Carnosine ameliorates morphine-induced conditioned place preference in rats

The histidine-containing dipeptide, carnosine (β-alanyl-l-histidine), is present in high concentrations in mammalian brain of mammals. There are many theories about its biological functions, such as anti-inflammatory agent, free radical scavenger, and protein glycosylation inhibitor, however, the role of carnosine in morphine addiction is less understood. Therefore, the objectives of this study were to determine the effects of carnosine on the development of morphine-induced conditioned place preference (CPP) and investigate its possible mechanism of action in Sprague-Dawley rats. Intraperitioneal (i.p.) injection of carnosine (200, 500, 1000 mg/kg) significantly inhibited the development of morphine-induced CPP in a dose-dependent manner. Although carnosine had no appreciable effect on the levels of histamine in the ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC), it significantly decreased glutamate level in the VTA, dopamine levels in the NAc and PFC, and DOPAC level in the NAc of morphine-treated rats. These results indicate that carnosine inhibits morphine-induced CPP in rats, and its action may be due to modulation of dopaminergic and glutaminergic activity. The study suggests that carnosine has potential as a new anti-addictive drug.     

Repeated paired-testing impairs extinction of morphine-induced conditioned place preference dependent on the inter-test interval in rats

Using exposure to morphine- and saline-paired sides alternatively as the extinction training procedure, we find that post-retrieval extinction training enhances or hinders the extinction of morphine-induced conditioned place preference (CPP) dependent on the retrieval-extinction training intervals. Here, we examine the influence of post-retrieval extinction training with repeated paired testing on extinction of morphine-induced CPP of rats. Our results demonstrate that paired-testing with a 10-min inter-test interval does not influence the extinction of CPP, while post-retrieval extinction training blocks the extinction of CPP with a 3-h retrieval-extinction interval. These results strongly indicate that the interval between exposure trials influences the outcome of exposure therapy in addiction treatment.     

Involvement of nitric oxide system in enhancement of morphine-induced conditioned place preference by agmatine in male mice

Agmatine recently has been suggested as a neurotransmitter, is able to interact with various effects of morphine like analgesia and dependence. In this study, the effects of agmatine on rewarding properties of morphine, and the possible involvement of nitric oxide (NO) system has been evaluated in an unbiased conditioned place preference (CPP) paradigm. Agmatine (1, 5 and 10 mg/kg, i.p.) alone induced neither CPP nor conditioned place aversion (CPA). Morphine (0.01, 0.05, 0.1 and 0.5 mg/kg, s.c.), while unable to show CPP or CPA, induced CPP in mice pretreated with agmatine. L-arginine (200 mg/kg, i.p.), a NO precursor, significantly enhanced the effect of agmatine (5 mg/kg) on morphine (0.5 mg/kg)-induced place preference. N^G-nitro-l-arginine methyl ester (l-NAME; 2.5 mg/kg, i.p.), a non specific nitric oxide synthase (NOS) inhibitor, and aminoguanidine (50 and 100 mg/kg, i.p.), a specific inducible NOS inhibitor, significantly reduced the effect of agmatine (5 mg/kg) on morphine (0.5 mg/kg)-induced place preference. These results suggest the possible involvement of inducible nitric oxide system in potentiating effects of agmatine on morphine-induced place preference.     

修治附子在吗啡诱导的大鼠条件性位置偏爱上的作用

目的: 探讨修治附子(PAT)在吗啡诱导的大鼠条件性位置偏爱(CPP)模型上的作用及其机制。方法: (1)40只SD大鼠分为5组(n=8):生理盐水组、吗啡组、吗啡+PAT处理1、2和3组。除生理盐水组外,其余4组连续8 d隔天交替皮下注射吗啡5 mg/kg或生理盐水建立CPP模型,并同时每日分别以蒸馏水或PAT(0.3或1.0或3.0g/kg)灌胃。(2)其余32只SD大鼠分为4组(n=8):吗啡组、nor-BNI(kappa受体拮抗剂)+吗啡组、吗啡+PAT组和nor-BNI+吗啡+PAT组。4组大鼠均采用上述方法建立CPP模型。各组大鼠均于吗啡注射前120 min皮下注射生理盐水或nor-BNI(5 mg/kg),PAT处理组每日PAT 3.0 g/kg灌胃,其余2组以蒸馏水灌胃。各组大鼠均于CPP训练前和训练后测定CPP值,训练后测定CPP值后取大鼠脑伏隔核并采用放射免疫法检测其所含强啡肽浓度。结果: (1)经CPP训练后,吗啡诱导引起了CPP值升高。(2)1.0或 3.0 g/kg的PAT剂量相关地降低了吗啡诱导引起的CPP升高(P<0.05)。(3)nor-BNI完全拮抗了PAT(3.0 g/kg)对吗啡CPP形成的抑制(P<0.05)。(4)PAT处理组大鼠脑伏隔核强啡肽的浓度比吗啡对照组高(P<0.05),也呈剂量相关。结论: PAT剂量相关地抑制吗啡诱导的CPP形成,具有抗成瘾作用,其抗成瘾作用可能与大鼠脑伏隔核强啡肽的浓度增加,从而激动kappa受体有关。     

