Conditioned Place Preference Paradigm Research Articles

Differences in the Alcohol Preference Assessment of Shy and Bold Zebrafish.

Individuals differ in their preference for alcohol and propensity to develop alcoholism, where the behavioral profile, such as the bold-shy axis, plays an important role for such a difference. However, literature is limited and conflicting on the causes and consequences of this relationship. Translational studies using animal models, such as zebrafish, can help identify behavioral traits that predispose individuals to drink alcohol compulsively. Here, the preference for alcohol was investigated in two distinct traits in zebrafish: shy and bold. For this purpose, fish were separated into shy and bold traits and then a conditioned place preference paradigm was used, a strategy that allows the rewarding effects from alcohol to be assessed by the ability to enhance the animal’s preference for an environment that initially was not preferred. It was found that bold zebrafish actively searched for the environment that was paired to alcohol after one acute exposure, whereas, shy fish changed their place preference even without alcohol administration, showing that the conditioned place preference protocol, given the short amount time to assess place preference, is not ample enough for shy fish to choose. Our results show that behavioral profiles must be considered in further studies since differences between shy and bold individuals on preference behavior can strongly interfere in the assessment of drug preference, mainly when using the conditioned place preference paradigm.

Neuropsychopharmacology of Emerging Drugs of Abuse: meta- and para-Halogen-Ring-Substituted α-PVP ("flakka") Derivatives.

Changes in the molecular structure of synthetic cathinones has led to an increase in the number of novel emerging drugs in the illicit drug market at an unprecedented rate. Unfortunately, little is known about the neuropsychopharmacology of recently emerged halogen-substituted α-PVP derivatives. Thus, the aim of this study was to investigate the role of para- and meta-halogen (F-, Cl-, and Br-) substitutions on the in vitro, in silico, and in vivo effects of α-pyrrolidinopentiophenone (α-PVP) derivatives. HEK293 cells expressing the human dopamine or serotonin transporter (hDAT and hSERT) were used for the uptake inhibition and transporter affinity assays. Molecular docking was used to model the interaction mechanism against DAT. Swiss CD-1 mice were used for the horizontal locomotor activity, open field test, and conditioned place preference paradigm. All compounds demonstrated potent DA uptake inhibition and higher DAT selectivity than cocaine. Meta-substituted cathinones showed higher DAT/SERT ratios than their para- analogs, which correlates with an increased psychostimulant effect in vivo and with different meta- and para-in silico interactions at DAT. Moreover, all compounds induced rewarding and acute anxiogenic effects in mice. In conclusion, the present study demonstrates the role of meta- and para-halogen substitutions in the mechanism of action and provides the first evidence of the rewarding and anxiety-like properties of halogenated α-PVP derivatives.

Effects of electrical stimulation and temporary inactivation of basolateral amygdala on morphine-induced conditioned place preference in rats

In the present study, to evaluate the role of the basolateral amygdala (BLA) in morphine addiction, the BLA was stimulated electrically, or inactivated temporarily using lidocaine. The electrical stimulation (ES) was delivered to BLA with low or high intensities (LI or HI: 25 or 150 µA, respectively), and five minutes before morphine administration with effective or ineffective doses, lidocaine was microinjected into the BLA. Using a 5-day conditioned place preference (CPP) paradigm, the dependence on morphine was evaluated. The results showed that LI-ES of BLA induced CPP in both the acquisition and expression phases, in the control and the ineffective dose of morphine groups. HI-ES had no effect on CPP acquisition but induced aversion in the expression, with both effective and ineffective doses of morphine. Inactivation of BLA using lidocaine, inhibited morphine-induced CPP in both acquisition and expression phases. The results of the present study indicate the prominent role of BLA in morphine addiction and dependence. Considering the contradictory results of different intensities of ES, it can be inferred that there are different neural circuits in this area of the brain, in relation to the reward responses.

Rabbits can be conditioned in a food-induced place preference paradigm

The conditioned place preference (CPP) paradigm has been employed in behavioral studies to investigate the responses to an environment where a reinforcing event occurs. It is applied to reveal incentive motivational responses to reward-related stimuli. It is standardized and widely applied in mice and rats, two of the most common species of laboratory animals. However, no studies using the CPP protocol have been performed in rabbits, even though this animal model is commonly used in pharmacological and behavioral research. There are important physiological and behavioral differences between rodents and rabbits. For example, rodents are spontaneous ovulators while rabbits are induced ovulators. In addition, lactation in the rabbit is circadian, which is unique among mammals. The present investigation aims to establish whether rabbits can be conditioned by using a food-induced CPP protocol in subjects with caloric restriction. Adult female rabbits were subjected to a three-compartment CPP protocol. The food produced place preference, demonstrating for the first time that rabbits can be conditioned using the CPP paradigm opening a new field of opportunities for behavioral studies of positive affective states in a species with important behavioral and physiological differences from rodents.

