Conditioned Place Preference Procedure Research Articles

Western diet consumption does not impact the rewarding and aversive effects of morphine in male Sprague-Dawley rats

The impacts of high-fat and/or high-sugar diets on opioid-induced effects are well documented; however, little is known about the effect of such diet on the affective responses to opiates. To address this issue, in the present experiment male Sprague-Dawley rats were given ad libitum access to a western-style diet (high in saturated fat and sugar) or a standard laboratory chow diet beginning in adolescence and continuing into adulthood at which point they were trained in a combined conditioned taste avoidance (CTA)/conditioned place preference (CPP) procedure to assess the aversive and rewarding effects of morphine, respectively. On four conditioning cycles, animals were given access to a novel saccharin solution, injected with morphine (1 mg/kg or 5 mg/kg), and then placed on one side of a place preference chamber. Animals were then tested for place preference and saccharin preference. All subjects injected with morphine displayed significant avoidance of the morphine-associated solution (CTA) and preferred the side associated with the drug (CPP). Furthermore, there were no differences between the two diet groups, indicating that chronic exposure to the western diet had no impact on the affective properties of morphine (despite increasing caloric intake, body weight, body fat and lean body mass). Given previously reported increases in drug self-administration in animals with a history of western-diet consumption, this study suggests that western-diet exposure may increase drug intake via mechanisms other than changes in the rewarding or aversive effects of the drug.

Strawberry Additive Increases Nicotine Vapor Sampling and Systemic Exposure But Does Not Enhance Pavlovian-Based Nicotine Reward in Mice.

Nicotine is an addictive drug whose popularity has recently increased, particularly among adolescents, because of the availability of electronic nicotine devices (i.e., "vaping") and nicotine e-liquids containing additives with rich chemosensory properties. Some efforts to understand the role of these additives in nicotine reward suggest that they increase nicotine reward and reinforcement, but the sensory contributions of additives, especially in their vapor forms, are largely untested. Here, to better understand how a fruit-flavored (i.e., strawberry) additive influences nicotine reward and aversion, we used a conditioned place preference (CPP) procedure in which nicotine and a strawberry additive were delivered as a vapor to male and female adolescent mice. We found that nicotine vapor alone can lead to a dose-dependent CPP when using a biased design. The strawberry additive did not produce CPP on its own, and we did not observe an effect of the strawberry additive on nicotine vapor-induced reward. Nevertheless, mice exposed to nicotine plus strawberry additive vapor had higher plasma cotinine concentrations, which did not appear to reflect altered nicotine metabolism. Instead, by directly measuring vapor sampling through respiration monitoring, we uncovered an increase in the amount of sniffing toward strawberry-containing nicotine vapor compared with nicotine vapor alone. Together these data indicate that chemosensory-rich e-liquid additives may enhance the perceived sensory profile of nicotine vapors rather than the reward value per se, which leads to overall increased nicotine exposure.

Neural correlates of cocaine-induced conditioned place preference in the posterior cerebellar cortex.

Addictive drugs are potent neuropharmacological agents capable of inducing long-lasting changes in learning and memory neurocircuitry. With repeated use, contexts and cues associated with consumption can acquire motivational and reinforcing properties of abused drugs, triggering drug craving and relapse. Neuroplasticity underlying drug-induced memories takes place in prefrontal-limbic-striatal networks. Recent evidence suggests that the cerebellum is also involved in the circuitry responsible for drug-induced conditioning. In rodents, preference for cocaine-associated olfactory cues has been shown to correlate with increased activity at the apical part of the granular cell layer in the posterior vermis (lobules VIII and IX). It is important to determine if the cerebellum's role in drug conditioning is a general phenomenon or is limited to a particular sensory modality. The present study evaluated the role of the posterior cerebellum (lobules VIII and IX), together with the medial prefrontal cortex (mPFC), ventral tegmental area (VTA), and nucleus accumbens (NAc) using a cocaine-induced conditioned place preference procedure with tactile cues. Cocaine CPP was tested using ascending (3, 6, 12, and 24 mg/kg) doses of cocaine in mice. Compared to control groups (Unpaired and Saline animals), Paired mice were able to show a preference for the cues associated with cocaine. Increased activation (cFos expression) of the posterior cerebellum was found in cocaine CPP groups and showed a positive correlation with CPP levels. Such increases in cFos activity in the posterior cerebellum significantly correlated with cFos expression in the mPFC. Our data suggest that the dorsal region of the cerebellum could be an important part of the network that mediates cocaine-conditioned behavior.

