Conditioned Place Preference Response Research Articles

BNT12, a novel hybrid peptide of opioid and neurotensin pharmacophores, produces potent central antinociception with limited side effects

The development of multitarget opioid drugs has emerged as an attractive approach for innovative pain management with reduced side effects. In the present study, a novel hybrid peptide BNT12 containing the opioid and neurotensin (NT)-like fragments was synthesized and pharmacologically characterized. In acute radiant heat paw withdrawal test, intracerebroventricular (i.c.v.) administration of BNT12 produced potent antinociception in mice. The central antinociceptive activity of BNT12 was mainly mediated by μ-, δ-opioid receptor, neurotensin receptor type 1 (NTSR1) and 2 (NTSR2), supporting a multifunctional agonism of BNT12 in the functional assays. BNT12 also exhibited significant antinociceptive effects in spared nerve injury (SNI)-neuropathic pain, complete Freund's adjuvant (CFA)-induced inflammatory pain, acetic acid-induced visceral and formalin-induced pain after i.c.v. administration. Furthermore, BNT12 exhibited substantial reduction of acute antinociceptive tolerance, shifted the dose-response curve to the right by only 1.3-fold. It is noteworthy that BNT12 showed insignificant chronic antinociceptive tolerance at the supraspinal level. In addition, BNT12 exhibited reduced or no opioid-like side effects on conditioned place preference (CPP) response, naloxone-precipitated withdrawal response, acute hyperlocomotion, motor coordination, gastrointestinal transit, and cardiovascular responses. The present investigation demonstrated that the novel hybrid peptide BNT12 might serve as a promising analgesic candidate with limited opioid-like side effects.

Novel endomorphin analogues CEMR-1 and CEMR-2 produce potent and long-lasting antinociception with a favourable side effect profile at the spinal level.

Endomorphins have shown great promise as pharmaceutics for the treatment of pain. We have previously confirmed that novel endomorphin analogues CEMR-1 and CEMR-2 behaved as potent μ agonists and displayed potent antinociceptive activities at the supraspinal and peripheral levels. The present study was undertaken to evaluate the antinociceptive properties of CEMR-1 and CEMR-2 following intrathecal (i.t.) administration. Furthermore, their antinociceptive tolerance and opioid-like side effects were also determined. The spinal antinociceptive effects of CEMR-1 and CEMR-2 were determined in a series of pain models, including acute radiant heat paw withdrawal test, spared nerve injury-induced neuropathic pain, complete Freund's adjuvant-induced inflammatory pain, visceral pain and formalin pain. Antinociceptive tolerance was evaluated in radiant heat paw withdrawal test. Spinal administration of CEMR-1 and CEMR-2 produced potent and prolonged antinociceptive effects in acute pain. CEMR-1 and CEMR-2 may produce their antinociception through distinct μ receptor subtypes. These two analogues also exhibited significant analgesic activities in neuropathic, inflammatory, visceral and formalin pain at the spinal level. It is noteworthy that CEMR-1 showed non-tolerance-forming analgesic properties, while CEMR-2 exhibited substantially reduced antinociceptive tolerance. Furthermore, both analogues displayed no or reduced side effects on conditioned place preference response, physical dependence, locomotor activity and gastrointestinal transit. The present investigation demonstrated that CEMR-1 and CEMR-2 displayed potent and long-lasting antinociception with a favourable side effect profile at the spinal level. Therefore, CEMR-1 and CEMR-2 might serve as promising analgesic compounds with minimal opioid-like side effects.

