Conditioned place preference to morphine in cannabinoid CB1 receptor knockout mice

Recent reports have suggested an involvement of the brain cannabinoid system in the morphine-reward pathway. To address this question we evaluated whether CB1 receptor knockout mice would show a conditioned place preference to morphine. CB1 receptor knockout mice developed a strong place preference to 4 and 8 mg/kg morphine, similar to that in wild-type Swiss-Webster mice. This data thus does not support a contribution of the brain cannabinoid system to morphine reward.     

Increase of morphine withdrawal in mice lacking A2a receptors and no changes in CB1/A2a double knockout mice

CB1 cannabinoid and A2a adenosine receptors are highly expressed in the central nervous system where they modulate numerous physiological processes including emotional behaviour and the responses of several drugs of abuse. To investigate the contribution of these receptors in emotional-like responses and opioid dependence we have generated CB1/A2a double deficient mice (CB1-/-/A2a-/-). The spontaneous locomotor activity was reduced in double knockout as compared to wild-type animals. Emotional-like responses of CB1-/-/A2a-/- mice were investigated using the elevated plus-maze and the lit-dark box. Mutant mice exhibited an increased level of anxiety in both behavioural models. The specific involvement of CB1 and A2a receptors in morphine dependence was evaluated by using A2a knockout mice and CB1/A2a double mutant mice. The severity of naloxone-precipitated morphine withdrawal syndrome was significantly increased in the absence of A2a adenosine receptors whereas no modifications were observed in the double knockout mice. These results suggest that both receptors participate in the control of emotional behaviour and seem to play an opposite role in the expression of opioid physical dependence.     

Haloperidol (but not ziprasidone) withdrawal enhances cocaine-induced locomotor activation and conditioned place preference in mice

It has been empirically suggested that the high incidence of drug abuse in schizophrenic patients is related to chronic neuroleptic treatment. We investigated the effects of withdrawal from long-term administration of the typical neuroleptic haloperidol and/or the atypical agent ziprasidone on the acute locomotor stimulant effect of cocaine as well as on cocaine-induced conditioned place preference (CPP). In the first experiment, mice were i.p. treated with haloperidol (1.0 mg/kg) and/or ziprasidone (4.0 mg/kg) for 15 days. At 72 h after the last injection, animals received an i.p. injection of cocaine (10 mg/kg) and their locomotor activity was quantified. In the second experiment, mice were withdrawn from the same haloperidol or ziprasidone treatment schedule and submitted to CPP. Withdrawal from haloperidol (but not ziprasidone or ziprasidone plus haloperidol) increased both cocaine-induced hyperactivity and CPP. These findings indicate that withdrawal from long-term treatment with typical neuroleptic drugs such as haloperidol (but not the atypical compound ziprasidone) may enhance some behavioral effects of cocaine in mice which have been related to drug dependence in humans.     

The caudal part of the posterior insula of rats participates in the maintenance but not the acquisition of morphine conditioned place preference

The heterogeneous insular cortex plays an interoceptive role in drug addiction by signaling the availability of drugs of abuse. Here, we tested whether the caudal part of the multisensory posterior insula (PI) stores somatosensory‐associated rewarding memories. Using Sprague Dawley rats as subjects, we first established a morphine‐induced conditioned place preference (CPP) paradigm, mainly based on somatic cues. Secondly, an electrolytic lesion of the caudal portion of the PI was carried out before and after the establishment of CPP, respectively. Our data demonstrated that the caudal PI lesions disrupted the maintenance, but not the acquisition of morphine‐induced CPP. Lesion or subtle disruption of the PI had no major impact on locomotor activity. These findings indicate that the caudal portion of the PI might be involved in either the storage or the retrieval of morphine CPP memory.     

