Place Preference In Male Rats Research Articles

S-3,4-DCPG, a potent orthosteric agonist for the mGlu8 receptor, facilitates extinction and inhibits the reinstatement of morphine-induced conditioned place preference in male rats

The limbic system, particularly the NAc, shows a high concentration of metabotropic glutamate receptors (mGluRs). Recent evidence suggests the significant involvement of mGluRs in mental disorders, including substance abuse and addiction. The objective of this study was to examine the involvement of mGlu8 receptors in the NAc in the mechanisms underlying the extinction and reinstatement of conditioned place preference (CPP) induced by morphine. Male Wistar rats underwent surgical implantation of bilateral cannulas in the NAc and were assessed in a CPP protocol. In study 1 at the same time as the extinction phase, the rats were given varying doses of S-3,4-DCPG (0.03, 0.3, and 3 μg/0.5 μl). In study 2, rats that had undergone CPP extinction were given S-3,4-DCPG (0.03, 0.3, and 3 μg/0.5 μl) five minutes prior to receiving a subthreshold dose of morphine (1 mg/kg) in order to reactivate the previously extinguished morphine response. The findings demonstrated that administering S-3,4-DCPG directly into the accumbens nucleus resulted in a decrease in the duration of the CPP extinction phase. Moreover, dose-dependent administration of S-3,4-DCPG into the NAc inhibited CPP reinstatement. The observations imply that microinjection of S-3,4-DCPG as a potent orthosteric agonist with high selectivity for the mGlu8 receptor into the NAc promotes the process of extinction while concurrently exerting inhibitory effects on the reinstatement of morphine-induced CPP. This effect may be associated with the modulation of glutamate engagement within the NAc and the plasticity of reward pathways at the synaptic level.

Rewarding effects in 4-AcO-DMT administration and withdrawal in rats: A challenge to the opponent-process theory

According to the opponent-process theory of drug addiction, the intake of an addictive substance initiates two processes: a rapid primary process that results in the drug’s rewarding effects, and a slower opponent process that leads to the aversive motivational state of drug aftereffects. This aversive state is integral in the desire, pursuit, and maintenance of drug use, potentially leading to dependence and addiction. However, current observational and experimental evidence suggests that the administration of a 5-hydroxytryptamine receptors-type 2A (5-HT2A) agonist, while capable of inducing a positive mental state in humans, may not generate the behavioral patterns typically associated with drugs of abuse. In this study, we found that administering the 5-HT2A agonist 4-Acetoxy-N,N-dimethyltryptamine fumarate (4-AcO-DMT) did not result in place preference in male rats compared to control saline administration 24 h later, after the drug has been cleared from the organism. However, in a modified place preference test where only the acute motivational effects of the drug were evaluated (excluding withdrawal), 4-AcO-DMT was found to be rewarding. Furthermore, in another modified place preference test where only the motivational effects of drug withdrawal were evaluated (excluding the acute effects of drug administration), the 24-hour aftereffect of 5-HT2A agonist administration also resulted in a robust place preference. Therefore, while 4-AcO-DMT administration was able to induce place preference, its 24-hour aftereffect also produced a strong reward. In the counterbalanced test, this reward from the aftereffect effectively overshadowed its acute rewarding properties, which could potentially create a false impression that 4-AcO-DMT lacks motivational properties. This suggests that 5-HT2A agonist administration follows a different dynamic than that proposed by the opponent-process theory of motivation and implies that the administration of 5-HT2A agonists may lead to behavioral patterns less typical of drugs associated with addiction.