Effects of imidazoline agents in a rat conditioned place preference model of addiction

Agmatine (AG), idazoxan (IDZ), and efaroxan (EFR) are imidazoline receptor ligands with beneficial effects in central nervous system disorders. The present study aimed to evaluate the interaction between AG, IDZ, and EFR with an opiate, tramadol (TR), in a conditioned place preference (CPP) paradigm. In the experiment, we used five groups with 8 adult male Wistar rats each. During the condition session, on days 2, 4, 6, and 8, the rats received the drugs (saline, or TR, or IDZ and TR, or EFR and TR, or AG and TR) and were placed in their least preferred compartment. On days 1, 3, 5, and 7, the rats received saline in the preferred compartment. In the preconditioning, the preferred compartment was determined. In the postconditioning, the preference for one of the compartments was reevaluated. TR increased the time spent in the non-preferred compartment. AG decreased time spent in the TR-paired compartment. EFR, more than IDZ, reduced the time spent in the TR-paired compartment, but without statistical significance. AG reversed the TR-induced CPP, while EFR and IDZ only decreased the time spent in the TR-paired compartment, without statistical significance.

Insulin replacement prevents the acquisition but not the expression of morphine-induced conditioned place preference in streptozotocin-induced diabetic rats

Insulin receptors have distributed in all brain regions, including the nucleus Accumbens (NAc), and where is implicated in the reward properties of drugs. It is well known that insulin signaling can regulate dopamine release. Therefore, in the present study, we tried to examine the effect of insulin replacement on the acquisition and expression of morphine-induced conditioned place preference (CPP) in diabetic rats. Forty-eight male Wistar rats were divided into two non-diabetic (Naïve) and diabetic groups rendered by a single injection of streptozotocin (STZ). These groups separately received insulin (10U/kg) or saline (1 ml/kg) one hour prior to morphine administration (5mg/kg;s.c.) during conditioning days (acquisition phase) or post-conditioning day (expression phase) in the CPP paradigm. In this paradigm, conditioning score (CS) and locomotion activity were recorded by Ethovision. The STZ-induced diabetic rats displayed higher CS compared to naïve rats (P<0.05). This effect was abolished in all diabetic rats that received insulin during conditioning days but not the expression phase. This study has provided evidence that insulin plays a modulatory role in morphine-induced CPP, and insulin replacement during the acquisition phase could reduce the rewarding properties of morphine in diabetes conditions through a possible modulating effect on dopamine release in the NAc region.

Dogs’ Preference for White Coat versus No White Coat When Offered a Food Reward in the Exam Room

The wearing of a white lab coat during a visit to the veterinarian is common practice in veterinary medicine to avoid cross contamination or the spread of diseases in a clinical setting. “White Coat Effect” in both human and animal medicine has been of research interest. This study sought to explore if the visual of a white coat does in fact play a role in eliciting avoidance in dogs measured by preference for a veterinarian wearing a white coat versus one not wearing it. We investigated whether dogs would choose to retrieve a food reward from the veterinarian not wearing a white coat more often. We predicted that dogs would approach the veterinarian not wearing a coat first, would avoid approaching the veterinarian with the white coat, and would spend more time around the veterinarian not wearing the coat. A modified conditioned place preference paradigm was used to design this study. Two veterinarians were in a room, one wearing a white coat and one not wearing it, with a dog and the dog’s owner. Data was recorded for how many times the dog approached each of the veterinarians, and how much time it spent in proximity of the individuals in the room. Dogs showed preference for the veterinarian not wearing a white coat and spent more time between the owner and the veterinarian not wearing a coat. This study gives insight on how veterinarians can decrease stress during a vet visit. The white coat appears to be a stressor making the visit to the vet more challenging to the canine patient. Veterinarians and staff shall provide a comfortable setting for patients so that they can properly assess and treat them, while decreasing fear of the vet visit.

Involvement of Basolateral Amygdala Dopamine D1 Receptors in the Acquisition and Expression of Morphine-Induced Place Preference in Rats.