高频电刺激伏隔核对吗啡诱导大鼠条件性位置偏爱行为的影响

目的研究高频电刺激伏隔核(nucleus accumbens,NAc)对吗啡诱导戒断大鼠觅药行为的影响,分析NAc在大鼠成瘾行为中的作用。方法26只雄性SD大鼠通过吗啡强化形成条件性位置偏爱后,13只予以120Hz高频电刺激伏隔核(吗啡刺激组),另13只予以假刺激(吗啡假刺激组)。15d后给予注射吗啡,诱导大鼠恢复位置偏爱行为,测量并比较两组的位置偏爱得分。结果吗啡电刺激组大鼠在注射吗啡诱导下不易恢复对吗啡的条件性位置偏爱,位置偏爱得分为(237.59±79.89)s,吗啡假刺激组为(441.29±212.68)s,两组比较,差异有统计学意义(P<0.01)。结论电刺激NAc能阻断注射吗啡诱导戒断大鼠恢复觅药行为。在成瘾药物诱导戒断动物觅药行为的过程中,NAc起重要作用。     

A cannabinoid receptor antagonist attenuates conditioned place preference but not behavioural sensitization to morphine

The present study compared the effects of the cannabinoid receptor antagonist SR 141716 on morphine-induced locomotor sensitization (Experiment 1) and conditioned place preference (CPP, Experiment 2) in male albino Wistar rats. In Experiment 1, rats received seven consecutive daily treatments with morphine (10 mg/kg, SC) in combination with either SR 141716 (0, 0.1, 0.5 or 3.0 mg/kg, IP), or naloxone (10 mg/kg, IP). Three days later, all rats were challenged with a lower dose of morphine (5 mg/kg, SC). Rats pre-treated with morphine showed significantly elevated locomotor activity during the challenge session compared to vehicle-pre-treated animals indicating behavioural sensitization. Prior naloxone, but not SR 141716, co-administration with morphine, significantly attenuated the locomotor sensitization observed. In Experiment 2A, SR 141716 (0.1 mg/kg, IP), co-administered during conditioning, significantly attenuated the place preference produced by morphine (4 mg/kg, SC) in a standard unbiased two compartment place conditioning task. In Experiment 2B, the timing of drug administration and drug doses used were altered to be similar to Experiment 1, such that a comparison between the sensitization and CPP paradigms could be made. Thus, rats were conditioned with morphine (10 mg/kg, SC) combined with SR 141716 (0, 0.1, 0.5 or 3.0 mg/kg, IP) and tested for place preference under the influence of morphine (5 mg/kg, SC). SR 141716 attenuated morphine place preference at a dose (3.0 mg/kg) that did not itself affect place conditioning. Morphine also induced locomotor sensitization in the drug-paired compartment in Experiment 2B which was not blocked by any dose of SR 141716. We conclude that CB1 receptor antagonism modulates the rewarding value of opioids, but not the behavioural sensitization induced by chronic opioid administration.     

强迫游泳和糖皮质激素促进小鼠对吗啡的条件性位置偏爱

目的　探讨应激和糖皮质激素在发生药物依赖行为中的作用机制。方法　 (1)将 30只雄性昆明品系小鼠随机分为盐水组、糖皮质激素组 (2 0mg- 1 ·kg- 1 ,皮下注射 )、强迫游泳组 (2 5℃强迫游泳 10min) ,每组 10只 ,观察 3种措施对小鼠条件性位置偏爱形成的影响 ;将 30只雄性昆明品系小鼠先进行吗啡条件性位置偏爱实验 ,再随机分为盐水组、糖皮质激组和强迫游泳组 ,每组 10只 ,处理条件同前 ,持续 6天 ,观察 3种措施对小鼠条件性位置偏爱消退的影响。结果　 (1)强迫游泳组和糖皮质激素组在吗啡搭配箱体中停留时间 [分别为 (9 6± 1 0 )min ,(9 4± 1 3)min]均分别高于盐水组[(7 3± 0 8)min];t1 =4 5 6 ,P1 <0 0 1;t2 =4 5 8,P2 <0 0 1,而强迫游泳组和糖皮质激素组之间差异无显著性 (t=0 41,P >0 0 5 ) ;(2 )经过 6天消退期后 ,强迫游泳组和糖皮质激素组在吗啡搭配箱体中停留时间 [分别为 (7 6± 1 1)min ,(7 4± 0 8)min]亦均分别高于盐水组 [(7 3± 1 0 )min];t1 =4 15 ,P1 <0 0 1;t2 =3 38,P2 <0 0 1。结论　强迫游泳和注射糖皮质激素均能促进小鼠对吗啡的条件性位置偏爱 ,并能延缓条件性位置偏爱的消退。     