Susceptibility to arecoline in male C57BL/6 J mice correlates with age factor

Epidemiological investigations and clinical studies have confirmed that human chewing of betel nut is an addictive behavior, and the proportion of teenagers chewing betel nut is increasing. Previous studies have shown that adolescence shows higher sensitivity to many addictive substances compared with adulthood, and that adult susceptibility to addictive substances is usually changed after exposure to addictive substances during adolescence. However, there are no reports of age-related animal experiments on betel nut or dependence to its active ingredients. Therefore, the two-bottle choice (TBC) (experiment 1 and 2) and conditioned place preference (CPP) (experiment 3 and 4) models with mice were used in this study to explore age-related differences in intake and preference of arecoline, the alkaloid in betel nut with highest content, and to explore the effect of arecoline exposure during adolescence on the re-exposure of arecoline in adulthood in mice. The results of experiment 1 showed that the intake of 80 μg/ml arecoline in adolescent mice was significantly higher than that in adult mice. However, there was no significant difference between adult and adolescent mice in preference for arecoline at any tested concentration (5–80 μg/ml), which may be due to the significantly higher intake of total fluid in adolescent mice compared to adult mice. The preference of arecoline in adolescent mice peaked at 20 μg/ml, and in adult mice peaked at 40 μg/ml. The results of experiment 2 showed that oral arecoline (5–80 μg/ml) in mice during adolescence caused a significant increase in the intake (days 3–16) and preference (days 5–8) for 40 μg/ml arecoline in adulthood. The results of experiment 3 showed that the doses of 0.03 or 0.1 mg/kg of arecoline produced the highest CPP response in adolescent or adult mice, respectively. The results of experiment 4 showed that mice exposed to arecoline in adolescence had significantly increased the CPP scores induced by arecoline in adulthood compared to mice that were not exposed. These data suggested that adolescent mice were more sensitive to arecoline, and exposure of mice to arecoline during adolescence increased the susceptibility to arecoline in adulthood.

Effects of chronic methamphetamine exposure on rewarding behavior and neurodegeneration markers in adult mice.

Recreational and medical use of stimulants among young adults have gained popularity in the United States over the last decade and their use may increase vulnerability to brain biochemical changes and addictive behaviors. The long-term effects of chronic stimulant exposure in later adulthood have not been fully elucidated.Our study investigated whether chronic exposure to methamphetamine (METH), at a dose designed to emulate human therapeutic dosing for ADHD, would promote biochemical alterations and affect sensitivity to the rewarding effects of subsequent METH dosing.Groups of 3.5-month-old male and female C57BL/6J mice were administered non-contingent intraperitoneal injections of either saline or METH (1.4 mg/kg) twice a day for 1 month (5 days/week). METH (0.5 mg/kg)-induced conditioned place preference (CPP) was tested in mice to determine the effects of previous METH exposure on reward-related behavior. Mice were randomly assigned to Experiment I (males and females) or Experiment II (females only) in which CPP testing was respectively performed either 0.5 or 5 months after the end of METH injections, at ~5 or 10 months old respectively. The midbrain and striatum, regions involved in reward circuit, were assessed for markers associated with neurotoxicity, dopaminergic function, neuroinflammation and epigenetic changes after behavioral testing.Previous exposure to chronic METH did not have significant short-term effects on CPP response but led to a decreased CPP response in 10-month-old females. Previous exposure to METH induced some short-term changes to biochemical markers measured in a brain region and sex-dependent manner, while long-term changes were only observed with GFAP and KDM5C.In conclusion, our data suggest sex- and post-exposure duration-dependent outcomes and warrant further exploration of the long-term neurobehavioral consequences of psychostimulant use in both sexes.

Pronociceptive autoantibodies in the spinal cord mediate nociceptive sensitization, loss of function, and spontaneous pain in the lumbar disk puncture model of chronic back pain.

Previously, we observed that B cells and autoantibodies mediated chronic nociceptive sensitization in the mouse tibia fracture model of complex regional pain syndrome and that complex regional pain syndrome patient antibodies were pronociceptive in fracture mice lacking mature B cells and antibodies (muMT). The current study used a lumbar spinal disk puncture (DP) model of low back pain in wild-type (WT) and muMT mice to evaluate pronociceptive adaptive immune responses. Spinal disks and cords were collected 3 weeks after DP for polymerase chain reaction and immunohistochemistry analyses. Wild-type DP mice developed 24 weeks of hindpaw mechanical allodynia and hyperalgesia, grip weakness, and a conditioned place preference response indicative of spontaneous pain, but pain responses were attenuated or absent in muMT DP mice. Spinal cord expression of inflammatory cytokines, immune cell markers, and complement components were increased in WT DP mice and in muMT DP mice. Dorsal horn immunostaining in WT DP mice demonstrated glial activation and increased complement 5a receptor expressionin spinal neurons. Serum collected from WT DP mice and injected into muMT DP mice caused nociceptive sensitization, as did intrathecal injection of IgM collected from WT DP mice, and IgM immune complexes were observed in lumbar spinal disks and cord of WT DP mice. Serum from WT tibia fracture mice was not pronociceptive in muMT DP mice and vice versa, evidence that each type of tissue trauma chronically generates its own unique antibodies and targeted antigens. These data further support the pronociceptive autoimmunity hypothesis for the transition from tissue injury to chronic musculoskeletal pain state.

