adjunctive therapeutic strategy may exert a protective effect against opiate-related rewards, while it may be ineffective to prevention of motivation or drug-seeking reinstatement (relapse).

The role of heterodimers formed by histamine H3 receptors and dopamine D1 receptors on the methamphetamine-induced conditioned place preference

RationaleThe rewarding effect of Methamphetamine (METH) is commonly believed to play an important role in METH use disorder. The altered expression of dopamine D1 receptor (D1R) has been suggested to be essential to the rewarding effect of METH. Notably, D1R could interact with histamine H3 receptors (H3R) by forming a H3R-D1R heteromer (H3R-D1R). ObjectivesThis study was designed to specifically investigate the involvement of H3R-D1R in the rewarding effect of METH. MethodsC57BL/6 mice were treated with intraperitoneal injections of a selective H3R antagonist (Thioperamide, THIO; 20 mg/kg), an H1R antagonist (Pyrilamine, PYRI; 10 mg/kg), or microinjections of cytomegalovirus (CMV)-transmembrane domain 5 (TM5) into the nucleus accumbens (NAc). The animal model of Conditioned Place Preference (CPP) was applied to determine the impact of H3R-D1R on the rewarding effect of METH. ResultsMETH resulted in a significant preference for the drug-associated chamber, in conjunction with increased H3R and decreased D1R expression in both NAc and the ventral tegmental area (VTA). THIO significantly attenuated the rewarding effect of METH, accompanied by decreased H3R and increased D1R expression. In contrast, pyrilamine failed to produce the similar effects. Moreover, the inhibitory effect of THIO on METH-induced CPP was reversed by SKF38393, a D1R agonist. Furthermore, SCH23390, a D1R antagonist, counteracted the ameliorative effect of SKF38393 on THIO. Co-immunoprecipitation (CO-IP) experiments further demonstrated the specific interaction between H3R and D1R in METH CPP mice. The rewarding effect of METH was also significantly blocked by the interruption of CMV-transmembrane domain 5 (TM5), but not CMV-transmembrane domain 7 (TM7) in NAc. ConclusionThese results suggest that modulating the activity of H3R-D1R complex holds promise for regulating METH use disorder and serves as a potential drug target for its treatment.

The Effect of Probiotic Supplementation on Morphine Preference in Rats: Possible Antioxidative/Oxidative Signaling Pathway

Background: Many studies have revealed various aspects of the relationship between the stomach and the brain, but there has been no systematic study of the role of gut microbiota in drug addiction to date. This investigation is based on the novel concept that gut dysbiosis plays an important role in addiction disorders. Probiotic supplements (PBS) are thought to be a useful therapy method for opiate addiction and substance misuse. Therefore, it is postulated that changes in gut flora can play a significant part in the addiction process. Objectives: The aim of this study was to observe whether PBS, through the gut-brain axis in drug addiction, can decrease morphine (Mor) tendency in rats by affecting oxidative stress (OS) markers, using a conditioned place preference (CPP) paradigm. Methods: Forty-two rats (weight 180 - 200 g) were divided into six groups (n = 7 in each). The effective dose of morphine (Mor) was 7.5 mg/kg. Two probiotic supplements were used: Prodigest (Prd) containing Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium longum, and Prokid (Prk) containing Lactobacillus acidophilus, Bifidobacterium lactis, Lactobacillus rhamnosus, and Bifidobacterium bifidum. These were administered via gavage for 14 days. The animals were given PBS after each conditioning session in the conditioned place preference (CPP) model. The animals' locomotor activity was then evaluated using an open field apparatus. The brain was tested for malondialdehyde (MDA), nitric oxide (NO), catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (TAC), and thiol levels. Results: Only the Prd group, but not the Prk group, significantly increased the time spent in the Mor chamber (the location preference index) during the acquisition phase (P < 0.05). The anti-oxidation/oxidation profiles (MDA, NO, CAT, SOD, TAC, and thiol) were altered by PBS. Conclusions: Given the elevated location preference index generated by Mor, it may be argued that PBS influences mood and behavior via antioxidative/oxidative signaling, thereby potentiating the effect of Mor.