Inhibition by MK-801 of cocaine-induced sensitization, conditioned place preference, and dopamine-receptor supersensitivity in mice

Repeated administration of cocaine led to increases in ambulation-accelerating activity (sensitization) and conditioned place preference (CPP). Dopamine (DA)-receptor supersensitivity was also developed in cocaine-induced sensitized and CPP mice. An N-methyl-d-aspartate (NMDA)-receptor antagonist, MK-801, blocked simultaneously developments of cocaine-induced behavioral sensitization, CPP, and DA-receptor supersensitivity. Furthermore, MK-801 inhibited a apomorphine-induced striatal dopaminergic action: climbing behavior. These results suggest that the cocaine-induced dopaminergic behaviors such as sensitization to ambulatory activity and CPP may be produced via activation of the NMDA receptor. The development of postsynaptic DA-receptor supersensitivity may be an underlying common mechanism that mediates cocaine-induced behavioral sensitization and CPP.     

Morphine conditioned place preference depends on glucocorticoid receptors in both hippocampus and nucleus accumbens

Learned association between drugs of abuse and context is essential for the formation of drug conditioned place preference (CPP), which is believed to engage many brain regions including hippocampus and nucleus accumbens (NAc). The underlying mechanisms are not fully understood. Here, we examined whether glucocorticoid receptors (GRs) of hippocampus and NAc influenced the formation of morphine CPP in Sprague Dawley rats. We found that systemic or intrahippocampal infused DMSO vehicle (DMSO 20% in saline) 30 min before daily morphine (10 mg/kg, s.c.) conditioning did not affect the formation of morphine CPP. In contrast, systemic administration (5 mg/kg, s.c.) or intrahippocampal infusion (0, 0.1, 1.0, 10, 20 microg per side) of the GR antagonist RU38486 blocked or impaired the formation of CPP in a dose-dependent manner, respectively. Furthermore, intra-NAc infused RU38486 (10 microg per side) but not DMSO vehicle also prevented the formation of CPP. These results demonstrate that both the GRs of hippocampus and NAc are necessary for the formation of morphine CPP, suggesting a neural network function of the GRs in forming the opiate-associated memory.     

Combined action of MK-801 and ceftriaxone impairs the acquisition and reinstatement of morphine-induced conditioned place preference, and delays morphine extinction in rats

Objective It is well established that glutamate and its receptors, particularly the N-methyl-D-aspartate receptor (NMDAR), play a significant role in addiction and that the inhibition of glutamatergic hyperfunction reduces addictive behaviors in experimental animals. Specifically, NMDAR antagonists such as MK-801, and an inducer of the expression of glutamate transporter subtype-1 (GLT-1) (ceftriaxone) are known to inhibit addictive behavior. The purpose of this study was to determine whether the combined action of a low dose of MK-801 and a low dose of ceftriaxone provides better inhibition of the acquisition, extinction, and reinstatement of morphine-induced conditioned place preference (CPP) than either compound alone. Methods A morphine-paired CPP experiment was used to study the effects of low doses of MK-801, ceftriaxone and a combination of both on reward-related memory (acquisition, extinction, and reinstatement of morphine preference) in rats. Results A low dose of neither MK-801 (0.05 mg/kg, i.p.) nor ceftriaxone (25 mg/kg, i.p.) alone effectively impaired CPP behaviors. However, when applied in combination, they reduced the acquisition of morphine-induced CPP and completely prevented morphine reinstatement. Their combination also notably impaired the extinction of morphine-induced CPP. Conclusion The combined action of a low dose of an NMDAR antagonist (MK-801) and GLT-1 activation by ceftriaxone effectively changed different phases of CPP behavior.     