Individual differences in the effects of midazolam on anxiety-like behavior, learning, reward, and choice behavior in male mice.

The aim of the present study was to investigate the behavioral effects of the benzodiazepine midazolam in male mice, in models of anxiolysis, learning, and abuse-related effects. In a first set of experiments, male Swiss mice were submitted to the training session of a discriminative avoidance (DA) task on the elevated plus maze to evaluate anxiety-like behavior and learning after vehicle or midazolam (1, 2 or 5 mg/kg, i.g.) administration. The same animals were submitted to a conditioned place preference (CPP) protocol with midazolam (1, 2 or 5 mg/kg, i.g.). In a second experiment, outbred (Swiss) and inbred (C57BL/6) male mice were submitted to a two-bottle choice (TBC) oral midazolam drinking procedure. Animals were exposed to one sucrose bottle and one midazolam (0.008, 0.016 or 0.032 mg/ml) plus sucrose bottle. Midazolam (1 and 2 mg/kg) induced anxiolytic-like effects, and all doses of midazolam prevented animals from learning to avoid the aversive closed arm during the DA training session. Assessment of midazolam reward via the CPP procedure and choice via the TBC procedure showed notable variability. A 2-step cluster analysis for the CPP data showed that midazolam data were well-fitted to 2 separate clusters (preference vs. aversion), albeit with the majority of mice showing preference (75%). Correlational and regression analyses showed no relationship between midazolam reward and anxiolytic-like effects (time spent in the open arms in the DA test) or learning/memory. Two-step cluster analysis of the TBC data also demonstrated that, regardless of strain, mice overall fell into two clusters identified as midazolam-preferring or midazolam-avoiding groups. Both midazolam preference and avoidance were concentration-dependent in a subset of mice. Our findings show that midazolam preference is a multifactorial behavior, and is not dependent solely on the emergence of therapeutic (anxiolytic-like) effects, learning impairments, or on genetic factors (inbred vs. outbred animals).

PT150 blocks the rewarding properties of ethanol and attenuates ethanol-induced reduction of egg laying in Coturnix quail.

Alcohol use disorder (AUD) has been shown to be associated with a dysregulated stress system. Reducing the stress hormone corticosterone (CORT), that binds to glucocorticoid receptors, may attenuate the rewarding properties of drugs of abuse. However, the effect of blocking corticosterone receptors on ethanol reward has yet to be investigated. The current study investigated whether the stress hormone receptor antagonist, PT150, would block the rewarding properties of ethanol via the glucocorticoid receptor system and attenuate other ethanol-induced effects. A conditioned place preference (CPP) procedure was used to examine the rewarding properties of ethanol in an avian preclinical model. Ethanol was paired with the least preferred chamber. On alternate days, water was paired with the preferred chamber. After eight pairings, a place preference test was given that allowed subjects to have access to both chambers. Half of the subjects received PT150 prior to ethanol administration. The other half received vehicle. Time spent in each chamber during the preference tests, locomotor activity during the pairings, and egg production in female birds was recorded. Ethanol treatment resulted in a CPP and pretreatment of PT150 blocked the acquisition of the ethanol-induced place preference. Neither ethanol nor PT150 altered locomotor activity. Pretreatment of PT150 also increased egg production in female quail treated with ethanol. These findings suggest repeated ethanol pairings with visual cues can produce a CPP. Furthermore, pretreatment of PT150 may be a potential pharmacotherapy for blocking the rewarding properties of ethanol and may enhance egg production in female quail treated with ethanol.