Background:In the present study, the effects of intra-basolateral amygdala (BLA) blockade of dopamine D1 receptor on morphine-induced conditioned place preference (CPP) were investigated in male Wistar rats.Materials and Methods:A 5-day CPP paradigm was used. Morphine was injected subsequently at effective (5 mg/kg) and ineffective (0.5 mg/kg) doses. SCH 23390 (0.5– μg/rat), as a selective D1 receptor antagonist, was microinjected bilaterally into the BLA.Results:Effective dose of morphine induced a significant CPP, and increased the locomotor activity during the testing phase. The results showed that morphine-induced CPP was significantly suppressed by D1 receptors antagonist in BLA in the acquisition phase and caused an aversion even at high doses. The antagonist also significantly prevented CPP expression. Morphine increased the motor activity, but the D1 receptors blockade, significantly reduced it.Conclusions:The findings of this study suggest a possible role for BLA dopamine D1 receptors in reward responses in morphine dependency.

Differential Effects of Cannabidiol and a Novel Cannabidiol Analog on Oxycodone Place Preference and Analgesia in Mice: an Opioid Abuse Deterrent with Analgesic Properties.

Background and Purpose: This study sought to determine whether cannabidiol (CBD) or a CBD derivative, CBD monovalinate monohemisuccinate (CBD-val-HS), could attenuate the development of oxycodone reward while retaining its analgesic effects. Experimental Approach: To determine the effect on oxycodone reward, animals were enrolled in the conditioned place preference paradigm and received either saline or oxycodone (3.0 mg/kg) in combination with either CBD or CBD-val-HS utilizing three sets of drug-/no drug-conditioning trials. To determine if the doses of CBD or CBD-val-HS that blocked opioid reward would affect nociceptive processes, animals were enrolled in the hot plate and abdominal writhing assays when administered alone or in combination with a subanalgesic (1.0 mg/kg) or analgesic (3.0 mg/kg) dose of oxycodone. Key Results: Results from condition place preference demonstrated CBD was not able attenuate oxycodone place preference while CBD-val-HS attenuated these rewarding effects at 8.0 mg/kg and was void of rewarding or aversive properties. In contrast to CBD, CBD-val-HS alone produced analgesic effects in both nociceptive assays but was most effective compared with oxycodone against thermal nociception. Of interest, there was a differential interaction of CBD and CBD-val-HS×oxycodone across the two nociceptive assays producing subadditive responses on the hot plate assay, whereas additive responses were observed in the abdominal writhing assay. Conclusion: These findings suggest CBD-val-HS alone, a nonrewarding analgesic compound, could be useful in pain management and addiction treatment settings.

Ayahuasca blocks ethanol preference in an animal model of dependence and shows no acute toxicity

Ethnopharmacological relevanceAyahuasca, a psychoactive beverage prepared from Banisteriopsis caapi and Psychotria viridis, is originally used by Amazon-based indigenous and mestizo groups for medicinal and ritualistic purposes. Nowadays, ayahuasca is used in religious and shamanic contexts worldwide, and preliminary evidence from preclinical and observational studies suggests therapeutic effects of ayahuasca for the treatment of substance (including alcohol) use disorders. Aim of the studyTo investigate the initial pharmacological profile of ayahuasca and its effects on ethanol rewarding effect using the conditioned place preference (CPP) paradigm in mice. Materials and methodsAyahuasca beverage was prepared using extracts of B. caapi and P. viridis, and the concentration of active compounds was assessed through high performance liquid chromatography (HPLC). The following behavioral tests were performed after ayahuasca administration: general pharmacological screening (13, 130, or 1300 mg/kg – intraperitoneally – i.p., and 65, 130, 1300, or 2600 mg/kg – via oral – v.o.); acute toxicity test with elevated doses (2600 mg/kg – i.p., and 5000 mg/kg – v.o.); motor activity, motor coordination, and hexobarbital-induced sleeping time potentiation (250, 500, or 750 mg/kg ayahuasca or vehicle – v.o.). For the CPP test, the animals received ayahuasca (500 mg/kg – v.o.) prior to ethanol (1.8 g/kg – i.p.) or vehicle (control group – i.p.) during conditioning sessions. ResultsAyahuasca treatment presented no significant effect on motor activity, motor coordination, hexobarbital-induced sleeping latency or total sleeping time, and did not evoke signs of severe acute toxicity at elevated oral doses. Ayahuasca pre-treatment successfully inhibited the ethanol-induced CPP and induced CPP when administered alone. ConclusionsOur results indicate that ayahuasca presents a low-risk acute toxicological profile when administered orally, and presents potential pharmacological properties that could contribute to the treatment of alcohol use disorders.