Lesions of the medial prefrontal cortex prevent the acquisition but not reinstatement of morphine-induced conditioned place preference in mice

In order to further investigate the role of the mPFC in morphine reward and drug priming induced relapse, the present study examined the effects of the mPFC lesions on the acquisition and morphine priming induced reinstatement of conditioned place preference (CPP). In the first experiment, mice received sham or bilateral kainic acid lesions of the mPFC and were subsequently tested for the acquisition of a morphine-induced CPP. In the second experiment, each mouse received lesions of mPFC following the establishment of morphine-induced CPP. Nine days later, a priming injection of morphine was given (2 mg/kg, i.p.) to reinstate the extinguished CPP. The results showed that pre-conditioning lesions of the mPFC blocked the acquisition of morphine-induced CPP, while post-conditioning lesions of the mPFC failed to prevent morphine priming induced reinstatement of CPP. These results provide the first direct evidence that the mPFC may be involved in the acquisition, but not morphine priming induced reinstatement of CPP.     

Tramadol induces conditioned place preference in rats: Interactions with morphine and buprenorphine

Surveys and drug surveillance have demonstrated that the abuse liability of tramadol is considerably low in the general population but appears to be higher in opiate addicts, and this difference could attribute to the poly-drug abuse of opioid addicts, although this hypothesis has not been tested in the laboratory. The present study examined the interactions between tramadol and a full μ opioid receptor agonist morphine or a partial μ opioid receptor agonist buprenorphine in a conditioned place preference (CPP) paradigm in rats. Rats were conditioned with tramadol (2–54 mg/kg, i.p.), morphine (0.125–8 mg/kg, s.c.), buprenorphine (0.01–0.316 mg/kg, s.c.) or a combination of a subeffective dose of tramadol (2 mg/kg) with a subeffective dose of morphine or buprenorphine and the CPP effect was measured. The retention of CPP effect was also examined. Tramadol, morphine and buprenorphine all produced a dose-dependent and significant CPP. A smaller dose of tramadol (2 mg/kg) enhanced morphine- and buprenorphine-induced CPP and shifted the dose-effect curves of both drugs leftward. In addition, the combination of tramadol with morphine or buprenorphine prolonged the retention of CPP. These findings indicate that tramadol potentiates the rewarding effects of morphine or buprenorphine largely in an additive manner and support the general contention that tramadol has relatively low abuse liability.     

Morphine induces conditioned place preference behavior in histidine decarboxylase knockout mice

Pharmacological and lesion studies have shown that histamine exerts inhibitory effects on morphine-induced reward-seeking behavior. The present study was designed to further investigate the involvement of endogenous histamine in morphine-induced reward-seeking behavior using histidine decarboxylase gene knockout (HDC-KO) mice. Conditioned place preference (CPP) was present in both wild-type (WT) and HDC-KO mice treated with 5 or 10 mg/kg morphine. HDC-KO mice showed stronger morphine-induced CPP as compared with WT mice. Meanwhile, morphine significantly increased dopamine level in the VTA and NAc, especially in HDC-KO mice. However, the extinction of CPP is similar between WT and HDC-KO mice. Moreover, naloxone-precipitated withdrawal jumping was markedly decreased in HDC-KO mice. These results indicate that endogenous histamine inhibits the development, but not the extinction, of morphine-induced CPP and reduces morphine withdrawal sign, probably through modulating dopaminergic activity in the brain.     