VU0155041, a positive allosteric modulator of mGluR4, in the nucleus accumbens facilitates extinction and inhibits the reinstatement of morphine-induced conditioned place preference in male rats

Nucleus accumbens (NAc) neurons appear to be at the hub of the reward circuit. New evidence suggests that the behavioural effects of morphine substances may be significantly regulated by glutamate-mediated transmission, notably by metabotropic glutamate (mGlu) receptors. Here, we examined the hypothesis that the mGlu4 receptor within that NAc has a role in the extinction and reinstatement of morphine-induced conditioned place preference (CPP). The animals received bilaterally microinjections of VU0155041, a positive allosteric modulator (PAM) and partial agonist of mGlu4 receptor, into the NAc. In Experiment 1, the rats received VU0155041 (10, 30 and 50 μg/0.5 μL) during the extinction period. In Experiment 2, the CPP extinguished rats received VU0155041 (10, 30 and 50 μg/0.5 μL) five minutes prior to the administration of morphine (1 mg/kg) in order to reinstate the extinguished CPP. The results showed that the intra-accumbal administration of VU0155041 reduced the extinction period of CPP. Furthermore, the administration of VU0155041 into the NAc dose-dependently inhibited the reinstatement of CPP. The findings suggested that the mGluR4 in the NAc facilitates the extinction and inhibits the reinstatement of the morphine-induced CPP, which could be mediated by an increase in the release of extracellular glutamate.

The electrical stimulation of the central nucleus of the amygdala in combination with dopamine receptor antagonist reduces the acquisition phase of morphine-induced conditioned place preference in male rat.

The central nucleus of the amygdala (CeA) is one of the nuclei involved in the reward system. The aim of the current study was to investigate the electrical stimulation (e-stim) effect of the CeA in combination with dopamine D1 receptor antagonist on morphine-induced conditioned place preference (CPP) in male rats. A 5-day procedure of CPP was used in this study. Morphine was administered at an effective dose of 5 mg/kg, and SCH23390 as a selective D1 receptor antagonist was administrated into the CeA. In addition, the CeA was stimulated with an intensity of the current of 150 μA. Finally, the dependence on morphine was evaluated in all experimental groups. Morphine significantly increased CPP. While the blockade of the D1 receptor of the CeA reduced the acquisition phase of morphine-induced CPP. Moreover, the combination of D1 receptor antagonist and e-stim suppressed morphine-induced CPP, even it induced an aversion. The current study suggests that the administration of dopamine D1 receptor antagonist into the CeA in combination with e-stim could play a prominent role in morphine dependence.

Paired Housing or a Socially-Paired Context Decreases Ethanol Conditioned Place Preference in Male Rats.

Alcohol abuse dramatically affects individuals' lives nationwide. The 2020 National Survey on Drug Use and Health (NSDUH) estimated that 10.2% of Americans suffer from alcohol use disorder. Although social support has been shown to aid in general addiction prevention and rehabilitation, the benefits of social support are not entirely understood. The present study sought to compare the benefits of social interaction on the conditioned ethanol approach behavior in rats through a conditioned place preference (CPP) paradigm in which a drug is paired with one of two distinct contexts. In experiment 1A, rats were single-housed and received conditioning trials in which ethanol was paired with the less preferred context. In experiment 1B, rats underwent procedures identical to experiment 1A, but were pair-housed throughout the paradigm. In experiment 1C, rats were single-housed, but concurrently conditioned to a socially-paired context and an ethanol-paired context. By comparing the time spent between the ethanol-paired environment and the saline-paired or socially-paired environment, we extrapolated the extent of ethanol approach behavior in the pair-housed, single-housed, and concurrently conditioned rats. Our results revealed that social interaction, both in pair-housed animals or concurrently socially-conditioned animals, diminished the ethanol approach behavior, which highlights the importance of social support in addiction prevention, treatment, and recovery programs.

Individual differences in cocaine-induced conditioned place preference in male rats: Behavioral and transcriptomic evidence.