Co-treatment with low doses of buspirone prevents rewarding effects of methylphenidate and upregulates expression of 5-HT1A receptor mRNA in the nucleus accumbens

Accumulating studies consistently show that methylphenidate (MPD), the first line drug for treating Attention-Deficit Hyperactivity Disorder (ADHD), is abused by patients to whom the drug is prescribed. Like other psychostimulants, only low doses of MPD improve cognitive performance while higher doses impair it. Preventing the use of high doses of MPD is important for retaining its therapeutic efficacy. Previously, it has been shown that performance in Morris water maze test is improved in rats treated, orally, with MPD in doses of 2.5 mg/kg; but higher doses (5 mg/kg) impair it. The present study is designed to monitor rewarding effects of 2.5 mg/kg MPD in conditioned place preference (CPP) paradigm and its potential inhibition in buspirone co-treated animals. Our results show that rewarding effects of MPD in CPP paradigm are prevented in rats co-treated with buspirone in doses of 0.1 and 0.3 mg/kg. Animals treated with MPD exhibit a downregulation of 5-HT1A receptor mRNA in the nucleus accumbens which is also prevented in rats co-treated with 0.1 and 0.3 mg/kg but not 1.0 and 2.0 mg/kg buspirone. Administration of buspirone in these doses is not rewarding in CPP test and upregulates 5-HT1A receptor mRNA in the nucleus accumbens. The findings suggest that co-use of low doses of buspirone can prevent rewarding effects of MPD to help retain its therapeutic efficacy

Evaluation of Kratom Opioid Derivatives as Potential Treatment Option for Alcohol Use Disorder.

Background and Purpose: Mitragyna speciosa extract and kratom alkaloids decrease alcohol consumption in mice at least in part through actions at the δ-opioid receptor (δOR). However, the most potent opioidergic kratom alkaloid, 7-hydroxymitragynine, exhibits rewarding properties and hyperlocomotion presumably due to preferred affinity for the mu opioid receptor (µOR). We hypothesized that opioidergic kratom alkaloids like paynantheine and speciogynine with reduced µOR potency could provide a starting point for developing opioids with an improved therapeutic window to treat alcohol use disorder. Experimental Approach: We characterized paynantheine, speciociliatine, and four novel kratom-derived analogs for their ability to bind and activate δOR, µOR, and κOR. Select opioids were assessed in behavioral assays in male C57BL/6N WT and δOR knockout mice. Key Results: Paynantheine (10 mg∙kg−1, i.p.) produced aversion in a limited conditioned place preference (CPP) paradigm but did not produce CPP with additional conditioning sessions. Paynantheine did not produce robust antinociception but did block morphine-induced antinociception and hyperlocomotion. Yet, at 10 and 30 mg∙kg−1 doses (i.p.), paynantheine did not counteract morphine CPP. 7-hydroxypaynantheine and 7-hydroxyspeciogynine displayed potency at δOR but limited µOR potency relative to 7-hydroxymitragynine in vitro, and dose-dependently decreased voluntary alcohol consumption in WT but not δOR in KO mice. 7-hydroxyspeciogynine has a maximally tolerated dose of at least 10 mg∙kg−1 (s.c.) at which it did not produce significant CPP neither alter general locomotion nor induce noticeable seizures. Conclusion and Implications: Derivatizing kratom alkaloids with the goal of enhancing δOR potency and reducing off-target effects could provide a pathway to develop novel lead compounds to treat alcohol use disorder with an improved therapeutic window.

Cannabinoid receptor GPR55 activation blocks nicotine use disorder by regulation of AMPAR phosphorylation.

Nicotine use disorder can alter synaptic plasticity correlated with learning and memory process. G protein-coupled receptor 55 (GPR55), a novel cannabinoid receptor, which is highly expressed in the central nervous system, plays a prominent role in learning and memory. However, the role of GPR55 in nicotine use disorder remains unclear. In this study, we used the conditioned place preference (CPP) paradigm, a standard and well-established model for evaluating the rewarding effect of drug abuse, to investigate nicotine use disorder behavior in mice. After behavioral tests, the effect of GPR55 on nicotine response was evaluated using Western blotting, immunofluorescence staining, whole-cell patch-clamp recordings, and ELISA. GPR55 activation significantly reduced nicotine-CPP behavior by decreasing the spontaneous excitatory postsynaptic currents frequency in the nucleus accumbens (NAc) and the release of dopamine in serum. Furthermore, we found that the inhibition effects of nicotine response were mediated by phosphorylation of AMPAR. The PI3K-Akt signaling was involved in nicotine-CPP via GPR55 activation. Our findings showed that GPR55 in the NAc plays a specific role in blocking nicotine-CPP behavior and might be a potential target for the treatment of nicotine use disorder.