Distinct roles for orexin-1 and orexin-2 receptors in the dentate gyrus of the hippocampus in the methamphetamine-seeking behavior in the rats

Because of the relapsing properties of psychostimulants such as methamphetamine (Meth), there is no established pharmacotherapy for Meth addiction. The orexinergic system is a promising target for treating psychostimulant use disorders and relapse. However, to the best of our knowledge, no investigation regarding the role of orexin receptors in the dentate gyrus (DG) region of the hippocampus has been conducted in the extinction and reinstatement of Meth-seeking behavior. Two stainless-steel guide cannulae were bilaterally implanted into the DG of the rats' brains. The unbiased conditioned place preference (CPP) procedure was conducted to induce Meth conditioning. Following the five days Meth injections (1 mg/kg; sc), animals received intra-DG microinjection of SB334867 or TCS OX2 29, as orexin 1 (OX1) or orexin 2 (OX2) receptor antagonists, respectively (without Meth administration) during extinction phase to elucidate the role of orexin receptors in the latency of the extinction period in the Meth-conditioned rats. To evaluate the role of orexin receptors in the DG region in the reinstatement of Meth-seeking behavior, the extinguished rats received SB334867 or TCS OX2 29 before injecting a priming dose of Meth (0.25 mg/kg; sc). The results indicated two distinct roles for the OX1 and OX2 receptors in the DG region. TCS OX2 29 attenuated the extinction latency, and SB334867 considerably reduced the reinstatement of Meth-seeking behavior in this region. Therefore, the DG region's orexinergic system might be a potential therapeutic target for psychostimulant use disorders.

Operant social seeking to a novel peer after social isolation is associated with activation of nucleus accumbens shell in rats.

Deprivation of social interaction promotes social reward seeking in rodents, assessed primarily by the conditioned place preference procedure. Here, we used an operant social procedure in rats and examined the effect of the housing condition (pair-housing vs. single-housing) during or after social self-administration on social reward seeking. We first trained paired-housed or single-housed rats to gain access to an age- and sex-matched novel peer. On post-training day 1 (PTD1), we tested both groups for social seeking without the presence of the novel peer. Next, we divided each group into pair-housing or single-housing conditions and tested all four groups (pair-pair, pair-single, single-pair, and single-single) for social seeking on post-training day 12 (PTD12). Finally, we analyzed Fos expression in the striatum associated with social seeking on PTD12. Single-housed rats earned more social rewards during social self-administration than pair-housed rats. Social isolation during social self-administration also promoted social seeking on PTD1 and PTD12, regardless of their housing conditions after social self-administration training. Additionally, in pair-housed rats, social isolation during the post-training period led to a time-dependent increase of social seeking on PTD12 compared with PTD1. Finally, the Fos analyses revealed an increase of Fos expression in NAc shell of single-single rats after social seeking test on PTD12 compared with pair-pair rats. Our data suggest that social isolation promotes operant social self-administration and social seeking. In addition, neuronal activation of NAc shell is associated with social seeking after social isolation.

Intermittent voluntary wheel running promotes resilience to the negative consequences of repeated social defeat in mice