Investigation of the impact of antiparasitic drug moxidectin on the rewarding effects of alcohol.

Alcohol addiction or alcoholism constitutes a significant risk factor worldwide for morbidity and mortality. Moxidectin is a recently approved anthelmintic drug, which also activates the gamma-aminobutyric acid receptors. The objective of the present study was to examine the impact of moxidectin on rewarding effects of ethanol in the conditioned place preference (CPP) model in mice. In separate experiments, mice were administered intraperitoneal (i.p.) injections of moxidectin (5 or 10 mg/kg, i.p.) before a) acquisition of alcohol-induced CPP, b) each extinction session, and c) alcohol-induced reinstatement of CPP. The present experiments provide consistent data about ethanol place preference in mice (2 g/kg, i.p.), with mice in all tests spending significantly more time on the ethanol-paired side. The acquisition of the CPP response to ethanol was prevented by the administration of moxidectin at a dose of 10 mg/kg. Additionally, moxidectin treatment accelerated the extinction of ethanol CPP when given repeatedly during the extinction phase. Ethanol-induced reinstatement of CPP following an extinction phase was inhibited by moxidectin. Ethanol alone and co-administration with moxidectin did not change locomotor activity and motor coordination. In conclusion, we suggest that moxidectin may be a promising therapeutic candidate for prevention of ethanol-induced addiction and relapse as well as detoxification.

Behavioural and biochemical responses to methamphetamine are differentially regulated by mGlu2 and mGlu3 metabotropic glutamate receptors in male mice

Group II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors) shape mechanisms of methamphetamine addiction, but the individual role played by the two subtypes is unclear. We measured methamphetamine-induced conditioned place preference (CPP) and motor responses to single or repeated injections of methamphetamine in wild-type, mGlu2−/−, and mGlu3−/− mice. Only mGlu3−/− mice showed methamphetamine preference in the CPP test. Motor response to the first methamphetamine injection was dramatically reduced in mGlu2−/− mice, unless these mice were treated with the mGlu5 receptor antagonist, MTEP. In contrast, methamphetamine-induced sensitization was increased in mGlu3−/− mice compared to wild-type mice. Only mGlu3−/− mice sensitized to methamphetamine showed increases in phospho-ERK1/2 levels in the nucleus accumbens (NAc) and free radical formation in the NAc and medial prefrontal cortex. These changes were not detected in mGlu2−/− mice.We also measured a series of biochemical parameters related to the mechanism of action of methamphetamine in naïve mice to disclose the nature of the differential behavioural responses of the three genotypes. We found a reduced expression and activity of dopamine transporter (DAT) and vesicular monoamine transporter-2 in the NAc and striatum of mGlu2−/− and mGlu3−/− mice, whereas expression of the DAT adaptor, syntaxin 1A, was selectively increased in the striatum of mGlu3−/− mice. Methamphetamine-stimulated dopamine release in striatal slices was largely reduced in mGlu2−/−, but not in mGlu3−/−, mice. These findings suggest that drugs that selectively enhance mGlu3 receptor activity or negatively modulate mGlu2 receptors might be beneficial in the treatment of methamphetamine addiction and associated brain damage.