English

Nalbuphine, a semi-synthetic opioid drug, is a kappa (κ) agonist/ mu (μ) partial agonist. It is clinically used for moderate to severe pain. It produces the analgesic effect largely by binding to kappa opioid receptors. The present study was designed to investigate locomotor sensitization as well reinforcing effects of different doses (5, 10 and 20 mg/kg) of nalbuphine in rats. Potential analgesic and hyperalgesic effects after single and repeated administration respectively were also monitored. Reinforcing effects were monitored in a conditioned place preference (CPP) paradigm and associated changes in motor activity were monitored during a drug conditioning phase. The hot plate test was used to monitor nociceptive response. The present study showed that low (5 mg/kg) and high (20 mg/kg) doses of nalbuphine were reinforcing, while the moderate dose (10 mg/kg) had no reinforcing effect in the CPP paradigm. All doses were analgesic after the first administration and on repeated administration hyperalgesia did not develop to any dose. Analgesic effects still occurred at moderate doses of nalbuphine. Sensitization-like effects were produced following moderate and high doses of nalbuphine. These findings suggested that a moderate dose of nalbuphine did not produce reinforcing effects and hyperalgesia so this dose can be used safely for treating pain.

Effects of fentanyl on acute locomotor activity, behavioral sensitization, and contextual reward in female and male rats

BackgroundAlthough fentanyl has gained widespread prominence, there remains a lack of knowledge on this opioid synthetic agonist, particularly related to sex effects. Therefore, we conducted behavioral tests in female and male rats to measure drug abuse-related responses to fentanyl hypothesizing sex-specific responses. MethodsUsing female and male rats, we measured the effects of acute or repeated administration of fentanyl (20 μg/kg) on locomotor activity (LMA) and behavioral sensitization in an open field test. We further measured contextual-reward and associated locomotor activity during training in a conditioned place preference (CPP) paradigm using a low (4 μg/kg) or high (16 μg/kg) dose of fentanyl. Vaginal lavage samples were collected from female rats in the CPP study, and the estrous phase was determined based on the cytological characterization. ResultsFemale, but not male, rats showed elevated LMA in response to acute fentanyl and behavioral sensitization to repeated administration of fentanyl. Fentanyl produced significant CPP in both sexes, but it was more potent in males. Finally, our secondary investigation of the estrous cycle on fentanyl-CPP suggests that non-estrus phases, likely reflecting high estradiol, may predict the degree of fentanyl preference in females. ConclusionsFentanyl was more potent and/or effective to produce LMA and LMA sensitization in females but more potent to produce CPP in males. Furthermore, the role of sex in fentanyl responses varied across endpoints, and sex differences in LMA were not predictive of sex differences in CPP.

Role of cytokine and neurotrophic factors in nicotine addiction in the conditioned place preference paradigm

The mechanisms involved in the maintenance of cigarette smoking and nicotine reward remain unclear. Immune response might play an important role in this context. Nicotine may induce both central and systemic inflammatory responses as well as changes in the regulation of brain-derived neurotrophic factor (BDNF). The conditioned place preference (CPP) is a method used for the evaluation of nicotine-induced reward, reproducing nicotine-seeking behavior in humans. So far, there are no studies investigating the relationship between neuroinflammation and nicotine-induced CPP. This study aimed to evaluate the levels of inflammatory mediators and neurotrophic factors in key areas of the central nervous system (CNS) of mice subject to nicotine-induced CPP. CPP was induced with an intraperitoneal administration of 0.5 mg/kg of nicotine in male Swiss mice, using an unbiased protocol. Control group received vehicle by the same route. The levels of cytokines, chemokines, and neurotrophic factors were measured using Enzyme-Linked Immunosorbent Assay (ELISA) in the brain after CPP test. As expected, nicotine induced place preference behavior. In parallel, we observed increased peripheral levels of IL-6 and IL-10 alongside increased hippocampal levels of NGF but decreased GDNF in mice treated with nicotine compared to controls. In the striatum, nicotine promoted decrease of IL-1ß, IL-10 and GDNF levels, while the levels of all the mediators were similar between groups in the pre-frontal cortex. Our results provide evidence on the role of cytokines and neurotrophic factors in nicotine-induced CPP in mice.