(—)-nicotine produces conditioned place preference in Lewis,but not Fischer 344 rats

In this study, we sought to determine if Fischer 344 (F344) and Lewis rats showed different conditioned place preference (CPP) responses to subcutaneously administered (—)-nicotine. Lewis rats displayed a CPP response to (—)-nicotine after five pairings, whereas F344 rats showed no preference for nicotine compared to vehicle. After 10 pairings, the F344 rats showed a conditioned place aversion to (—)-nicotine, whereas the Lewis rats still displayed a significant CPP response. These results suggest that the differences in appetitiveness shown between Lewis and F344 rats to other drugs of abuse extend also to (—)-nicotine. Synapse 26:93–94, 1997. © 1997 Wiley-Liss, Inc.     

Tamoxifen and mifepriston modulate nicotine induced conditioned place preference in female rats

An increasing number of studies suggest that nicotine/tobacco addiction is modulated by ovarian hormones. The levels of estrogen and progesterone appear to be important in the success of quit attempts and smoking cessation. In women smokers with the diagnosis or risk of breast cancer, the estrogen receptor modulator tamoxifen (TAM) is widely used, and even though the detrimental health effects of smoking are known, this vulnerable group has difficulty quitting and continues to smoke. The current study tested the effect of the estrogen receptor modulator TAM and the progesterone receptor antagonist mifepriston (RU486) on nicotine-induced conditioned place preference (CPP) in adult female rats. A three chambered CPP apparatus was used and nicotine was paired with the initially non-preferred chamber. Rats received nicotine or saline and hormone receptor modulators (vehicle, TAM, RU486) in a 2 × 3 experimental design. We have previously shown that nicotine induces CPP in male Sprague-Dawley rats but not in females. Our results show that while nicotine alone does not induce CPP in female rats, rats treated with TAM exhibit nicotine-induced CPP. Although RU486 has an aversive effect when applied alone, this is ameliorated by nicotine. These results confirm the role of ovarian hormone receptors in nicotine-induced CPP and may have clinical implications for developing more efficient smoking cessation approaches in women smokers.     

Systemic administration of 1R,4S-4-amino-cyclopent-2-ene-carboxylic acid, a reversible inhibitor of GABA transaminase, blocks expression of conditioned place preference to cocaine and nicotine in rats

We examined the effect of 1R,4S-4-amino-cyclopent-2-ene-carboxylic acid (ACC), a reversible inhibitor of GABA transaminase, on the expression of conditioned place preference response to cocaine and nicotine in rats. Cocaine (20 mg/kg i.p.) and nicotine (0.4 mg/kg s.c.), but not vehicle or 300 mg/kg i.p. of ACC, produced a significant conditioned place preference response. Pretreatment of animals with 300 and 75 mg/kg i.p. of ACC significantly attenuated the expression of the cocaine- and nicotine-induced conditioned place preference responses, respectively. These results are the first to suggest that reversible inhibition of GABA transaminase may be useful in blocking cue-induced relapse to nicotine and cocaine.     

Effects of oil intake in the conditioned place preference test in mice

We investigated the effects of corn oil intake in the conditioned place preference (CPP) test in mice. Voluntary intake of corn oil in the light box in the CPP test showed place preference, but its peroral administration 60 min before conditioning did not show either place preference or aversion. Acquisition of the place preference by corn oil intake was blocked by i.p. injection of SCH 23390 (0.03 mg/kg) and haloperidol (0.1 mg/kg), but not by that of (±)-sulpiride (100 mg/kg), (−)-sulpiride (100 mg/kg), and L-741,626 (1 mg/kg) 15 min before conditioning. These results suggest that stimulation of corn oil in the oral cavity, but not its postingestive effects, have positive reinforcing effects and the stimulation of corn oil is at least partly mediated via dopaminergic systems through the D₁ receptors. Moreover, the present results suggest that the CPP test is useful for the study of preferable stimulation and rewarding effects of food intake.     