Valproic acid sodium inhibits the morphine-induced conditioned place preference in the central nervous system of rats

The present study was performed to investigate the effects of valproic acid sodium (VPA), a widely utilized antiepileptic drug, on the establishment of chronic morphine-induced conditioned place preference (CPP). The rat model of morphine-induced CPP was conditioned with alternating intracerebroventricular (i.c.v.) injections of morphine (60 microg/6 microl) and saline for 5 days. To investigate the influence of VPA on morphine-induced CPP, rats received chronic pretreatment of i.c.v. VPA (500 microg/rat) 10 min previous to the daily morphine injection. The results demonstrated that the morphine-induced CPP was significantly attenuated by VPA pretreatment, while the VPA itself could not induce any CPP or conditioned place aversion (CPA) effects. The results of the present study not only confirmed the reliability of establishing morphine-induced CPP model by i.c.v. injection, but also suggest that the antiepileptic drug VPA may be utilized as potential therapeutic medications for drug abuse in the future.     

Oral methylphenidate establishes a conditioned place preference in rats

Emerging data suggest that illicit methylphenidate abuse is a growing problem. Although abuse of the drug typically occurs by the intranasal route, oral (per os; p.o.) methylphenidate also has abuse potential. The present study compared the effects of p.o. and intraperitoneal (i.p.) methylphenidate in rats using the conditioned place preference (CPP) procedure. Young adult male Sprague-Dawley rats were trained to consume oyster crackers injected initially with saline. Next, rats were randomly assigned to receive p.o. or i.p. methylphenidate (3 or 10mg/kg) or saline immediately or 30min prior to 30min conditioning trials. Methylphenidate or saline were each paired 4 times with an end compartment; preference for the methylphenidate-paired compartment was then assessed on a drug-free session. When given immediately prior to conditioning, significant CPP was obtained with both 3 and 10mg/kg of i.p. methylphenidate, but only with 10mg/kg of p.o. methylphenidate. When given 30min prior to conditioning, there was no evidence of CPP for any dose of i.p. or p.o. methylphenidate. These findings are the first demonstration that p.o. methylphenidate has rewarding effects, although i.p. methylphenidate is obtained at a 3mg/kg dose which did not establish CPP with p.o. administration. The lack of CPP following 30min pretreatment also suggests that conditioning may require the CS to be associated with a US of ascending, rather than descending, brain levels of methylphenidate. These results are consistent with clinical evidence of the reduced abuse liability of p.o. methylphenidate relative to methylphenidate taken by other (e.g., intranasal) routes.     

The role of vaginal stimulation for the acquisition of conditioned place preference in female Syrian hamsters

This study investigated the importance of vaginal stimulation on conditioned place preference by sexual behavior in female Syrian hamsters. Hormonally primed female hamsters given vaginal masks and topical lidocaine prior to conditioning sessions were no different in their place preference conditioning compared to female controls with no vaginal mask or lidocaine. Control females not provided a sexually active male did not show any preference for either compartment of the conditioning apparatus. These results suggest that stimuli, in addition to vaginal stimulation, are effective in producing a place preference during the mating experience in female hamsters.     

Nicotine-induced conditioned place preference in adolescent and adult rats

About 1 million American adolescents start smoking every year. Adolescents may be unusually sensitive to certain consequences of nicotine, demonstrating, for instance, significantly higher rates of dependence than adults at the same level of nicotine use. To explore whether adolescents may be more sensitive to rewarding properties of nicotine than adults, the present study used an animal model to assess the rewarding effects of a low nicotine dose (0.6 mg/kg) in a conditioned place preference (CPP) paradigm. Locomotor activity during conditioning and testing was also evaluated. Nicotine was observed to induce place preference conditioning in adolescent Sprague-Dawley rats, whereas the training dose of 0.6 mg/kg failed to produce convincing place preference in their adult counterparts. Age differences were also apparent in terms of nicotine influences on motor activity, with adults being more sensitive to nicotine-suppressant effects and only adolescents showing an emergence of nicotine-stimulatory effects upon repeated exposures. An increased predisposition to stimulatory nicotine effects during adolescence may contribute to age-specific rewarding properties of the drug as revealed using the CPP paradigm in this experiment. Increased sensitivity to stimulatory and rewarding effects during adolescence could potentially contribute to the high rate of nicotine use and dependence among human adolescents.     

Pre-treatment with high doses of cocaine decreases the reinforcing effects of cocaine in the conditioned place preference paradigm

The aim of the present study was to determine if pre-exposure to high doses of cocaine can subsequently alter the rewarding effects of this drug. Adult male mice received a pretreatment of physiological saline, or 12.5 or 25 mg/kg of cocaine (one injection a day for five days). After an interval of six days without injections, the rewarding effects of low doses of cocaine (0.5, 1 or 1.5 mg/kg) were evaluated in the conditioned place preference (CPP) paradigm. Doses of 1 and 1.5 mg/kg induced a clear CPP in animals pre-treated with saline but were ineffective in those pre-treated with 25 mg/kg of cocaine. Only the dose of 1.5 mg/kg induced CPP in mice pre-treated with 12.5 mg/kg of cocaine. Our results, which reveal a decrease in the conditioned rewarding effects of threshold doses of cocaine, demonstrate that exposure to high doses of this drug can alter the reward system.     

