Cannabidiol attenuated the maintenance and reinstatement of extinguished methylphenidate-induced conditioned place preference in rats

A cerebral bridge from olfactory cognition to spatial navigation

The present study examined the influence of the cholinesterase inhibitors donepezil (a selective inhibitor of acetylcholinesterase) and rivastigmine (also an inhibitor of butyrylcholinesterase) on the acquisition and reinstatement of ethanol-induced conditioned place preference (CPP) in rats. Before the CPP procedure, animals received a single injection of ethanol (0.5 g/kg, 10% w/v, intraperitoneally [i.p.]) for 15 days. The ethanol-induced CPP (biased method) was developed by four injections of ethanol (0.5 g/kg, 10% w/v, i.p.) every second day. Control rats received saline instead of ethanol. Donepezil (0.5, 1 or 3 mg/kg, i.p.) or rivastigmine (0.03, 0.5 or 1 mg/kg, i.p.) were administered before ethanol during conditioning or before the reinstatement of ethanol-induced CPP. The cholinesterase inhibitors were equally effective in increasing (dose dependently) the acquisition of ethanol-induced CPP. Furthermore, priming injections of both inhibitors reinstated (cross-reinstatement) the ethanol-induced CPP with similar efficacy. These effects of both cholinesterase inhibitors were reversed by mecamylamine (3 mg/kg, i.p.), a nicotinic acetylcholine receptor antagonist, but not by scopolamine (0.5 mg/kg, i.p.), a muscarinic acetylcholine receptor antagonist. Thus, our results show that the cholinergic system is involved in the reinforcing properties of ethanol, and nicotinic acetylcholine receptors play an important role in the relapse to ethanol-seeking behaviour.

Involvement of orexin-2 receptor in the ventral tegmental area in stress- and drug priming-induced reinstatement of conditioned place preference in rats

Aripiprazole blocks reinstatement but not expression of morphine conditioned place preference in rats

Maternal separation (MS) is an animal model widely used to evaluate the influence of early-life stress exposure on ethanol consumption and dependence. The goal of this study was to evaluate the effects of brief and prolonged MS on the pattern of consumption and ethanol conditioned place preference (CPP) in male and female rats during adolescence and adulthood. Wistar rat pups were separated daily from their dams for 15 or 180 minutes during the 2 to 10 postnatal days (PND). In adolescence, half of the litter from each group was evaluated in the ethanol consumption test using the three-bottle test choice paradigm. In addition, using biased procedure, ethanol-conditioned place preference was also evaluated. In adulthood, the other half of the litter was evaluated on the same tests. Our results showed that there are differences in consumption pattern and in alcohol reinforcement between males and females, adolescents and adults. While prolonged MS had no effect on total ethanol consumption in adolescents of both sexes, it induced CPP in these animals. In turn, in adults, previous exposure to prolonged MS increased ethanol consumption without altering ethanol-CPP.Lay summaryGiving the importance of the mother-children (dam-pups when talking about rodents) relationship to proper brain development, the separation of pups from their dam is broadly used as an animal model to study the impact of early-life stress exposure. Here, we used a protocol of brief or prolonged maternal separation to study the impact of early-life stress exposure in the alcohol consumption and conditioned place preference in rats, and how age and sex influence it. We showed that, overall, the prolonged maternal separation increased alcohol consumption in both males and females, but only when animals were tested during the adulthood. In the other hand, prolonged maternal separation increased ethanol conditioned place preference in adolescent rats, both male and female.

Effects of processed Aconiti tuber on the extinction and reinstatement of morphine-induced conditioned place preference in rats

Three experiments were performed to study the effects of immune challenge on the rewarding properties of opiates. Intraperitoneal injection of polyinosinic-polycytidylic acid (Poly I:C, 1 mg/kg) was used to trigger an immune challenge. Conditioned place preference (CPP) in rats trained with alternating subcutaneous injections of morphine (5 mg/kg) and saline was used to assess the rewarding effect of morphine. Poly I:C administered before CPP training had no effects on CPP acquisition. Poly I:C administered during CPP training enhanced CPP acquisition. Poly I:C administered after morphine-induced CPP acquisition retarded CPP extinction. These results show that the immune challenge by Poly I:C augmented morphine CPP in rats depending on the onset time of the challenge. The findings suggest that immune challenge may enhance the rewarding properties of opiates.