Naltrexone attenuates methamphetamine-induced behavioral sensitization and conditioned place preference in mice

Methamphetamine addiction causes serious public health problems worldwide. However, there is no effective medication licensed for methamphetamine addiction. The endogenous opioid system is considered to be a common substrate in drug addiction due to its regulation of dopamine release. In recent clinical trials, (-)-naltrexone, an opioid receptors and Toll-like receptor 4 antagonist, has exhibited encouraging findings for treating methamphetamine addiction; however, the understanding of its pharmacological mechanisms remains insufficient. By using mice models of behavioral sensitization and conditioned place preference (CPP), the present study was performed to investigate the effects of naltrexone on the methamphetamine-associated properties of incentive salience and reward-related memory, the two crucial factors for the development of addictive process and relapse. We found that naltrexone reduced single methamphetamine-induced hyperlocomotion in mice. In the paradigm of methamphetamine-induced behavioral sensitization paired with contextual cues in mice, naltrexone suppressed the development and expression of locomotor sensitization, suggesting the decrease in incentive salience to methamphetamine and context. In the methamphetamine-induced CPP paradigm in mice, naltrexone attenuated both the expression and methamphetamine-priming reinstatement of CPP response, suggesting the impairment of either contextual cue- or drug-induced retrieval of methamphetamine-associated memory. After the establishment of methamphetamine-induced CPP in mice, naltrexone treatment during the extinction training produced conditioned place adverse response, suggesting that naltrexone facilitated negative affection-associated extinction learning. Taken together, these findings demonstrate that naltrexone could intervene in the properties of incentive salience and reward-related memory in methamphetamine addiction, which may contribute to its therapeutic effects on methamphetamine addicts in clinical studies.

Heat shock disrupts expression of excitatory and extinction memories in planaria: Interaction with amount of exposure

In planarians, as seen in rodents, natural reinforcers (sucrose) and drugs of abuse support Conditioned Place Preference (CPP), which is a form of Pavlovian learning to examine the rewarding effects of natural reinforcers and drugs of abuse. Using this preparation, we have previously observed acquisition, extinction and reinstatement of sucrose CPP. In the present experiments, we used planaria to investigate the amnestic effects of Heat Shock (HS, a known stressor in planaria) following different amounts of CPP extinction sessions. Experiment 1 showed that planarians developed a CPP response to a sucrose-paired surface. Heat shock, when given in conjunction with exposure to the sucrose-paired surface, produced amnesia as assessed by a subsequent sucrose reinstatement test. We interpreted that the amnesic effect of HS was due to HS affecting the dominant excitatory memory at the time of HS exposure. Thus, we hypothesized that after extensive extinction training (10 exposures), HS would lead to recovery from extinction (when the new inhibitory memory is dominant at the time of HS exposure). Experiment 2 explored this possibility and showed that given HS following 10 extinction sessions had no amnestic effect on the excitatory CPP response. In Experiment 3, we hypothesized that 16 extinction sessions would produce a stronger (and hence dominant) extinction inhibitory trace, which then would be vulnerable to HS. We observed that HS impaired the expression of the extinction memory following 16 exposures. These results reveal different effects of HS on CPP memories depending on the amount of extinction, and are fully consistent with the literature using rodents and humans. In addition, they suggest that planaria is a promising pre-clinical model to assess fundamental memory processes.

Cocaine-induced conditioned place preference and locomotor response are distinctively regulated by glutamate and dopamine receptor signaling in the prefrontal cortex

Cocaine-induced conditioned place preference and locomotor response are distinctively regulated by glutamate and dopamine receptor signaling in the prefrontal cortex

Mammalian target of rapamycin complex 1 and its downstream effector collapsin response mediator protein-2 drive reinstatement of alcohol reward seeking.