A novel approach to reduce the incidence of substance use disorders is to promote resilience to stress using environmental resources such as physical exercise. In the present study we test the hypothesis that Voluntary Wheel Running (VWR) during adolescence blocks the negative consequences of stress induced by intermittent repeated social defeat (IRSD). Four groups of adolescent male C57BL/6 mice were employed in the experiment; two groups were exposed to VWR (1 h, 3 days/week) from postnatal day (PND) 21 until the first social defeat (PND 47), while the remaining two groups did not have access to activity wheels (controls). On PND 47, 50, 53 and 56 mice, who had performed VWR, were exposed to an episode of social defeat by a resident aggressive mouse (VWR+IRSD group) or allowed to explore an empty cage (VWR+EXPL group). The same procedure was performed with control mice that had not undergone VWR (CONTROL+IRSD and CONTROL+EXPL groups). On PND 57, all the mice performed the Elevated Plus Maze (EPM), Hole-Board, Social Interaction, Tail Suspension and Splash tests. After an interval of 3 weeks, all mice underwent a conditioned place preference (CPP) procedure with 1 mg/kg of cocaine. Exposure to VWR prevented the negative consequences of social stress in the EPM, splash test and CPP, since the VWR+IRSD group did not display anxiety- or depression-like effects or the potentiation of cocaine reward observed in the Control+IRSD group. Our results support the idea that physical exercise promotes resilience to stress and represents an excellent target in drug abuse prevention.

SCH 23390 inhibits the acquisition of nitrous oxide-induced conditioned place preference and the changes in ERK phosphorylation expression in nucleus accumbens of mice

Nitrous oxide (N2O) has a long history of abuse, but its abuse mechanism has not been clear yet. This research aimed at the possibility of mesolimbic dopaminergic system (MLDS) involved in the rewarding effect of N2O. In this work, the rewarding behavior of N2O in mice was evaluated using a typical gas-administered conditioned place preference (CPP) procedure. SCH 23390, a Dopamine D1 receptor (D1R) antagonist, and Haloperidol, a Dopamine D2 receptor (D2R) antagonist were administered during CPP to evaluate the role of dopamine receptors in the N2O-induced CPP. The accompanying changes in phosphorylation of extracellular signal-regulated kinase (ERK) in MLDS related brain regions, including the ventral tegmental area (VTA), caudate putamen (CPu), prefrontal cortex (PFC), and nucleus accumbens (NAc) were measured to assess the neural plasticity changes in the CPP mice by Western blot analysis. Results revealed that 60% N2O induced CPP in the gas-administered mice and promoted the ERK phosphorylation (p-ERK) in the NAc and CPu during the test session of the CPP test. Pretreatment of SCH 23390 (0.5 mg/kg) inhibited the acquisition of N2O-induced CPP and the enhanced p-ERK in NAc. It suggested that Dopamine D1 receptor may play an important role in the acquisition of N2O-induced CPP and the accompanied ERK activation in the NAc, which provide insight into the molecular mechanism in the rewarding properties of nitrous oxide.

Neuroinflammatory Response in Reward-Associated Psychostimulants and Opioids: A Review.

Substance abuse is one of the significant problems in social and public health worldwide. Vast numbers of evidence illustrate that motivational and reinforcing impacts of addictive drugs are primarily attributed to their ability to change dopamine signaling in the reward circuit. However, the roles of classic neurotransmitters, especially dopamine and neuromodulators, monoamines, and neuropeptides, in reinforcing characteristics of abused drugs have been extensively investigated. It has recently been revealed that central immune signaling includes cascades of chemokines and proinflammatory cytokines released by neurons and glia via downstream intracellular signaling pathways that play a crucial role in mediating rewarding behavioral effects of drugs. More interestingly, inflammatory responses in the central nervous system modulate the mesolimbic dopamine signaling and glutamate-dependent currents induced by addictive drugs. This review summarized researches in the alterations of inflammatory responses accompanied by rewarding and reinforcing properties of addictive drugs, including cocaine, methamphetamine, and opioids that were evaluated by conditioned place preference and self-administration procedures as highly common behavioral tests to investigate the motivational and reinforcing impacts of addictive drugs. The neuroinflammatory responses affect the rewarding properties of psychostimulants and opioids.

Ca2+-permeable AMPA receptors set the threshold for retrieval of drug memories.