Background:Substance use disorder emerges in a small proportion of drug users and has the characteristics of a chronic relapsing pathology.Aims:Our study aimed to demonstrate and characterize the variability in the expression of the rewarding effects of cocaine in the conditioned place preference (CPP) paradigm.Methods:A cocaine-CPP paradigm in male Sprague–Dawley rats with an extinction period of 12 days and reinstatement was conducted. A statistical model was developed to distinguish rats expressing or not a cocaine-induced place preference.Results:Two groups of rats were identified: rats that did express rewarding effects (CPP expression (CPPE), score >102 s) and rats that did not (no CPP expression (nCPPE), score between −85 and 59 s). These two groups did not show significant differences in a battery of behavioral tests. To identify differentially expressed genes in the CPPE and nCPPE groups, a whole-transcriptome ribonucleic acid-sequencing analysis was performed in the nucleus accumbens (NAc) 24 h after the CPP test. Four immediate early genes (Fos, Egr2, Nr4a1, and Zbtb37) were differentially expressed in the NAc of CPPE rats after expression of CPP. Variability in cocaine-induced place preference persisted in the CPPE and nCPPE groups after the extinction and reinstatement phases. Transcriptomic differences observed after reinstatement were distinct from those observed immediately after expression of CPP.Conclusion:These new findings provide insights into the identification of mechanisms underlying interindividual variability in the response to cocaine’s rewarding effects.

Involvement of GABAA receptors of lateral habenula in the acquisition and expression phases of morphine-induced place preference in male rats.

The lateral habenula (LHb) is a critical brain structure involved in the aversive response to drug abuse. It has been determined that the gamma-aminobutyric acid (GABA)-ergic system plays the main role in morphine dependency. The role of GABA type A receptors (GABAARs) in LHb on morphine-induced conditioned place preference (CPP) remains unknown. In this study, the effect of bilateral intra-LHb microinjection of GABAAR agonist and antagonist on the acquisition and expression phases of CPP, utilizing a 5-day CPP paradigm in male rats, was evaluated. Subcutaneous administration of different doses of morphine caused a dose-dependent CPP. Intra-LHb microinjection of the GABAAR agonist, muscimol, in combination with morphine (5 mg/kg; subcutaneously) enhanced CPP scores in the acquisition phase of morphine CPP, whereas the GABAAR antagonist, bicuculline, significantly reduced the conditioning scores in the acquisition phase. Furthermore, pretreatment with a high dose of bicuculline reversed the additive effect of muscimol during the acquisition phase, yet the low dose of antagonist had no significant effect on agonist-induced CPP scores. On the other hand, muscimol (3 µg/rat) significantly increased CPP scores in the expression phase but bicuculline did not induce a significant effect on CPP scores. Bicuculline and muscimol microinjections did not affect locomotor activity in the testing sessions. Our results confirm that GABAARs in LHb play an active role in morphine reward. In addition, microinjections of bicuculline/muscimol may alter the morphine response through the GABAergic system.

Cannabidiol attenuates methamphetamine-induced conditioned place preference in male rats and viability in PC12 cells through the Sigma1R/AKT/GSK3β/CREB signaling pathway

ABSTRACT Background: Methamphetamine use is associated with several negative consequences, including neurotoxicity and greater probability of exhibiting a substance use disorder. Sigma1 receptor is involved in the neurobiological basis of several drug use disorders. Cannabidiol has received attention in the treatment of drug use disorders and neurotoxicity. Objectives: To investigate the effects of cannabidiol on methamphetamine-induced conditioned place preference (CPP) and the viability of PC12 cells. Methods: Adult male rats (n = 70) underwent methamphetamine (2 mg/kg, IP) induced CPP, and were administered cannabidiol (10, 20, 40, or 80 mg/kg, IP) during the methamphetamine withdrawal period for five consecutive days. Methamphetamine (0.5 mg/kg) was then injected to reactivate CPP. Four brain regions (ventral tegmental area, nucleus accumbens, prefrontal cortex, and hippocampus) were extracted after the last test. PC12 cells were treated with cannabidiol, Sigma1R-siRNA, or BD1047 before methamphetamine exposure. Results: Administration of 20, 40, or 80 mg/kg cannabidiol facilitated CPP extinction (80 mg/kg, p < .001) and prevented CPP development (80 mg/kg, p < .0001). This was associated with changes in the expression of Sigma1R (ventral tegmental area, 80 mg/kg, p < .0001) in the four brain regions. Cannabidiol protected the PC12 cell’s viability (10 μM, p = .0008) and inhibited the methamphetamine-induced activation of the AKT/GSK3β/CREB signaling pathway by mediating Sigma1R (10 μM, p < .0001). Conclusions: Cannabidiol seems to inhibit the rewarding effects of methamphetamine and the effects of this drug on cell viability. Sigma1R should be given further consideration as a potential target for cannabidiol.