Alcohol use disorder is a chronic relapsing disease. Maintaining abstinence represents a major challenge for alcohol-dependent patients. Yet the molecular underpinnings of alcohol relapse remain poorly understood. In the present study, we investigated the potential role of the mammalian target of rapamycin complex 1 (mTORC1) in relapse to alcohol-seeking behavior by using the reinstatement of a previously extinguished alcohol conditioned place preference (CPP) response as a surrogate relapse paradigm. We found that mTORC1 is activated in the nucleus accumbens shell following alcohol priming-induced reinstatement of alcohol place preference. We further report that the selective mTORC1 inhibitor, rapamycin, abolishes reinstatement of alcohol place preference. Activation of mTORC1 initiates the translation of synaptic proteins, and we observed that reinstatement of alcohol CPP is associated with increased protein levels of one of mTORC1's downstream targets, collapsin response mediator protein-2 (CRMP2), in the nucleus accumbens. Importantly, the level of mTORC1 activation and CRMP2 expression positively correlate with the CPP score during reinstatement. Finally, we found that systemic administration of the CRMP2 inhibitor, lacosamide, attenuates alcohol priming-induced reinstatement of CPP. Together, our results reveal that mTORC1 and its downstream target, CRMP2, contribute to mechanisms underlying reinstatement of alcohol reward seeking. Our results could have important implications for the treatment of relapse to alcohol use and position the Food and Drug Administration approved drugs, rapamycin and lacosamide, for the treatment of alcohol use disorder.

Dissociation of place preference and tolerance responses to sucrose using a dopamine antagonist in the planarian

In rodents, sucrose has been found to elicit addictive-like behaviours like the development of tolerance and the association with cues present at the time of consumption. Furthermore, the neurochemical response to sucrose binges is equivalent to the one observed in response to the abuse of addictive substances like cocaine. The experiments reported here address the effects of sucrose on an invertebrate model, the Platyhelminth brown planarian. The animals exposed to a 10% sucrose solution in one context developed a conditioned place preference (CPP) which was subsequently extinguished in the absence of the rewarding agent. However, one exposure to sucrose per se sufficed to reinstate the CPP response, suggesting sucrose-induced CPP can be characterised as a standard Pavlovian response. The same training procedure led to the development of context-specific tolerance to the effects of sucrose. However, comparing animals treated with dopamine D1 antagonist (SCH-23390) with control animals showed that the establishment of CPP, but not the development of tolerance, is mediated by the dopamine reward system.

Cav1.2, but not Cav1.3, L-type calcium channel subtype mediates nicotine-induced conditioned place preference in mice

Nicotine use is one of the most common forms of drug addiction. Although L-type calcium channels (LTCCs) are involved in nicotine addiction, the contribution of the two primary LTCC subtypes (Cav1.2 and 1.3) is unknown. This study aims to determine the contribution of these two LTCC subtypes to nicotine-induced conditioned place preference (CPP) responses by using transgenic mouse models that do not express Cav1.3 (Cav1.3−/−) or contain a mutation in the dihydropyridine (DHP) site of the Cav1.2 (Cav1.2DHP−/−). We found a hyperbolic dose dependent nicotine (0.1–1mg/kg; 0.5mg/kg optimum) effect on place preference in wild type (WT) mice, that could be prevented by the DHP LTCC blocker nifedipine pretreatment. Similarly, Cav1.3−/− mice showed nicotine-induced place preference which was antagonized by nifedipine. In contrast, nifedipine pretreatment of Cav1.2DHP−/− mice had no effect on nicotine-induced CPP responses, suggesting an involvement of Cav1.2 subtype in the nicotine-induced CPP response. Nifedipine alone failed to produce either conditioned place aversion or CPP in WT mice. These results collectively indicate Cav1.2, but not Cav1.3 LTCC subtype regulates, at least in part, the reinforcing effects of nicotine use.

CRF1 receptor-deficiency increases cocaine reward

Stimulant drugs produce reward but also activate stress-responsive systems. The corticotropin-releasing factor (CRF) and the related hypothalamus-pituitary-adrenal (HPA) axis stress-responsive systems are activated by stimulant drugs. However, their role in stimulant drug-induced reward remains poorly understood. Herein, we report that CRF1 receptor-deficient (CRF1-/-), but not wild-type, mice show conditioned place preference (CPP) responses to a relatively low cocaine dose (5 mg/kg, i.p.). Conversely, wild-type, but not CRF1-/-, mice display CPP responses to a relatively high cocaine dose (20 mg/kg, i.p.), indicating that CRF1 receptor-deficiency alters the rewarding effects of cocaine. Acute pharmacological antagonism of the CRF1 receptor by antalarmin also eliminates cocaine reward. Nevertheless, CRF1-/- mice display higher stereotypy responses to cocaine than wild-type mice. Despite the very low plasma corticosterone concentration, CRF1-/- mice show higher nuclear glucocorticoid receptor (GR) levels in the brain region of the hippocampus than wild-type mice. Full rescue of wild-type-like corticosterone and GR circadian rhythm and level in CRF1-/- mice by exogenous corticosterone does not affect CRF1 receptor-dependent cocaine reward but induces stereotypy responses to cocaine. These results indicate a critical role for the CRF1 receptor in cocaine reward, independently of the closely related HPA axis activity.