Frequent relapse prevents the successful treatment of substance use disorders and is triggered in part by retrieval of drug-associated memories. Drug-conditioned behaviours in rodents are reinstated upon drug memory retrieval following re-exposure to cues previously associated with the drug, or the drug itself. Therapies based on mechanistic insights from rodent studies have focused on amnesic procedures of cue-drug associations but with so far limited success. Conversely, more recent studies propose that inhibiting drug memory retrieval offers improved anti-relapse efficacy. However, mechanisms of memory retrieval are poorly understood. Here, we used a conditioned place preference (CPP) procedure in mice to investigate the cellular and molecular underpinnings of drug-induced memory retrieval. After extinction training of CPP, Ca2+-permeable AMPA receptors (CP-AMPARs) accumulated at drug-generated silent synapses of nucleus accumbens (NAc) medium spiny neurons. The NAc CP-AMPARs regulated the retrieval mechanism of drug memories after extinction. Specifically, we used different priming doses of cocaine, fentanyl, or a cue associated with drug exposure to reinstate CPP, providing different memory retrieval conditions. Although both high and low doses of these two drugs induced CPP reinstatement, compromising CP-AMPAR accumulation impaired CPP reinstatement, induced by low doses of each drug or the cue. This threshold effect was mediated by NAc CP-AMPARs as region specific knock-down of PSD-95 prevented low-dose cocaine-induced retrieval selectively. These results demonstrate the NAc as a brain region and CP-AMPARs as key synaptic substrates that govern the threshold for drug-induced retrieval and behavioural expression of drug memories.

Brief Maternal Separation Inoculates Against the Effects of Social Stress on Depression-Like Behavior and Cocaine Reward in Mice

Exposure to intermittent repeated social defeat (IRSD) increases the vulnerability of mice to the rewarding effects of cocaine in the conditioned place preference (CPP) paradigm. According to the “inoculation of stress” hypothesis, a brief period of maternal separation (MS) can provide protection against the negative effects of IRSD. The aim of the present study was to assess whether exposure to a brief episode of MS prevents the subsequent short-term effects of IRSD on depression- and anxiety-like behaviors and to explore its long-term effects on cocaine CPP in mice. Four groups of male C57BL/6 mice were employed; two groups were separated from their mother [6 h on postnatal day (PND) 9], while the other two groups were not (controls). On PND 47, 50, 53 and 56, mice that had experienced MS were exposed to social defeat in the cage of an aggressive resident mouse (MS + IRSD group) or were allowed to explore an empty cage (MS + EXPL group). The same procedure was performed with control mice that had not experienced MS (CONTROL + IRSD and CONTROL + EXPL groups). On PND57-58, all the mice performed the elevated plus maze and the hole-board, social interaction and splash tests. Three weeks after the last episode of defeat, all the mice underwent the CPP procedure with cocaine (1 mg/kg). Irrespective of whether or not MS had taken place, a reduction in open arms measures, dips, and social interaction was observed in mice that experienced IRSD. A higher latency of grooming and acquisition of cocaine-induced CPP were observed only in mice exposed to IRSD alone (CONTROL + IRSD). These results suggest that exposure to a brief episode of stress early in life increases the subsequent resilience of animals to the effects of social stress on vulnerability to cocaine.

Molecular chaperone heat shock protein 70 inhibitors suppress conditioned place preference induced by morphine exposure in male rats.

Previous studies have indicated a role for molecular chaperone heat shock protein 70 (Hsp70) in the development of behavioural sensitization to morphine in rodents, suggesting that Hsp70 expression following morphine exposure is involved in molecular changes that may underlie addiction vulnerability. The current study was carried out to investigate the role of Hsp70 in the positive reinforcing properties of morphine using conditioned place preference (CPP) in male rats. An unbiased CPP procedure of three phases (pre-conditioning: d1-d3; conditioning: d4-d6; and testing: d7) was used. During the conditioning phase, morphine injections (5 mg/kg, subcutaneously) were administered to induce significant place preference. To explore the effect of Hsp70 on the development and expression of morphine CPP, Hsp70 inhibitors (PES, KNK437 and methylene blue) were administered into the lateral ventricle prior to either morphine conditioning sessions or a morphine challenge on the test day. Furthermore, Hsp70 expression within the mesocorticolimbic system was measured after the treatment with KNK437, a transcriptional inhibitor. We found that PES and KNK437, respectively, injected intracerebroventricularly dose-dependently attenuated both the development and expression of morphine CPP. Methylene blue treatment demonstrated an attenuation of the development, but had no effect on the expression of morphine CPP. Following KNK437 treatment, Hsp70 expression was significantly inhibited in the shell of nucleus accumbens (NAc) during both the development and expression of morphine CPP. The findings suggest that Hsp70 in the NAc shell plays an important role in the reinforcing effects of morphine and may be involved in the development of morphine dependence.