Previous exercise training history reduces drug addiction through brain orexinergic pathway in rodents: Conditioned Place Preference (CPP) model

Methamphetamine, commonly known as METH, is a potent and highly addict-forming stimulant substance that has a significant impact on the brain and poses a substantial health challenge in certain areas. Previous studies have pointed to the involvement of orexinergic pathway in reward-related behavior which is directly involved in acquisition phase of METH induced conditioned place preference (CPP). Besides, while numerous studies have explored the impact of exercise training on METH addiction, there is a limited body of research investigating as a form of preconditioning to prevent drug dependence. In this study, 48 male Wistar rats were assigned into six groups: Saline control, METH1 control, METH2 control, METH1 exercise, METH2 exercise. The exercise groups underwent eight weeks of forced running wheel training, five days a week, at 65% of their maximum running speed (Vmax). Following preconditioning with exercise training, METH groups received intraperitoneal (IP) methamphetamine injections at doses of 1 mg/kg (METH1 control, METH1 exercise) and 2 mg/kg (METH2 control, METH2 exercise) for five days to induce addiction (acquisition phase) according to the CPP model. Immediately following conditioning, hippocampus tissues were extracted to measure OX1R levels using western blotting. The results of the study indicated the conditioning of rats in both METH1 and METH2 control groups while preconditioning with exercise training prevent the addiction with low does of METH and only induced acquisition with double does in METH2 exercise group represented with reduced CPP scores in compare with METH2 control group (p<0.05). Molecular analysis revealed a significant increased in OX1R levels according to METH administration in hippocampus, although exercise training appeared to inhibit OX1R expression. Only conditioning with a high dose of METH was able to increase OX1R levels significantly. As these molecular results are in line with CPP scores it could further support the role of orexinergic pathway in addiction behavior in hippocampus. Furthermore, previous exercise training seems to affect this pathway and prevent conditioning with METH in an effective manner which suggests adaptation in the mesolimbic reward pathway protecting against methamphetamine addiction. Further investigation is warranted to find out the effectiveness of different training interventions in orexinergic pathway to inhibit dependance to METH. In this study, there was no external funding or financial support provided. This work was entirely self-funded by the authors. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation

Substance use disorders (SUDs) are highly comorbid with HIV infection, necessitating an understanding of the interactive effects of drug exposure and HIV. The relationship between HIV infection and cocaine use disorder is likely bidirectional, with cocaine use directly impacting immune function while HIV infection alters addiction-related behavior. To better characterize the neurobehavioral and immune consequences of HIV infection and cocaine exposure, this study utilizes a humanized mouse model to investigate the outcomes of HIV-1 infection on cocaine-related behaviors in a conditioned place preference (CPP) model, and the interactive effects of cocaine and HIV infection on peripheral and central nervous system inflammation. HIV infection selectively impairs cocaine CPP extinction without effecting reinstatement or cocaine seeking under conflict. Behavioral alterations are accompanied by immune changes in HIV infected mice, including increased prefrontal cortex astrocyte immunoreactivity and brain-region specific effects on microglia number and reactivity. Peripheral immune system changes are observed in human cytokines, including HIV-induced reductions in human TNFα, and cocaine and HIV interactions on GM-CSF levels. Together these data provide new insights into the unique neurobehavioral outcomes of HIV infection and cocaine exposure and how they interact to effect immune responses.

Methamphetamine use shortens telomere length in male adults and rats

BackgroundMethamphetamine (MA) use increases the risk of age-related diseases. However, it remains uncertain whether MA use exhibits accelerated biological aging, as indicated by telomere length (TL), a proposed marker of aging. Here we conducted studies in both humans and rats to investigate the association between MA use and TL. MethodsWe recruited 125 male MA users and 66 healthy controls, aged 30–40 years. MA users were diagnosed using DSM-5 criteria and categorized into two groups: non-severe (n = 78) and severe (n = 47) MA use disorder (MUD). MA-treated conditioned place preference (CPP) rats were utilized to validate our clinical investigations. TL was assessed using real-time polymerase chain reaction. ResultsAt clinical levels, MA users exhibited significantly shorter leukocyte TL compared to healthy controls. Among MA users, individuals with severe MUD had significantly shorter leukocyte TL than those with non-severe MUD. Importantly, both univariate and multivariate linear regression analyses demonstrated a negative association between the severity of MA use and leukocyte TL. In a rat model of MA-induced CPP, leukocyte TL was also significantly shortened after MA administration, especially in rats with higher CPP expression or reinstatement scores. ConclusionMA use shortened TL, and the severity of MA use was negatively correlated with TL. These findings provide new insights into the pathophysiology of accelerated aging caused by MA use and may have implications for identifying biomarkers and developing novel treatment strategies for MUD.