Different effects of GABAergic receptors located in the ventral tegmental area on the expression of morphine-induced conditioned place preference in rat

Objective To evaluate the role of μ-δ heterodimer in down-regulation of the expression of excitatory amino acid transporter 3 (EAAT3) in hippocampi caused by reinstatement of morphine-induced conditioned place preference (CPP) in rats. Methods Thirty-two healthy clean-grade male Sprague-Dawley rats, weighing 200-240 g, were assigned into 4 groups (n=8 each) using a random number table method: control group (group C), extinction group (group E), reinstatement group (group R) and reinstatement plus interference plasmid group (group RI). The model of morphine-induced CPP was established, and extinction of CPP was gradually induced by stopping administration.A small dose of morphine 5 mg/kg was intraperitoneally injected again to induce CPP reinstatement, and dwell time around the medicine box was recorded.μ-δ heterodimer interference plasmid 5 μl was injected into the lateral cerebral ventricle after successful establishment of CPP model in group RI.The content of glutamate (Glu) in hippocampi was measured using high-performance liquid chromatography.The EAAT3 expression in hippocampal CA1 and CA3 regions was detected using Western blot. Results Compared with group C, no significant change was found in the dwell time around the medicine box or content of Glu in hippocampi (P>0.05), and the expression of EAAT3 in hippocampal CA1 and CA3 regions was significantly up-regulated in group E, and the dwell time around the medicine box was significantly prolonged, the content of Glu in hippocampi was increased (P 0.05). Compared with group E, the dwell time around the medicine box was significantly prolonged, the content of Glu in hippocampi was increased, and the expression of EAAT3 in hippocampal CA1 and CA3 regions was down-regulated in group R (P<0.05). Compared with group R, the dwell time around the medicine box was significantly shortened, the content of Glu in hippocampi was decreased, and the expression of EAAT3 in hippocampal CA1 and CA3 regions was up-regulated in group RI (P<0.05). Conclusion μ-δ heterodimer is involved in down-regulation of EAAT3 expression in the hippocampus caused by reinstatement of morphine-induced CPP in rats. Key words: Receptors, opioid; Morphine Dependence; Excitatory amino acid transporter 3; Hippocampus; Heterodimer

The purpose of the investigation was to clear the significance of dopamine, GABA, opioids and sodium influx ionic currents of the nucleus accumbens neurons for the reinforcing effects of a number of psychotropic drugs (opiates, opioids, psychostimulants) on conditioned place preference (CPP) in rats. The microcannules were implanted into the nucleus accumbens (the extended amygdala system) of the Wistar male rats to inject the drugs studied (1 μg in 1 μl in volume for each injection). The rats were learned CPP of a one of narcogenics during 8 days. Some drugs, lidocain, a blocker of sodium influx ionic currents, antagonists of GABAA receptors bicuculline, D1 dopamine receptors SCH23390, D2 dopamine receptors sulpiride and opioid receptors naloxone, administered intrastructurally into the nucleus accumbens, were used for pharmacological analysis. The majority of the blockers studied decreased or abolished the reinforcing effects of amphetamine. Activation of reinforcement by means of fentanyl was reversed with bicuculline, lidocain and naloxone but did not change with dopamine antagonists (SCH23390 and sulpiride). None of the blockers studied effect on CPP of sodium ethaminal excluding bicuculline which reduced it. At last, the leu-enkephaline effects were reversed with naloxone and SCH23390, but strengthened with bicuculline. Sulpiride and lidocain did not effect on CPP of leu-enkephaline. Therefore, the different mechanisms (GABA-, dopamine- and opioidergic) controlling the positive conditioned reinforcement are collected in the nucleus accumbens.