Alteration of Ethanol Reward by Prior Mephedrone Exposure: The Role of Age and Matrix Metalloproteinase-9 (MMP-9).

Mephedrone, a synthetic cathinone, is widely abused by adolescents and young adults. The aim of this study was to determine: (i) whether prior mephedrone exposure would alter ethanol reward and (ii) whether age and matrix metalloproteinase-9 (MMP-9) are important in this regard. In our research, male Wistar rats at postnatal day 30 (PND30) received mephedrone at the dose of 10 mg/kg, i.p., 3 times a day for 7 days. To clarify the role of MMP-9 in the mephedrone effects, one mephedrone-treated group received minocycline, as an MMP-9 antagonist. Animals were then assigned to conditioned place preference (CPP) procedure at PND38 (adolescent) or at PND69 (adult). After the CPP test (PND48/79), expression of dopamine D1 receptors (D1R), Cav1.2 (a subtype of L-type calcium channels), and MMP-9 was quantified in the rat ventral striatum (vSTR). The influence of mephedrone administration on the N-methyl-D-aspartate glutamate receptors (NMDAR) subunits (GluN1, GluN2A, and GluN2B) was then assessed in the vSTR of adult rats (only). These results indicate that, in contrast with adolescent rats, adult rats with prior mephedrone administration appear to be more sensitive to the ethanol effect in the CPP test under the drug-free state. The mephedrone effect in adult rats was associated with upregulation of D1R, NMDAR/GluN2B, MMP-9, and Cav1.2 signaling. MMP-9 appears to contribute to these changes in proteins expression because minocycline pretreatment blocked mephedrone-evoked sensitivity to ethanol reward. Thus, our results suggest that prior mephedrone exposure differentially alters ethanol reward in adolescent and adult rats.

Cannabidiol impairs the rewarding effects of methamphetamine: Involvement of dopaminergic receptors in the nucleus accumbens

Cannabidiol, as component of cannabis, can potentially hinder the rewarding impact of drug abuse; however, its mechanism is ambiguous. Moreover, the nucleus accumbens (NAc), as a key area in the reward circuit, extensively receives dopaminergic projections from the ventral tegmentum area. To elucidate the role of accumbal D1 and D2 dopamine receptor families in Cannabidiol's inhibitory impact on the acquisition and expression phases of methamphetamine (MET), the conditioned place preference (CPP) procedure as a common method to assay reward characteristics of drugs was carried out. Six groups of rats were treated by various doses of SCH23390 or Sulpiride (0.25, 1, and 4 μg/0.5 μL) in the NAc as D1 or D2 dopamine receptor family antagonists, respectively, prior to infusion of Cannabidiol (10 μg/5 μL) in the lateral ventricle (LV) over conditioning phase in the acquisition experiments. In the second step of the study, animals received SCH23390 or Sulpiride in the NAc before Cannabidiol (50 μg/5 μL) infusion into the LV in the expression phase of MET to illuminate the influence of SCH23390 or Sulpiride on the inhibitory impact of Cannabidiol on the expression of MET-induced CPP. Intra-NAc administration of either SCH23390 or Sulpiride impaired Cannabidiol's suppressive impact on the expression phase, while just Sulpiride could suppress the Cannabidiol's impact on the acquisition phase of the MET-induced CPP. Also, the inhibitory impact of Sulpiride was stranger in both phases of MET reward. It seems that Cannabidiol prevents the expression and acquisition phases of MET-induced CPP partly through the dopaminergic system in the NAc.