Effect of electrical stimulation of central nucleus of the amygdala on morphine conditioned place preference in male rats.

Objective(s):The central nucleus of the amygdala (CeA) is one of the most important areas for the morphine reward system. This study investigated the effect of electrical stimulation of CeA on morphine conditioned place preference (CPP) in male rats. Materials and Methods:After anesthetizing male Wistar rats, both electrode and cannula were implanted into CeA for stimulating (low intensity: 25 μA, and high intensity: 150 μA) and injecting (lidocaine and dopamine D2 receptor antagonist), respectively. Then, CPP induced by effective (5 mg/kg) and ineffective (0.5 mg/kg) doses of morphine was evaluated for five consecutive days (n = 6 / group).Results:The low electrical stimulation intensity of 25 μA suppressed both acquisition and expression phases, but the high intensity of 150 µA attenuated only the expression phase. On the other hand, intra-CeA administration of dopamine D2 receptor antagonist, eticlopride (2 µg/rat), with the effective dose of morphine, decreased CPP. In addition, infusion of lidocaine into the CeA inhibited morphine-induced CPP in both acquisition and expression phases with the effective dose of morphine.Conclusion:Electrical stimulation of the CeA may play an important role in attenuating morphine induced CPP via possible changes in neurotransmitters involved in the reward system such as dopamine (DA) and gamma-aminobutyric acid (GABA).

Docosahexaenoic acid attenuates the rewarding property of nicotine-induced conditioned place preference in male rats

Docosahexaenoic acid attenuates the rewarding property of nicotine-induced conditioned place preference in male rats

Stimulation and transient inactivation of ventral tegmental area modify reinstatement of acquisition phase of morphine-induced conditioned place preference in male rats

For processing the development of psychological dependency, opioid reinforcement, and opiate-related associative reward, learning, and memory in the brain, the ventral tegmental area (VTA) is considered the key zone. As the responsible region for the morphine role in conditioned place preference (CPP), this area has an important role. So, the present research was conducted to investigate the effects of different intensities of electrical stimulation on VTA utilizing CPP, with two morphine doses. Reversible inactivation of VTA was performed via bilateral microinjection of Lidocaine into this area with two implanted separate cannulas. Our findings indicated that 5 mg/kg morphine-induced CPP was suppressed by 150 μA VTA electrical stimulation. The results also showed that bilateral Intra-VTA administration of Lidocaine significantly decreased the 5 mg/kg morphine-induced CPP acquisition phase in comparison with their respective sham group, which reversed in the reinstatement test. It should be concluded that these findings are important for the detection of mesolimbic nervous system ties and could help to find new ways to attenuate the rewarding action of morphine.

Similar role of mPFC orexin-1 receptors in the acquisition and expression of morphine- and food-induced conditioned place preference in male rats

Self-control problems are a typical character of drug addiction and excessive food consumption and it has been shown that natural rewards and drugs of abuse share parts of the same neural substrate and reward processing in the brain. Different brain areas are involved in natural and drug reward processing including the mesolimbic pathway, amygdala, nucleus accumbens (NAc), and prefrontal cortex. Considering the important role of orexins in the addictive behavior and the presence of orexin-1 subtype receptors (Orx1R) in the medial prefrontal cortex (mPFC), this study investigated the role of mPFC in natural- and drug-reward seeking behaviors to deepen our understanding of possible similarities or differences. To induce food- or morphine-conditioned place preference (CPP), adult male Wistar rats underwent CPP testing and received intra-mPFC doses of SB334867 (3, 10, or 30 nM/0.5 μl DMSO 12%), as an Orx1R antagonist, during the acquisition or expression phases of the CPP test. Results indicated that microinjection of Orx1R antagonist into the mPFC had similar effects on both morphine- and food-induced CPP and attenuated CPP scores in the acquisition and expression phases of the CPP test. The data demonstrated that Orx1Rs in the mPFC regulate the reward-related effects of morphine- and food-induced reward.