Expression and acquisition of the conditioned place preference response to cocaine in rats is blocked by selective inhibitors of the enzyme N-acetylated-alpha-linked-acidic dipeptidase (NAALADASE)

In this study we examined the effect of 2-(phosphonomethyl)pentanedioic acid (2-PMPA) and GPI 5693, selective inhibitors of the enzyme N-Acetylated-alpha-Linked-Acidic Dipeptidase (NAALADase; glutamate carboxypeptidase II; EC no. 3.4.17.21), which cleaves glutamate from the dipeptide N-acetyl-aspartyl-glutamate (NAAG), on the conditioned place preference (CPP) response to cocaine in male rats. The i.p. administration of 15 mg/kg of cocaine produced a significant CPP response. The acquisition and expression of the CPP response to cocaine was blocked by the i.p. administration of 100 mg/kg of 2-PMPA and the p.o. administration of 30 mg/kg of GPI 5693. In contrast, neither 2-PMPA nor GPI 5693 produced a CPP or conditioned place aversion response when administered alone. Furthermore, neither 2-PMPA or GPI 5693 altered the expression of the CPP response to food. These results indicate that NAALADase inhibitors block the incentive motivational value of cocaine, suggesting that such agents may be of use in treating cue-induced craving in cocaine addicts.     

Increased adult hippocampal neurogenesis is not necessary for wheel running to abolish conditioned place preference for cocaine in mice

Recent evidence suggests that wheel running can abolish conditioned place preference (CPP) for cocaine in mice. Running significantly increases the number of new neurons in the hippocampus, and new neurons have been hypothesised to enhance plasticity and behavioral flexibility. Therefore, we tested the hypothesis that increased neurogenesis was necessary for exercise to abolish cocaine CPP. Male nestin–thymidine kinase transgenic mice were conditioned with cocaine, and then housed with or without running wheels for 32 days. Half of the mice were fed chow containing valganciclovir to induce apoptosis in newly divided neurons, and the other half were fed standard chow. For the first 10 days, mice received daily injections of bromodeoxyuridine (BrdU) to label dividing cells. On the last 4 days, mice were tested for CPP, and then euthanized for measurement of adult hippocampal neurogenesis by counting the number of BrdU‐positive neurons in the dentate gyrus. Levels of running were similar in mice fed valganciclovir‐containing chow and normal chow. Valganciclovir significantly reduced the numbers of neurons (BrdU‐positive/NeuN‐positive) in the dentate gyrus of both sedentary mice and runner mice. Valganciclovir‐fed runner mice showed similar levels of neurogenesis as sedentary, normal‐fed controls. However, valganciclovir‐fed runner mice showed the same abolishment of CPP as runner mice with intact neurogenesis. The results demonstrate that elevated adult hippocampal neurogenesis resulting from running is not necessary for running to abolish cocaine CPP in mice.     

Involvement of the dorsal hippocampus in expression and extinction of cocaine‐induced conditioned place preference