A novel dopamine D2 receptor-NR2B protein complex might contribute to morphine use disorders

Dopamine receptors can form heteromeric interactions with other receptors, including glutamate receptors, and present a novel pharmacological target because it contribute to dopamine-dysregulated brain disorders such as addiction and other motor-related diseases. In addition, dopamine receptors D2 (D2Rs) and glutamate NMDA receptors subtype-NR2B have been implicated in morphine use disorders; however, the molecular mechanism underlying the heteromeric complex of these two receptors in morphine use disorders is unclear. Herein, we focus on interactions between D2R and NR2B in morphine-induced conditioned place preference (CPP) and hyperlocomotion mice models. We found that the D2R–NR2B complex significantly increases in morphine-induced mice models, accompanied by ERK signaling impairment, implying the complex could contribute to the morphine addiction pathophysiological process. Further, we design a brain-penetrant interfering peptide (TAT-D2-KT), which could disrupt interactions of D2R–NR2B and decrease addictive-like behaviors concurrent to ERK signaling improvement. In summary, our data provided the first evidence for a D2R-NMDAR complex formation in morphine use disorders and its underlying mechanism of ERK signaling, which could present a novel therapeutic target with direct implications for morphine acquisition and relapse treatment.

The effects of ketamine and methamphetamine on neurotransmitters, glutamate receptors, and conditioned place preference in rat

Combined methamphetamine (MA) and ketamine (KET) abuse is a serious issue. At present, however, few studies have explored the mechanism underlying their combined addiction. We established a rat conditioned place preference (CPP) model. We investigated the role of dopamine (DA), 5-hydroxytryptamine (5-HT), monoamine oxidase (MAO), glutamate receptor 1 (GluR1), and glutamate receptor 2 (GluR2) in combined MA and KET addiction. The expression levels of DA, 5-HT, and MAO were detected by enzyme-linked immunosorbent assay (ELISA), and the expressions levels of GluR1 and GluR2 were detected by western blotting. Our results showed that MA and KET successfully induced CPP in rats respectively, and KET enhanced MA-induced CPP effects, although not significantly, and KET can reduce the MA-induced increase in DA, 5-HT, MAO and promoted the MA-induced increase in GluR1 and GluR2. Therefore, it suggested that DA, 5-HT, MAO, GluR1, and GluR2 expression may be involved in the mechanism underlying MA and KET-induced drug addiction in rats. Moreover, When MA and KET are used in combination, KET appears to play a dual addictive and anti-addictive role in the regulation of MA addiction.

Fentanyl-induced reward seeking is sex and dose dependent and is prevented by D-cysteine ethylester.

Introduction: Despite their inclination to induce tolerance, addictive states, and respiratory depression, synthetic opioids are among the most effective clinically administered drugs to treat severe acute/chronic pain and induce surgical anesthesia. Current medical interventions for opioid-induced respiratory depression (OIRD), wooden chest syndrome, and opioid use disorder (OUD) show limited efficacy and are marked by low success in the face of highly potent synthetic opioids such as fentanyl. D-Cysteine ethylester (D-CYSee) prevents OIRD and post-treatment withdrawal in male/female rats and mice with minimal effect on analgesic status. However, the potential aversive or rewarding effects of D-CYSee have yet to be fully characterized and its efficacy could be compromised by interactions with opioid-reward pathology. Methods: Using a model of fentanyl-induced conditioned place preference (CPP), this study evaluated 1) the dose and sex dependent effects of fentanyl to induce rewarding states, and 2) the extent to which D-CYSee alters affective state and the acquisition of fentanyl-induced seeking behaviors. Results: Fentanyl reward-related effects were found to be dose and sex dependent. Male rats exhibited a range-bound dose response centered at 5µg/kg. Female rats exhibited a CPP only at 50µg/kg. This dose was effective in 25% of females with the remaining 75% showing no significant CPP at any dose. Pretreatment with 100mg/kg, but not 10mg/kg, D-CYSee prevented acquisition of fentanyl seeking in males while both doses were effective at preventing acquisition in females. Discussion: These findings suggest that D-CYSee is an effective co-treatment with prescribed opioids to reduce the development of OUD.