GABAB receptor system modulates mitragynine-induced conditioned place preference in rats

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.

The effects of environmental enrichment on nicotine condition place preference in male rats.

Environmental enrichment has previously been shown to alter sensitivity to psychostimulants and opiates in various preclinical models. However, little research has been conducted studying the effects of environmental enrichment on the more commonly abused drug, nicotine. The current study raised male rats in either enriched conditions (EC) or isolated conditions (IC) and tested the animals' sensitivity to acquisition, extinction and reinstatement of nicotine conditioned place preference (CPP). Using a 3-chamber CPP apparatus, male Sprague-Dawley rats were conditioned with 1 of 3 doses of nicotine (0.4, 0.6, and 0.8 mg/kg) or saline on alternating days across 8 conditioning trials, followed by a test day for a nicotine-induced CPP response. Next, the animals had 5 extinction sessions followed by a nicotine-primed reinstatement session. EC rats displayed nicotine CPP at all 3 doses, whereas IC rats failed to show significant nicotine CPP relative to saline controls. EC rats also showed extinction of the nicotine-induced CPP response by the fifth extinction session for all 3 nicotine doses tested. However, only the 2 highest doses of the nicotine prime reinstated a CPP response in EC rats relative to saline controls. Taken together, these findings suggest that environmental enrichment may increase sensitivity to the rewarding effects of nicotine.

The selective dopamine D₃ receptor antagonist SB-277011A attenuates drug- or food-deprivation reactivation of expression of conditioned place preference for cocaine in male Sprague-Dawley rats.

We determined the effect of the selective dopamine D3 receptor antagonist SB-277011A on reactivation of conditioned place preference (CPP) to cocaine elicited by priming injections of cocaine or exposure to food deprivation stress (21 h) in male Sprague-Dawley rats. Animals paired with the cocaine-associated chamber displayed a robust and consistent CPP response. This CPP was extinguished after repeated pairings of the conditioned stimuli (cocaine-paired chamber contextual cues) in the absence of the unconditioned stimulus (cocaine). Twenty-four hours later, the administration of 5 mg kg(-1) i.p. of cocaine (immediately before the test) or exposure to 21 h of food deprivation reactivated the expression of the cocaine-induced CPP. In contrast, administration of 1 ml kg(-1) i.p. of vehicle did not reactivate the CPP response. Administration of the selective dopamine D3 receptor antagonist SB-277011A (3-24 mg kg(-1) i.p.) 30 min before cocaine administration on the test day produced a significant attenuation of CPP reactivation. Reactivation of the CPP response produced by food deprivation was also significantly attenuated by SB-277011A (6 or 12 mg kg(-1) i.p.) given 30 min before the test session. SB-277011A (12 or 24 mg kg(-1) i.p.) did not itself produce reactivation of the CPP response. Overall, these results suggest that the reactivation of the incentive value of drug-associated cues by cocaine or food deprivation is attenuated by selective antagonism of D3 receptors.