The Abnormalities in Event-Related Oscillations in Patients With Dementia During Recognition of Emotional Facial Expressions

Attention deficit/hyperactivity disorder (ADHD) is a risk factor for tobacco use and dependence. This study examines the responsiveness to nicotine of an adolescent model of ADHD, the spontaneously hypertensive rat (SHR). The conditioned place preference (CPP) procedure was used to assess nicotine-induced locomotion and conditioned reward in SHR and the Wistar Kyoto (WKY) control strain over a range of nicotine doses (0.0, 0.1, 0.3 and 0.6 mg/kg). Prior to conditioning, SHRs were more active and less biased toward one side of the CPP chamber than WKY rats. Following conditioning, SHRs developed CPP to the highest dose of nicotine (0.6 mg/kg), whereas WKYs did not develop CPP to any nicotine dose tested. During conditioning, SHRs displayed greater locomotor activity in the nicotine-paired compartment than in the saline-paired compartment across conditioning trials. SHRs that received nicotine (0.1, 0.3, 0.6 mg/kg) in the nicotine-paired compartment showed an increase in locomotor activity between conditioning trials. Nicotine did not significantly affect WKY locomotor activity. These findings suggest that the SHR strain is a suitable model for studying ADHD-related nicotine use and dependence, but highlights potential limitations of the WKY control strain and the CPP procedure for modeling ADHD-related nicotine reward.

Decreased kynurenine pathway potentiate resilience to social defeat effect on cocaine reward

The kynurenine (KYN) pathway of tryptophan (TRP) degradation is activated by stress and inflammatory factors. It is now well established that social stress induces the activation of the immune system, with central inflammation and KYN metabolism being two of the main factors linking stress with depression.The aim of the present study was to evaluate the long-lasting changes in the KYN pathway induced by social defeat (SD) associated with the resilience or susceptibility to an increase in the conditioned rewarding effects of cocaine. Mice were exposed to repeated SD and 3 weeks later, a conditioned place preference (CPP) induced by a subthreshold dose of cocaine (1.5 mg/kg) was developed. KYN levels in plasma, cerebellum, hippocampus, striatum and limbic forebrain were studied at the end of the CPP procedure. Changes in the KYN pathway after exposure to pharmacological (oxytocin and indomethacin) and environmental interventions (environmental enrichment) were also evaluated.Our results showed that defeated susceptible (SD-S) mice had higher conditioning scores than resilient mice (SD-R). In addition, although KYN concentration was elevated in all defeated mice, SD-R mice showed smaller increases in KYN concentration in the cerebellum than SD-S mice. Oxytocin or Indomethacin treatment before SD normalized cocaine-induced CPP, although the increase in the KYN pathway was maintained. However, environmental enrichment before SD normalized cocaine-induced CPP and prevented the increase in the KYN pathway.The present study highlights the role of the KYN pathway and anti-inflammatory drugs acting on TRP metabolism as pharmacological targets to potentiate resilience to social stress effects.

Vulnerability factors for mephedrone-induced conditioned place preference in rats\u2014the impact of sex differences, social-conditioning and stress