The role of orexin-1 receptors within the ventral tegmental area in the extinction and reinstatement of methamphetamine place preference

Targeting the orexin system has recently been identified as one of the promising options for treating drug addiction. It may be more feasible and achievable if we investigate the accurate function of the orexin system in brain areas implicated in reward and addiction, such as the ventral tegmental area (VTA) by animal reward models. This study investigated the contribution of the orexin system, mainly the orexin-1 receptors (OX1R) in the VTA, in the extinction and reinstatement of methamphetamine (METH) related memories in the conditioned place preference (CPP) model. Animals after the acquisition of METH place preference were subjected to two separate sets of extinction and reinstatement experiments to receive various concentrations of selective OX1R antagonist, SB334867 into the bilateral VTA before extinction sessions (1, 3, and 10 nmol/0.3 μl DMSO per side) or only on the reinstatement phase (3, 10, and 30 nmol/0.3 μl DMSO per side), respectively. Intra-VTA infusion of SB334867 throughout the extinction phase could remarkably facilitate the extinction process and decrease the maintenance of reinforcing effects of METH at the highest dosage (10 nmol; p < 0.0001). Data also indicated a single microinfusion of SB334867 into the VTA before reinstatement of the METH-seeking behavior could considerably prevent the relapse of previously formed reward-context memories (10 nmol; p < 0.01 and 30 nmol; p < 0.001). The present study provided evidence supporting the potential therapeutic effects of the orexin system modulation, specifically in the VTA, on different stages of METH-induced place preference.

The effect of Varenicline on Betel nut dependence in Albino wistar rats

Betel nut is one of the most common addictive substance. Not many studies have explored the potential of varenicline as cessation therapy. We studied the benefits of varenicline in reducing the reward effects in rat model. Forty male albino rats of wistar strain weighing 150-250grams were used in the present study. Rats were randomized to 5 groups of 8 rats each to: Control; Betel nut group; Varenicline at doses of 0.5, 1 and 2mg/kg along with betel nut. Conditioned Place Preference (CPP) model was used for studying the drug seeking behavior. The CPP score was compared between the groups. Results showed a significant increase in body weight of rats at the end of the study compared to baseline in betel nut and varenicline groups. Compared to betel nut group (656.25±55) there was significant decrease in CPP score in Varenicline group at 0.5mg/kg (97.5±48); 1mg/kg (18.75±20) and at dose of 2mg/kg (-60±6). The study demonstrates the benefits of varenicline in betelnut dependence. There was dose dependent decrease in betel nut seeking behavior with varenicline in rat model of drug dependence.

Natural Polyphenols-Resveratrol, Quercetin, Magnolol, and β-Catechin-Block Certain Aspects of Heroin Addiction and Modulate Striatal IL-6 and TNF-α.

We have examined the effects of four different polyphenols in attenuating heroin addiction using a conditioned place preference (CPP) paradigm. Adult male Sprague Dawley rats received heroin (alternating with saline) in escalating doses starting from 10 mg/kg, i.p. up to 80 mg/kg/d for 14 consecutive days. The rats were treated with distilled water (1 mL), quercetin (50 mg/kg/d), β-catechin (100 mg/kg/d), resveratrol (30 mg/kg/d), or magnolol (50 mg/kg/d) through oral gavage for 7 consecutive days, 30 min before heroin administration, starting on day 8. Heroin withdrawal manifestations were assessed 24 h post last heroin administration following the administration of naloxone (1 mg/kg i.p). Heroin CPP reinstatement was tested following a single dose of heroin (10 mg/kg i.p.) administration. Striatal interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) were quantified (ELISA) after naloxone-precipitated heroin withdrawal. Compared to the vehicle, the heroin-administered rats spent significantly more time in the heroin-paired chamber (p < 0.0001). Concomitant administration of resveratrol and quercetin prevented the acquisition of heroin CPP, while resveratrol, quercetin, and magnolol blocked heroin-triggered reinstatement. Magnolol, quercetin, and β-catechin blocked naloxone-precipitated heroin withdrawal and increased striatal IL-6 concentration (p < 0.01). Resveratrol administration was associated with significantly higher withdrawal scores compared to those of the control animals (p < 0.0001). The results of this study show that different polyphenols target specific behavioral domains of heroin addiction in a CPP model and modulate the increase in striatal inflammatory cytokines TNF-α and IL-6 observed during naloxone-precipitated heroin withdrawal. Further research is needed to study the clinical utility of polyphenols and to investigate the intriguing finding that resveratrol enhances, rather than attenuates naloxone-precipitated heroin withdrawal.