Drug Repurposing Patent Applications April–June 2021

Drug Repurposing Patent Applications April–June 2021

DCA1-NAc shell glutamatergic projection mediates context-induced memory recall of morphine

Opioid relapse is generally caused by the recurrence of context-induced memory reinstatement of reward. However, the internal mechanisms that facilitate and modify these processes remain unknown. One of the key regions of the reward is the nucleus accumbens (NAc) which receives glutamatergic projections from the dorsal hippocampus CA1 (dCA1). It is not yet known whether the dCA1 projection to the NAc shell regulates the context-induced memory recall of morphine. Here, we used a common model of addiction-related behavior conditioned place preference paradigm, combined with immunofluorescence, chemogenetics, optogenetics, and electrophysiology techniques to characterize the projection of the dCA1 to the NAc shell, in context-induced relapse memory to morphine. We found that glutamatergic neurons of the dCA1 and gamma aminobutyric acidergic (GABA) neurons of the NAc shell are the key brain areas and neurons involved in the context-induced reinstatement of morphine memory. The dCA1-NAc shell glutamatergic input pathway and the excitatory synaptic transmission of the dCA1-NAc shell were enhanced via the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) when mice were re-exposed to environmental cues previously associated with drug intake. Furthermore, chemogenetic and optogenetic inactivation of the dCA1-NAc shell pathway decreased the recurrence of long- and short-term morphine-paired context memory in mice. These results provided evidence that the dCA1-NAc shell glutamatergic projections mediated the context-induced memory recall of morphine.

Prepulse inhibition can predict the motivational effects of cocaine in female mice exposed to maternal separation

The prepulse inhibition (PPI) of the startle response can identify the rodents that are more sensitive to the effects of cocaine. Mice with a lower PPI presented a higher vulnerability to the effects of cocaine and a higher susceptibility to developing a substance use disorder (SUD). Maternal separation with early weaning (MSEW) is a relevant animal model to induce motivational alterations throughout life. Nevertheless, only a few studies on females exist, even though they are more vulnerable to stress- and cocaine-related problems. Hence, the aim of the present study was to evaluate the ability of PPI to identify females with a greater vulnerability to the long-term consequences of early stress on the motivational effects of cocaine. Female mice underwent MSEW and were classified according to their high or low PPI. They were then assessed in the cocaine-induced locomotor sensitization test, the conditioned place preference paradigm or the operant self-administration paradigm. Additionally, they were also evaluated in the passive avoidance task, the tail-suspension and the splash tests. The results revealed that the females with lower PPI presented higher consequences of MSEW on the effects of cocaine and showed an increase in anhedonia-like behaviours. Our findings support that a PPI deficit could represent a biomarker of vulnerability to the effects of cocaine induced by MSEW.

Topiramate-chitosan nanoparticles prevent morphine reinstatement with no memory impairment: Dopaminergic and glutamatergic molecular aspects in rats

Besides their clinical application, chronic misuse of opioids has often been associated to drug addiction due to their addictive properties, underlying neuroadaptations of AMPA glutamate-receptor-dependent synaptic plasticity. Topiramate (TPM), an AMPAR antagonist, has been used to treat psychostimulants addiction, despite its harmful effects on memory. This study aimed to evaluate the effects of a novel topiramate nanosystem on molecular changes related to morphine reinstatement. Rats were previously exposed to morphine in conditioned place preference (CPP) paradigm and treated with topiramate-chitosan nanoparticles (TPM–CS–NP) or non-encapsulated topiramate in solution (S-TPM) during CPP extinction; following memory performance evaluation, they were re-exposed to morphine reinstatement. While morphine-CPP extinction was comparable among all experimental groups, TPM–CS–NP treatment prevented morphine reinstatement, preserving memory performance, which was impaired by both morphine-conditioning and S-TPM treatment. In the NAc, morphine increased D1R, D2R, D3R, DAT, GluA1 and MOR immunoreactivity. It also increased D1R, DAT, GluA1 and MOR in the dorsal hippocampus. TPM–CS–NP treatment decreased D1R, D3R and GluA1 and increased DAT in the NAc, decreasing GluA1 and increasing D2 and DAT in the dorsal hippocampus. Taken together, we may infer that TPM–CS–NP treatment was able to prevent the morphine reinstatement without memory impairment. Therefore, TPM–CS–NP may be considered an innovative therapeutic tool due to its property to prevent opioid reinstatement because it acts modifying both dopaminergic and glutamatergic neurotransmission, which are commonly related to morphine addiction.