Blockade of orexin receptors in the hippocampal dentate gyrus reduced the extinction latency of morphine-induced place preference in male rats

Relapse to drugs such as opioids is a major challenge in addiction therapy. It has been known that the orexinergic system has a significant role in mediating reward processing and addiction, as shown by the conditioned place preference (CPP). The dentate gyrus (DG) of the hippocampus receives orexinergic projections from the lateral hypothalamus that has been approved as a critical area arbitrating the maintenance of drug-seeking behavior following the extinction. The present study aimed to investigate the effects of intra-DG administration of the orexin-1 receptor (OX1R) and orexin-2 receptor (OX2R) antagonists on the extinction of morphine-induced CPP in male rats. Animals received different doses of SB334867 (as OX1R antagonist) or TCS OX2 29 (as OX2R antagonist) (0.5, 2.5, and 12.5 nM/0.5 μl DMSO 12 %) bilaterally into the DG during the extinction phase, after CPP had been induced by subcutaneous injection of morphine (5 mg/kg) during a 3-day conditioning phase. The conditioning scores were recorded during the test. The results demonstrated that intra-DG administration of the highest dose of OX1R antagonist (12.5 nM/0.5 μl DMSO 12 %) shortened the extinction latency of morphine-CPP compared to the DMSO group, while the OX2R antagonist did not significantly alter the latency. Findings imply that the blockade of OX1R, but not OX2R, within the DG facilitates the extinction of morphine-induced reward. In conclusion, the OX1R antagonist might be kept in mind as a convenient therapeutic factor in repressing drug-seeking behaviors in an optimum amount of treatment considering the low dose-treatments applied.

Methamphetamine‐induced conditioned place preference in male rats eating standard or high fat chow

Eating a high fat diet has several negative health consequences, including dysfunction to dopamine systems. It has also been shown to enhance the sensitivity of male rats to methamphetamine-induced locomotor sensitization. However, it is not known if sensitivity to the other (i.e., rewarding) effects of methamphetamine are similarly enhanced in rats eating a high fat diet. To test the hypothesis that eating high fat chow enhances sensitivity of rats to the rewarding effects of methamphetamine, male Sprague Dawley rats were fed standard (17% kcal from fat) or high fat chow (60% kcal from fat) for 4 weeks prior to conditioned place preference (CPP) training, using a biased design. Before training, rats were given free access to both sides of the chamber to determine a side preference. Rats were then trained on alternating days with saline or methamphetamine (0.1, 0.32 and 1.0 mg/kg, i.p.) with drug conditioned in the initially non-preferred side. A 2 × 4 between-subjects ANOVA revealed a significant main effect of methamphetamine dose, but no main effect of diet, and no significant diet × dose interaction effect. Tukey HSD post-hoc analyses revealed that male rats conditioned with 0.32 mg/kg and 1.0 mg/kg methamphetamine displayed significantly larger preference scores than male rats conditioned with saline, regardless of diet. That is, at the two largest doses, methamphetamine induced a significant CPP. Preference scores for rats conditioned with the smallest dose of methamphetamine (0.1 mg/kg) did not significantly differ from the saline conditioned group nor the two larger doses of methamphetamine. Though no effect of diet was found, in contrast to what might have been predicted based on previous studies with methamphetamine-induced locomotion, future studies should explore a wider range of doses, as well as other assays (e.g., intravenous self-administration). Future studies will also examine female rats to investigate potential sex differences.