RationaleMephedrone is a frequently overused drug of abuse that belongs to the group of novel psychoactive substances. Although its mechanism of action, as well as toxic and psychoactive effects, has been widely studied, the role of different factors that could contribute to the increased vulnerability to mephedrone abuse is still poorly understood.ObjectivesThe aim of the presented study was to assess the impact of several factors (sex differences, social-conditioning, and chronic mild unpredictable stress — CMUS) on the liability to mephedrone-induced reward in Wistar rats.MethodsThe rewarding effects of mephedrone in male and female rats were assessed using the conditioned place preference (CPP) procedure. Furthermore, the impact of social factor and stress was evaluated in male rats using social-CPP and CMUS-dependent CPP, respectively.ResultsMephedrone induced classic-CPP in female (10 mg/kg), as well as in male (10 and 20 mg/kg) rats. However, the impact of mephedrone treatment during social-CPP was highly dose-dependent as the rewarding effects of low dose of mephedrone (5 mg/kg; non-active in classic-CPP) were potentiated when administered during social-conditioning. Interestingly, social-conditioning with a higher dose of 20 mg/kg (that induced classic-CPP) was able to reverse these effects. Finally, CMUS potentiated rewarding effects of a low dose of mephedrone (5 mg/kg) and increased the level of corticosterone in rats’ prefrontal cortex and hippocampus.ConclusionsAltogether, the presented results give new insight into possible factors underlying the vulnerability to mephedrone abuse and can serve as a basis for further studies assessing mechanisms underlying observed effects.

Conditioned place preference following concurrent treatment with 3, 4-methylenedioxypyrovalerone (MDPV) and methamphetamine in male and female Sprague-Dawley rats

Synthetic cathinones gained initial popularity on the illicit drug market as a result of attempts to evade legal restrictions on other commonly abused psychostimulants. A body of published research has determined that the psychopharmacology of the synthetic cathinone 3, 4-methylenedioxypyrovalerone (MDPV) is comparable to cocaine and methamphetamine (METH). Few preclinical studies have systematically investigated concurrent use of synthetic cathinones with other psychostimulant drugs. The present study utilized conditioned place preference (CPP), a rodent model of conditioned drug reward, to evaluate the effects of concurrent treatment with MDPV and METH. Male (N = 72) and female (N = 105) Sprague-Dawley rats underwent a two-compartment biased CPP procedure, with one trial per day for eight consecutive days. Subjects were randomly assigned to the following treatment groups: saline, METH (1 mg/kg), MDPV (1, 3.2, 5.6 mg/kg) or a mixture consisting of METH (1 mg/kg) and MDPV (1, 3.2, 5.6 mg/kg). All treatments increased locomotor activity during drug conditioning trials, and most treatments produced higher activity increases in females compared to males. Although the level of CPP established by MDPV and MDPV + METH mixtures varied between males and females, sex differences were not statistically significant. Although none of the MDPV+METH mixtures produced stronger CPP than either substance alone, some mixtures of MDPV and METH produced higher increases in locomotor activity compared to either drug alone. Further studies with higher doses may be warranted to determine if concurrent use of MDPV and METH pose an enhanced risk for abuse.

Sensitivity to Morphine Reward Associates With Gut Dysbiosis in Rats With Morphine-Induced Conditioned Place Preference.

Gut microbiota has been found to establish a bidirectional relationship with the central nervous system. Variations of the gut microbiota has been implicated in various mental disorders, including opioid use disorders. Morphine exposure has been repeatedly found to disrupt the gut microbiota, but association between the gut microbiota and the sensitivity to morphine reward remains unknown. In this study the conditioned place preference (CPP) paradigm was used for morphine-treated rats and saline-treated rats. After the CPP procedure, the morphine-treated rats were divided equally into the low and high CPP (L- and H-CPP) groups according to the CPP scores. We adopted 16S rRNA sequencing for the fecal bacterial communities at baseline and post-conditioning. By comparing the morphine-treated group with saline-treated group, we found alterations of microbial composition in the morphine-treated group, but no significant differences in alpha diversity. The L-CPP group and H-CPP group differed in microbial composition both before and after morphine treatment. The relative abundance of certain taxa was correlated to the CPP scores, such as Alloprevotella and Romboutsia. This study provides direct evidence that morphine exposure alters the composition of the gut microbiota in rats and that microbial alterations are correlated to the sensitivity to morphine reward. These findings may help develop novel therapeutic and preventive strategies for opioid use disorder.