A key aspect of substance abuse is that drug taking often occurs in a specific context. As a consequence, exposure to drug‐associated contexts can trigger cravings and relapse, even after long periods of abstinence. Although many studies have demonstrated that the hippocampus is critical for developing and retrieving contextual and spatial memories, comparatively little is known about the role of the hippocampus in acquiring and inhibiting memories involving contexts and drugs of abuse. We examined the effects of hippocampal inactivation on expression of cocaine‐induced conditioned place preference (CPP) after initial acquisition or extinction of CPP in C57BL/6 mice. During acquisition of CPP, distinct tactile cues were paired with cocaine (20 mg kg^?1, intraperitoneal, CS+) and different tactile cues were paired with saline (CS?) on alternate days. Groups differed in whether the CS+ and CS? cues were presented in the same large space (one‐compartment procedure) or distinct small spaces (two‐compartment procedure), as previous findings demonstrate that a two‐compartment configuration facilitates acquisition and attenuates extinction of a cocaine‐induced CPP. Microinjection of the GABA_A agonist, muscimol, into the dorsal hippocampus impaired (1) retrieval of a place preference after acquisition, (2) extinction of a place preference, and (3) retrieval of extinction. These effects differed depending on the spatial configuration during acquisition or extinction, suggesting that the dorsal hippocampus may differentially modulate drug seeking during retrieval and extinction of CPP.     

Early maternal deprivation induces gender‐dependent changes on the expression of hippocampal CB1 and CB2 cannabinoid receptors of neonatal rats

Early maternal deprivation (MD) in rats (24 h, postnatal day 9–10) is a model for neurodevelopmental stress. There are some data proving that MD affects the endocannabinoid system (ECS) in a gender‐dependent manner, and that these changes may account for the proposed schizophrenia‐like phenotype of MD rats. The impact of MD on cannabinoid receptor distribution in the hippocampus is unknown. The aim of this study is to evaluate the expression of CB₁ and CB₂ receptors in diverse relevant subregions (DG, CA1, and CA3) of the hippocampus in 13‐day‐old rats by immunohistochemistry and densitometry. MD induced a significant decrease in CB₁ immunoreactivity (more marked in males than in females), which was mainly associated with fibers in the strata pyramidale and radiatum of CA1 and in the strata oriens, pyramidale, and radiatum of CA3. In contrast, MD males and females showed a significant increase in CB₂ immunoreactivity in the three hippocampal areas analyzed that was detected in neuropil and puncta in the stratum oriens of CA1 and CA3, and in the polymorphic cell layer of the dentate gyrus. A marked sex dimorphism was observed in CA3, with females exhibiting higher CB₁ immunoreactivity than males, and in dentate gyrus, with females exhibiting lower CB₂ immunoreactivity than males. These results point to a clear association between developmental stress and dysregulation of the ECS. The present MD procedure may provide an interesting experimental model to further address the role of the ECS in neurodevelopmental mental illnesses such as schizophrenia. © 2008 Wiley‐Liss, Inc.     

Blockade of alcohol-induced locomotor sensitization and conditioned place preference in DBA mice by 7-nitroindazole

Our previous studies indicated that inhibition or ablation of the neuronal nitric oxide synthase (nNOS) prevents the development of sensitization to the locomotor-stimulating effect of cocaine and cocaine-induced conditioned place preference (CPP). The present study was undertaken to investigate the effect of the nNOS inhibitor, 7-nitroindazole (7-NI), on ethanol-induced locomotor sensitization and CPP in DBA/2J mice. Administration of ethanol (1.5 g/kg; i.p.) for 7 days resulted in a progressive increase in the locomotor-stimulating effect of ethanol. Pretreatment with 7-NI (25 mg/kg) blocked the expression of the sensitized response to ethanol. A challenge injection of ethanol given 1 week and then 4 weeks following withdrawal from ethanol indicated that (a) ethanol sensitization was long lasting, and (b) the co-administration of 7-NI and ethanol attenuated the sensitized response to ethanol challenge. The CPP experiments showed that pairing four ethanol (2.5 g/kg) injections with a specific environment resulted in a marked preference for the drug-paired environment. The pretreatment with 7-NI (25 mg/kg) completely blocked ethanol-induced CPP. 7-NI alone produced neither rewarding nor aversive effects. Taken together, results of the present study indicate that blockade of nNOS by 7-NI-attenuated ethanol-induced behavioral sensitization and completely blocked the rewarding effect of ethanol. These findings support the role of NO in ethanol actions and further suggest that the nNOS system is relevant to the rewarding effects of various drugs of abuse.