Our previous study demonstrated that morphine dose- and time-dependently elevated dopamine (DA) concentrations in the nucleus accumbens (NAc) during the expression of morphine-induced conditioned place preference (CPP) in rats. However, still unknown are how DA concentrations dynamically change during the morphine-induced CPP test and whether tyrosine hydroxylase (TH) activity in the ventral tegmental area (VTA) plays a vital role in this process. In the present study, we measured dynamic changes in TH and phosphorylated TH serine 40 (pTH Ser(40)) and pTH Ser(31) proteins in the VTA, and DA concentrations in the NAc at 5 min intervals during a 30 min morphine-induced CPP test. Rats that underwent morphine-induced CPP training significantly preferred the morphine-paired chamber during the CPP expression test, an effect that lasted at least 30 min in the drug-free state. DA concentrations in the NAc markedly increased at 15 min when the rats were returned to the CPP boxes to assess the expression of preference for the previously drug-paired chamber. DA concentrations then declined 2 h after the CPP test. TH and pTH Ser(40) levels, but not pTH Ser(31) levels, in the VTA were enhanced during the CPP test. These results indicated that TH and the phosphorylation of TH Ser(40) in the VTA may be responsible for DA synthesis and release in the NAc during the behavioral expression of conditioned reward elicited by a drug-associated context.

Event Abstract Back to Event GABAB receptor system modulates mitragynine-induced conditioned place preference in rats Nurul H. Mohammad Yusoff1*, Sharif M. Mansor1, Navaratnam Visweswaran1, Christian P. Muller2 and Zurina Hassan1* 1 Universiti Sains Malaysia, Centre for Drug Research, Malaysia 2 Friedrich-Alexander-University Erlangen-Nuremberg, Department of Psychiatry and Psychotherapy, Germany Many drugs of abuse produce rewarding effects, as evidenced by their ability to induce conditioned place preference (CPP). Mitragynine, the major active alkaloid of Mitragyna speciosa (Kratom) plant, has been reported to possess this response in animal model. Considering the role of GABAB receptor subtypes in mediating the rewarding properties of various classes of addictive drugs, the present study aims to examine the involvement of GABAB receptor system on acquisition and expression of mitragynine-induced CPP. An unbiased 3-chamber CPP paradigm was employed, which consisted of 3 phases; pre-conditioning (2 days), conditioning (8 days), and CPP test. Pre-conditioning test was performed to assess initial individual preference for each CPP chamber. Groups of rats were conditioned with mitragynine (10 mg/kg), combination of mitragynine and baclofen (1.25, 2.5 and 5.0 mg/kg) or vehicle paired with a distinctive chamber. On alternating days, rats were given vehicle and paired with another distinctive chamber. After 8 conditioning sessions, a preference (CPP) test was conducted whereby rats had full access to the entire apparatus under the influence of either baclofen (1.25, 2.5 and 5.0 mg/kg) or saline. Mitragynine-conditioned animals showed CPP as demonstrated by an increased amount of time spent in the drug-associated chamber during the CPP test relative to pre-conditioning test. The administration of baclofen (2.5 and 5.0 mg/kg) 30 min prior to mitragynine injection inhibited the acquisition of mitragynine-induced CPP. In addition, the administration of baclofen (2.5 and 5.0 mg/kg) to the mitragynine-conditioned animals 30 min prior to the CPP test blocked the expression of CPP responses. These findings showed that activation of GABAB receptors by baclofen suppressed the acquisition and expression of CPP effects produced by mitragynine. Mitragynine-induced CPP effects are dependent on the activity of GABAB receptor system during acquisition and expression phases. Acknowledgements Financial support was received from Higher Education Centre of Excellence (HiCoE) special funding (304/CDADAH/650527/K134) and FRGS (203/CDADAH/6711469) Keywords: Addiction, GABA, conditioned place preference, in vivo, rewarding effect Conference: 14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016. Presentation Type: O03: Postgraduate Travel Awardees Oral Session 3 Topic: 14th Meeting of the Asian-Pacific Society for Neurochemistry Citation: Mohammad Yusoff NH, Mansor SM, Visweswaran N, Muller CP and Hassan Z (2016). GABAB receptor system modulates mitragynine-induced conditioned place preference in rats. Conference Abstract: 14th Meeting of the Asian-Pacific Society for Neurochemistry. doi: 10.3389/conf.fncel.2016.36.00090 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Aug 2016; Published Online: 11 Aug 2016. * Correspondence: Ms. Nurul H Mohammad Yusoff, Universiti Sains Malaysia, Centre for Drug Research, Minden, Penang, Malaysia, hess_myz@yahoo.com Dr. Zurina Hassan, Universiti Sains Malaysia, Centre for Drug Research, Minden, Penang, Malaysia, zurina_hassan@usm.my Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Nurul H Mohammad Yusoff Sharif M Mansor Navaratnam Visweswaran Christian P Muller Zurina Hassan Google Nurul H Mohammad Yusoff Sharif M Mansor Navaratnam Visweswaran Christian P Muller Zurina Hassan Google Scholar Nurul H Mohammad Yusoff Sharif M Mansor Navaratnam Visweswaran Christian P Muller Zurina Hassan PubMed Nurul H Mohammad Yusoff Sharif M Mansor Navaratnam Visweswaran Christian P Muller Zurina Hassan Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Methamphetamine (METH) is a highly addictive psychostimulant. Cannabidiol (CBD) is an exogenous cannabinoid without psychostimulating activity, which has potential therapeutic effects on opioid addiction. However, it is unclear whether CBD has therapeutic effects on METH-induced motivational effects. The present study examines whether CBD has a protective effect on METH-induced conditioned place preference (CPP) in rats by regulating the Sigma1R and AKT-GSK3β-CREB signaling pathway. Seventy rats were equally and randomly divided into seven groups. The rat CPP model was established via the intraperitoneal injection (IP) of 2mg/kg of METH. Next, the intraperitoneal injection of 10, 20, 40, and 80mg/kg CBD was performed 1h prior to the injection of saline or METH. The protein expression levels of Sigma1R, AKT, p-AKT, GSK-3β, p-GSK-3β, CREB, and p-CREB in the rats' prefrontal cortex, nucleus accumbens, and hippocampus and ventral tegmental were detected using western blot analysis. CBD was found to inhibit METH-induced CPP in a dose-dependent fashion. The expression levels of Sigma1R, p-AKT, p-GSK3β, and p-CREB increased significantly in the METH-induced CPP model. Treatment involving different doses of CBD caused differential inhibitory responses in the cellular protein abundance of Sigma1R, p-AKT, p-GSK3β, and p-CREB across various brain regions. The present study found that METH can induce CPP in rats. When a pretreatment of CBD is applied, the CBD can weaken CPP in METH-induced rats by regulating the SigmaR1/AKT/GSK-3β/CREB signaling pathway. The results of this study indicate that CBD has a potential therapeutic effect on METH-induced rewarding effects.