The role of mGlu4 receptors within the nucleus accumbens in acquisition and expression of morphine-induced conditioned place preference in male rats

BackgroundSeveral studies have shown that glutamate neurotransmission in the nucleus accumbens (NAc) is required for the development of morphine-induced conditional place preference (CPP). In addition, metabotropic glutamate receptors (mGluRs) in NAc play important roles in the reward pathways. However, the precise role of mGluR4 in different steps of the morphine-induced CPP is less well known. In the present study the effect of bilateral intra-accumbal infusion of VU0155041, as a specific mGluR4 agonist on the acquisition and expression of morphine induced CPP in male Wistar rats was investigated. The animals were bilaterally implanted with guide cannulae above the NAc. In the first step of the study, the VU0155041 was administered at doses of 10, 30 and 50 μg/0.5 μL saline per side into the NAc during the 3 days of morphine (5 mg/kg) conditioning (acquisition) phase of morphine-induced CPP. In the second step of the study, the rats bilaterally received VU0155041 at the dose of 50 μg/0.5 μL, 5 min before the post-conditioning test in order to check the effect of VU0155041 on the expression of morphine-induced CPP.ResultsThe results showed that the intra-accumbal injection of VU0155041 inhibits the acquisition of morphine-induced CPP in a dose dependent manner, but had no effect on expression.ConclusionsThe data indicated that intra-NAc administration of VU0155041 dose dependently blocks the establishment of morphine-induced CPP and reduces the rewarding properties of morphine. These effects may be related to changes in glutamate activity in the NAC and/or learning dependent mechanism of glutamate neurotransmission in reward pathway(s).

Cannabidiol enhanced the development of sensitization to the expression of methamphetamine-induced conditioned place preference in male rats

Cannabis and ecstasy are illicit substances, and currently, there are no approved treatments for methamphetamine (METH) use disorder. Some studies have proposed that cannabidiol (CBD) decreases the motivation for METH seeking, but reports indicate that the therapeutic benefits are only for heroin. Here, we studied the interaction between CBD and METH during the sensitization phase on the rewarding effect of METH, using the conditioned place preference (CPP) paradigm to measure possible alterations in sensitivity. Our data showed that i. p. injection of METH created METH-induced CPP at two of the highest applied doses (1 and 2 mg/kg), and injection of METH during the sensitization period caused an establishment of METH-induced CPP at lower doses (0.25 and 0.5 mg/kg). Data also revealed that i. c.v. administration of CBD during the sensitization phase, shifted the establishment of METH-induced CPP toward a lower dose (0.5 mg/kg). Concurrent administration of CBD (10 μg/5 μl, i. c.v.) and METH (0.25 mg/kg, i. p.) during sensitization phase established METH-induced CPP with sub-threshold doses of METH (0.125, 0.25, and 0.5 mg/kg). Our results suggest the involvement of CBD and prior exposure to METH in creating sensitization to METH CPP.

The effect of the mGlu8 receptor agonist, (S)-3,4-DCPG on acquisition and expression of morphine-induced conditioned place preference in male rats

BackgroundThe nucleus accumbens (NAc) plays a principal role in drug reward. It has been reported that metabotropic glutamate receptors (mGlu receptors) play a key role in the rewarding pathway(s). Previous studies have shown the vast allocation of the different types of mGlu receptors, including mGlu8 receptors, in regions that are associated with opioid rewards, such as the NAc. The aim of the present study was to evaluate the role of mGlu8 receptors within the NAc in the acquisition and expression phases of morphine induced conditioned place preference (CPP). Adult male Wistar rats were bilaterally implanted by two cannulas' in the NAc and were evaluated in a CPP paradigm. Selective mGlu8 receptor allosteric agonist (S-3,4-DCPG) was administered at doses of 0.03, 0.3, and 3 μg/0.5 μL saline per side into the NAc on both sides during the 3 days of morphine (5 mg/kg) conditioning (acquisition) phase, or before place preference test, or post-conditioning (expression) phase of morphine-induced CPP.ResultsThe results revealed that intra-accumbal administration of S-3,4-DCPG (0.3 and 3 μg) markedly decreased the acquisition in a dose-dependent manner but had no effect on expression of morphine-induced CPP.ConclusionsThe findings suggest that activation of mGlu8 receptors in the NAc dose-dependently blocks the establishment of morphine-induced CPP and reduces the rewarding properties of morphine which may be related to the glutamate activity into the NAc and in reward pathway(s). These data suggest that mGlu8 receptor may be involved in conditioned morphine reward.