Temporal and dose-dependent differences in simultaneously-induced cocaine hypervigilance and conditioned-place-preference in marmoset monkeys

BackgroundAlthough repeated exposure to cocaine can induce hypervigilance and conditioned-place-preference (CPP) in nonhuman primates (NHPs), more detailed analyses are warranted since the outcome can be influenced by different factors. MethodsWe evaluated in marmoset monkeys (Callithrix penicillata): (1) the onset time-course and dose-dependent (3 or 7mg/kg; i.p.) profile of their hypervigilance and CPP response to repeated cocaine exposure; (2) whether these behavioral measures are still detectable after a 15-day no-drug period; (3) the relationship between their hypervigilance and CPP responses; and (4) if these behavioral changes correlate with pre- and post-drug behaviors (i.e., vigilance, locomotion, exploration), and/or first response to cocaine. ResultsHypervigilance had a slow-onset, was only effective with the 7mg/kg dose of cocaine, lacked long-term conditioned effects and was not related to the initial cocaine response or pre-drug behaviors, regardless of the dose tested. CPP was promptly induced with the 3 and 7mg/kg doses, and had a dose-dependent long-term effect and negative correlation with pre-drug locomotion and exploration. Hypervigilance and CPP were not significantly correlated. ConclusionsAlthough hypervigilance and CPP were induced, they had distinct temporal and dose-dependent profiles, and were not equally co-expressed in the same marmoset. Also, in NHPs, pre-drug locomotion and exploration were predictive of the low-dose CPP response.

High versus low fat/sugar food affects the behavioral, but not the cortisol response of marmoset monkeys in a conditioned-place-preference task

The effect of a high (chocolate) versus low fat/sugar (chow) food on a conditioned-place-preference (CPP) task was evaluated in marmoset monkeys. Anxiety-related behaviors and cortisol levels before and after the CPP task were also measured. Subjects were habituated to a two-compartment CPP box and then, on alternate days, had access to only one compartment during daily 15-min conditionings, for a total of 14 trials. Marmosets were provisioned with chocolate chips in the CC-paired compartment on odd-numbered trials and standard chow in the CW-paired compartment on even-numbered trials. They were then tested for preferring the CC-paired context after a 24-h interval. During the conditioning, a significantly greater amount (in kcal/trial) of chocolate was consumed than chow, yet the foraging pattern of both food types was similar. On the test trial, the time spent in the CC-paired context increased significantly compared to pre-CPP levels, yet this response was not readily predicted by baseline behavioral or cortisol levels. Also, the chocolate CPP response was positively correlated with foraging time, rather than the amount of calories consumed. The sudden absence of the food increased exploration, while the chocolate CPP effect was associated with vigilance — both anxiety-related behaviors in marmosets. This behavioral profile occurred regardless of any concomitant change or correlation with cortisol. Therefore, the high fat/sugar food was more prone to be overly consumed by the marmosets, to induce a CPP response and to lead to anxiety-related behavior in its absence.

Conditioned place preference and self-administration induced by nicotine in adolescent and adult rats.

Nicotine addiction is a worldwide problem. However, previous studies characterizing the rewarding and reinforcing effects of nicotine in animal models have reported inconsistent findings. It was observed that the addictive effects are variable on different factors (e.g. route, dose, and age). Here, we evaluated the rewarding and reinforcing effects of nicotine in different routes of administration, across a wide dose range, and in different age groups. Two of the most widely used animal models of drug addiction were employed: the conditioned place preference (CPP) and self-administration (SA) tests. Nicotine CPP was evaluated in different routes [intraperitoneal (i.p.) and subcutaneous (s.c.)], doses (0.05 to 1.0 mg/kg) and age [adolescent and adult rats]. Similarly, intravenous nicotine SA was assessed in different doses (0.01 to 0.06 mg/kg/infusion) and age (adolescent and adult rats). In the CPP test, s.c. nicotine produced greater response than i.p. The 0.2 mg/kg dose produced highest CPP response in adolescent, while 0.6 mg/kg in adult rats; which were also confirmed in 7 days pretreated rats. In the SA test, adolescent rats readily self-administer 0.03 mg/kg/infusion of nicotine. Doses that produced nicotine CPP and SA induced blood nicotine levels that corresponded well with human smokers. In conclusion, we have demonstrated that nicotine produces reliable CPP [0.2 mg/kg dose (s.c.)] in adolescents and [0.6 mg/kg dose (s.c.)] in adults, and SA [0.03 mg/kg/infusion] in adolescent rats. Both tests indicate that adolescent rats are more sensitive to the rewarding and reinforcing effects of nicotine.