To investigate the changes in CREB (cAMP response element binding protein) in hippocampus, PFC (prefrontal cortex) and NAc (nucleus accumbens) during three phases of morphine induced CPP (conditioned place preference) in rats, and to elucidate the role of CREB during the progress of conditioned place preference. Morphine induced CPP acquisition, extinction and drug primed reinstatement model was established, and CREB expression in each brain area was measured by Western Blot methods. Eight alternating injections of morphine (10 mg/kg) induced CPP, and 8 d saline extinction training that extinguished CPP. CPP was reinstated following a priming injection of morphine (2.5 mg/kg). During the phases of CPP acquisition and reinstatement, the level of CREB expression was significantly changed in different brain areas. It was proved that CPP model can be used as an effective tool to investigate the mechanisms underlying drug-induced reinstatement of drug seeking after extinction, and that morphine induced CPP and drug primed reinstatement may involve activation of the transcription factor CREB in several brain areas, suggesting that the CREB and its target gene regulation pathway may mediate the basic mechanism underlying opioid dependence and its drug seeking behavior.

Methamphetamine (MA), a commonly abused psychostimulant, induces the drug dependence by enhancing the dopamine-mediated neurotransmission. Ketamine (KET) is a non-competitive N-methyl-D-aspartate receptor antagonist, which can be actually mixed with MA for polydrug abuse. In the present study, the individual and combined effects of KET (10 mg/kg, i.p.) and MA (1 mg/kg, i.p.) on conditioned place preference in rats were investigated. The alterations of serine 897 phosphorylations of NR1 receptors in the striatum and ventral tegmental area of after-conditioning rats were measured immunochemically. The results showed repeated administrations of MA, KET and their combination, at the doses studied, all could induce psychological dependences evaluated by conditioned place preference. KET was not able to suppress the MA-induced place preference. The modulations of NR1 phosphorylations in basal ganglia were partly responsible to place preference. Although the alterations induced by KET were not significant in most areas we studied, MA showed a significant increase in the ventral tegmental area but a marked decrease in caudate putamen and nucleus accumbens. Such alterations were much more significant when KET and MA were combined. These results have important implications for public awareness of harm with combined drug abuse. Further investigations toward the specific interaction of the two drugs are necessary.