Interaction of nicotine and social reward in group-reared male adolescent rats

Adolescents exhibit great sensitivity to nicotine and social interaction; accordingly, when both stimuli are presented together, they interact to enhance the incentive value of the context in which they occur. Noteworthy, most studies assessing the interaction between nicotine and social reward have used isolated-reared rats. Adolescent isolation is an adverse condition that impacts brain development and behavior, so it is not known if the interaction also occurs in rats without social deprivation. The present study used a conditioned place preference model (CPP) to examine the interaction between nicotine and social reward in group-reared male adolescent rats. At weaning, Wistar rats were randomly assigned to four groups: vehicle, vehicle and a social partner, nicotine (0.1 mg/Kg s.c.), and nicotine and a social partner. Conditioning trials occurred on eight consecutive days followed by a test session in which the preference change was assessed. Besides the establishment of CPP, we examined the effects of nicotine on (1) social behaviors during CPP trials and (2) tyrosine hydroxylase (TH) and oxytocin (OT) as markers of changes in the neuronal mechanisms for reward and social affiliation. Similar to previous results, the joint presentation of nicotine and social reward induced CPP, whereas either nicotine or social interaction presented alone did not. This finding coincided with an increase in TH levels observed after nicotine administration only in socially conditioned rats. The interaction between nicotine and social reward is not related to the effects of nicotine on social investigation or social play.

A morphine reward generalization mouse model based on conditioned place preference and aversion.

Conditioned place preference (CPP) is a common behavioral paradigm for studying the association of unconditioned stimulus reward memory with context. Generalization is a flexiblememory recall pattern developedon thebasis oforiginal memory. Drug-seeking behaviors in substance usedisorders(SUDs) exhibit diversity,which wegenerallyattribute to the highly generalizedfeaturesof SUD memory. However, to date, there are no animal models for SUD generalization studies. We design the generalization box (G-box) and the generalization retrieval process based on the conditioned place preference (CPP) model. In the memory retrieval stage, we replaced the conditioning CPP box (T-box) with a generalization box (G-box) to study drug generalization memory. For appearance, the generalized boxes have different angles and numbers of sides compared to the conditioning boxes. For the visual cues, the shapes of the symbols are different (triangle icons for the hexagonal chamber and dot icons for the round chamber), but the orientation information remains the same. To establish CPP generalization, the mice received morphine on the vertical or horizontal side of a conditioning box (T-box) andsaline on theotherside. Then, after CPP conditioning, the generalization test was performed in a generalization box (G-box: hexagonal chamber and Gr-box: round chamber) 21 days later. CPP-conditioned mice still displayed a clear preference for similar visual information in the G-box. CPA-conditioned mice behaved similarly to CPP, with mice consistently avoiding similar visual information in the G-box. We further observed that the generalization results are similar using two generalization boxes (G-box and Gr-box). In this study, we succeeded in creating a simple and effective generalization model for morphine reward. The establishment of this model provides a new tool for generalization studies of SUD and therapy in humans.

Evaluation of the effect of mesenchymal stem cells injection in the nucleus accumbens on the morphine reinstatement behavior in a conditioned place preference model in Wistar rat: Expression changes of NMDA receptor subunits and NT-3

Mesenchymal stem cells (MSCs) have been recently shown to improve functional recovery in animal models of CNS disorders and are currently being examined in clinical studies for sclerosis, stroke, and CNS lesions. The activation of endogenous CNS protection and repair mechanisms is unclear. MSC-based approaches are considered a new potential target for neurodegenerative disorders. This study was designed to discover the effect of MSCs injection in the nucleus accumbens (NAc) on the reinstatement of behavior in morphine-induced conditioned place preference (CPP) in male rats. The CPP was induced via intra-peritoneal (i.p.) morphine injection (5 mg/kg) for three consecutive days. After being tested for CPP induction, animals received MSCs or culture medium (DMEM F-12) in their NAc using stereotaxic surgery. Following extinction, a priming dose of morphine (2 mg/kg) was administered to induce reinstatement. Expression of GluN1, GluN2A, and GluN2B subunits of the NMDA receptor and the NT-3 gene in the NAc was assessed on the last day of extinction and following CPP reinstatement. The results showed that local injection of MSCs attenuated reinstatement after receiving a priming dose of morphine, and also shortened the period of CPP extinction. The mRNA expression of the NT-3 gene in the group receiving MSCs was increased compared to control animals, as was observed for GluN1 and GluN2B, but not GluN2A. It is concluded that intra-NAc injection of MSCs may facilitate morphine extinction and alleviate reinstatement behavior which may be via expression changes in NMDA receptor subunits and NT-3 gene.