The FDA Mandate to Reassess Benzodiazepines: Alprazolam Induces a Positive Conditioned Place-Preference in Male Rats

On September 23, 2020, in order “To address the serious risks of abuse, addiction, physical dependence, and withdrawal reactions, the U.S. Food and Drug Administration (FDA) is requiring the Boxed Warning be updated for all benzodiazepine medicines”. With this announcement, the FDA proclaimed that much more needs to be known about the initiation, continuation, and discontinuation of these widely-used drugs. Unfortunately, relevant information is lacking, since for many years, there has been a notable sparsity in the funding and conduct of basic and clinical research on these drugs. In order to begin to fill the void, it is valuable to (re)examine animal models. We here describe a model of conditioned place-preference (CPP) for rats and for the first time, to our knowledge, show that the representative benzodiazepine alprazolam induces positive place-preference in male rats.

The citrus flavanone naringenin prevents the development of morphine analgesic tolerance and conditioned place preference in male rats

ABSTRACT Background Opioids are effective analgesics in the management of chronic pain. However, their clinical use is hindered by adverse side effects such as addiction and analgesic tolerance. Naringenin is a common polyphenolic constituent of the citrus fruits and is one of the most commonly consumed flavonoids within our regular diet. However, its influences on opioid tolerance and addiction have not yet been clarified. Objectives To examine the effect of different doses of naringenin on analgesic tolerance, conditioned place preference and neuroinflammation in morphine-exposed rats. Methods Analgesic tolerance was induced by the injection of 10 mg/kg morphine twice daily for 8 days in 70 male Wistar rats. To evaluate the effect of naringenin on the development of morphine tolerance, different doses (10, 25 and 50 mg/kg i.p.) were injected 15 min before morphine. The tail-flick test was used to assess nociceptive threshold. Conditioned place preference test was used to evaluate morphine-seeking behaviors. The lumbar spinal cord was assayed to determine glial fibrillary acidic protein (GFAP) and cyclooxygenase-2 (COX-2) levels by Western blotting. Results The data showed that naringenin could significantly prevent morphine tolerance (p < .001) and conditioned place preference. In addition, chronic morphine-induced GFAP and COX-2 overexpression was significantly reversed by 50 mg/kg naringenin (p < .05 and p < .01, respectively). Conclusion Our results suggest that naringenin may have a potential anti-tolerant/anti-addiction property against chronic morphine misuse and that this preventive effect is associated with its anti-neuroinflammatory effects.

Environmental enrichment reduces cocaine neurotoxicity during cocaine-conditioned place preference in male rats

Environmental enrichment (EE) has a neuroprotective role and prevents the development of cocaine addiction behavior in rats. Studies showing the role of EE in cocaine toxicity are nonexistent. We hypothesized that rats exposed to EE are protected from cocaine-induced changes in the redox profile and DNA damage after undergoing conditioned place preference (CPP). Ten male Wistar rats were placed in EE cages equipped with toys, a ladder and tunnels, and ten were provided clean, standard laboratory housing (non-EE). EE and non-EE rats were randomly allocated to the classical CPP cocaine vs. saline (COC/Saline) group, where cocaine (15 mg/kg; i.p.) was tested alternately with saline. Afterwards, intracellular reactive species and antioxidant enzymes were evaluated and the comet essay was performed in the prefrontal cortex and hippocampus of rats. As expected, EE rats spent less time in the cocaine-paired chamber, and as a new result, less cocaine-induced DNA damage was observed in the two brain structures. Altogether, our results demonstrate that EE decreases neurotoxicity in brain regions linked to cocaine addiction but does not extinguish it completely.