The effect of intraperitoneal and intra-RMTg infusions of CTAP on rats’ social interaction

Social interaction is necessary for the development of individuals and society. Social interaction behaviors are rewarding. Similar to exogenous opioids, social interaction behaviors are able to induce rewarding effects that are regulated by the endogenous opioid system as well. As one type of opioid receptor, μ-opioid receptors (MORs), are densely expressed in the rostromedial tegmental nucleus (RMTg), which results in the RMTg being extremely sensitive to rewarding effects induced by exogenous and endogenous opioids. Here, we investigated how RMTg MORs played a role in rewarding effects induced by social interaction behaviors of male Wistar rats, using a conditioned place preference (CPP) model. Results showed that the CPP induced by social interaction behaviors was inhibited when the function of MORs was blocked via injecting CTAP (a selective MOR antagonist) intraperitoneally, and intra-RMTg injections of lower doses of CTAP affected the CPP in the same way. In addition, injecting CTAP intraperitoneally significantly inhibited the expression of pouncing behavior, while intra-RMTg injections of CTAP significantly inhibited the expression of all three types of social behaviors. These results suggest that RMTg MORs may be a crucial target and remain to be further explored in order to better understand the mechanism of the rewarding effects of social interaction behaviors.

Ethanol induces a dose-dependent conditioned place preference and conditioned place aversion in Japanese quail.

The conditioned place preference (CPP) paradigm is commonly used to investigate the motivational properties of drugs of abuse. Cues in the environment may become paired with these motivational properties and later result in drug seeking. Because many of these alcohol-paired cues are visual, Japanese quail may be a beneficial model to examine visual cue-induced alcohol seeking behavior. The aim of the present study was to examine the motivational properties of ethanol using a visual CPP model. During CPP, quail were given an initial preference test to determine their initially preferred chamber, during which time they could explore the entire chamber for 15 min. Following the initial preference test, quail were gavaged with their assigned treatment (water or 0.75 or 2.0 g/kg of ethanol) and were confined to their initially least preferred chamber every other conditioning day for 30 min. On alternate days, they were gavaged with water and confined to the preferred chamber for 30 min. After the 8th day of conditioning, a final preference test was given. Locomotor activity was also measured during conditioning. The findings indicated that quail that received the 0.75 g/kg ethanol developed a place preference to the ethanol-paired chamber, and that quail treated with 2 g/kg ethanol developed a place aversion to the ethanol-paired chamber. Additionally, locomotor activity was reduced in quail that received the high dose of ethanol. The findings suggest that both the rewarding and aversive properties of ethanol may be observable in this visual cue CPP model. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Identification of miRNA-mediated gene regulatory networks in L-methionine exposure counteracts cocaine-conditioned place preference in mice.

Background and Aims: Methionine has been proven to inhibit addictive behaviors of cocaine dependence. This study aimed to identify the potential mechanisms of MET relating to its inhibitory effects on cocaine induced cellular and behavioral changes. Methods: MRNA and miRNA high-throughput sequencing of the prefrontal cortex in a mouse model of cocaine conditioned place preference (CPP) combined with L-methionine was performed. Differentially expressed miRNAs (DE-miRNAs) and differentially expressed genes (DEGs) regulated by cocaine and inhibited by L-methionine were identified. DEGs were mapped to STRING database to construct a protein-protein interaction (PPI) network. Then, the identified DEGs were subjected to the DAVID webserver for functional annotation. Finally, miRNA-mRNA regulatory network and miRNA-mRNA-TF regulatory networks were established to screen key DE-miRNAs and coregulation network in Cytoscape. Results: Sequencing data analysis showed that L-methionine reversely regulated genes and miRNAs affected by cocaine. Pathways associated with drug addiction only enriched in CS-down with MC-up genes targeted by DE-miRNAs including GABAergic synapse, Glutamatergic synapse, Circadian entrainment, Axon guidance and Calcium signaling pathway. Drug addiction associated network was formed of 22 DEGs including calcium channel (Cacna1c, Cacna1e, Cacna1g and Cacng8), ephrin receptor genes (Ephb6 and Epha8) and ryanodine receptor genes (Ryr1 and Ryr2). Calcium channel gene network were identified as a core gene network modulated by L-methionine in response to cocaine dependence. Moreover, it was predicted that Grin1 and Fosb presented in TF-miRNA-mRNA coregulation network with a high degree of interaction as hub genes and interacted calcium channels. Conclusion: These identified key genes, miRNA and coregulation network demonstrated the efficacy of L-methionine in counteracting the effects of cocaine CPP. To a certain degree, it may provide some hints to better understand the underlying mechanism on L-methionine in response to cocaine abuse.

The effect of vitamin D on morphine preference in rats: Possible biochemical and DRD2-GDNF signaling.

Despite half a century of research on vitamin D (Vit. D), its link to substance abuse and dependence has only been discussed in recent decades. Evidence also shows the involvement of Vit. D in the evolution of dopaminergic neurons in the nucleus accumbens, an increase in the expression of tyrosine hydroxylase, and the regulation of dopaminergic processes. The novel idea for this work is taken from a hypothesis given about the effectiveness of Vit. D on dopamine signaling pathway. It is therefore presumed that Vit. D can be considered an effective therapeutic approach for narcotic addiction and substance abuse. The animals were assigned into six groups (control, vehicle, Morphine [Mor.], and Vit. D [250, 500, and 1000IU/kg, i.p.]). Following each conditioning session in a conditioned place preference (CPP) model, the animals received Vit. D. Afterward, the locomotor activity of the animals was assessed using open-field apparatus. Malondialdehyde (MDA), nitric oxide (NO), catalase (CAT), superoxide dismutase (SOD), thiol, and total antioxidant capacity (TAC) were measured in the brain. The relative DRD2 and GDNF expressions (%) were also measured in the hippocampus. Vit. D administration after Mor. caused a significant increase in the place preference index in the acquisition phase (p<.05). Vit. D altered the oxidation/antioxidation profiles (CAT, SOD, MDA, NO, TAC, and Thiol). Vit. D was more effective than Mor. in the expression of GDNF (p<.0001); however, in the expression of DRD2, this was only the case for 1000IU Vit. D (p<.0001). Considering the increased place preference index induced by Mor., it can be concluded that Vit. D interacts via the oxidative pathway and DRD2-GDNF signaling to potentiate the Mor. effect.

Psilocin suppresses methamphetamine-induced hyperlocomotion and acquisition of conditioned place preference via D2R-mediated ERK signaling.

Psilocin is an active metabolite form of psilocybin and exerts psychoactive effects. Recent studies suggest that psilocin may have regulatory effects on abuse drugs, but the mechanisms remain unclear. In this study, we want to explore the effects of psilocin on methamphetamine (METH)-induced alterations of behavior in mice and its molecular mechanisms. Acute METH administration model and conditioned place preference (CPP) model were used to investigate the effects of psilocin on METH-induced alterations of behavior. Western blot was used to detect the expression of proteins. In the acute 2mg/kg METH administration model, 1mg/kg psilocin counteracted METH-induced elevation of activity. In the 1mg/kg METH-induced CPP model, 1mg/kg psilocin inhibited CPP formation during the acquisition phase. However, psilocin did not impact METH extinction and relapse. Molecular results showed that the regulatory effect of psilocin on METH was underscored by altered expression of dopamine 2 receptor (D2R) and phosphorylated extra-cellular signal-regulated kinase (p-ERK) in the prefrontal cortex (PFC), nucleus accumbens (NAc), and ventral tegmental area (VTA). Trifluoperazine (TFP)-2HCl is a D2R inhibitor, and SCH772984 is a selective extra-cellular signal-regulated kinase (ERK) inhibitor that effectively inhibits ERK1/2 phosphorylation. The results indicated that 2mg/kg TFP-2HCl and 10mg/kg SCH772984 blocked METH-induced hyperactivity and acquisition of METH-induced CPP. Psilocin has regulatory effects on METH-induced alterations of behavior in mice via D2R-mediated signal regulation of ERK phosphorylation.