Intragastric infusion of glucose enhances the rewarding effect of sorbitol fatty acid ester ingestion as measured by conditioned place preference in mice

We investigated substances that induce a rewarding effect during the postingestive process using the conditioned place preference (CPP) test. Although mice showed high affinity for a low-energy fat substitute—sorbitol fatty acid esters and low-concentration linoleic acid solution—they did not exhibit a place preference toward a voluntary intake of fat substitute in the CPP test. However, during a conditioning session of CPP that involved intragastric administration of corn oil immediately before the intake of the fat substitute, the test mice displayed a place preference. Similarly, intragastric administration of glucose, galactose, and dextrin also induced CPP; however, fructose, mannose, and a nonmetabolized carbohydrate did not. These results suggest that administration of corn oil and glucose has the same postingestive effect with regard to inducing CPP and that the structural specificity of carbohydrates influences the postingestive effect.     

Kindling modifies morphine, cocaine and ethanol place preference

Brailowsky and Garcia (1999) proposed the existence of a relationship between epilepsy and addiction. To prove this hypothesis, pentylenetetrazol kindled rats were tested in the conditioned place preference (CPP) paradigm for their reaction to various addictive drugs with different modes of action (morphine, cocaine and ethanol). In separate experiments, locomotor activity and body temperature after application of the same drugs were tested in kindled and non-kindled rats. In the CPP experiment there were significant differences between both groups of rats. Non-kindled animals showed place preference to morphine (5.0 mg/kg) or cocaine (20.0 mg/kg). This reaction was abolished in the kindled rats. Moreover, control rats demonstrated aversion to 2.0 g/kg ethanol. However, ethanol aversion was not detectable in kindled rats. Moreover, there was no difference between non-kindled and kindled rats in locomotor activity and body temperature after morphine (1.0 and 5.0 mg/kg), cocaine (10.0 and 20.0 mg/kg), or ethanol (0.5 and 2.0 g/kg) application. This suggests alterations in reward systems as a consequence of kindling. It is hypothesised that GABAergic neurones in the ventral tegmental area might play a major role in the alterations found.     

Involvement of GABA(B) receptors of the dorsal hippocampus on the acquisition and expression of morphine-induced place preference in rats

In the present study, effects of intra-hippocampal CA1 (intra-CA1) injections of GABA(B) receptor agonist and antagonist on the acquisition and expression of morphine-induced place preference in male Wistar rats have been investigated. Subcutaneous administration of different doses of morphine sulphate (0.5-6 mg/kg) produced a dose-dependent conditioned place preference (CPP). Using a 3-day schedule of conditioning, it was found that the GABA(B) receptor agonist, baclofen (0.5-2 microg/rat; intra-CA1), or the GABA(B) receptor antagonist, phaclofen (1-3 microg/rat; intra-CA1), did not produce a significant place preference or place aversion. Intra-CA1 administration of baclofen (1 and 2 microg/rat; intra-CA1) decreased the acquisition of CPP induced by morphine (3 mg/kg; s.c.). On the other hand, intra-CA1 injection of phaclofen (1 and 2 microg/rat; intra-CA1) in combination with a lower dose of morphine (1 mg/kg) elicited a significant CPP. The response of baclofen (2 microg/rat; intra-CA1) was reversed by phaclofen (4 and 6 microg/rat; intra-CA1). Furthermore, intra-CA1 administration of baclofen but not phaclofen before testing significantly decreased the expression of morphine (3 mg/kg; s.c.)-induced place preference. Baclofen or phaclofen injections had no effects on locomotor activity on the testing sessions. It is concluded that the GABA(B) receptors in dorsal hippocampus may play an active role in morphine reward.     

Reducing hippocampal cell proliferation in the adult rat does not prevent the acquisition of cocaine-induced conditioned place preference

Neurogenesis is important for developing certain forms of memory. Recently, hippocampal cell proliferation has been implicated in the development of drug addiction, an extreme form of emotional/motivational pathological memory. Aiming to explore the role of hippocampal neural cell proliferation in cocaine-induced conditioned place preference (CPP), we treated rats with whole brain X-irradiation, which substantially decreases the number of progenitor cells in the subventricular zone of the lateral ventricles and subgranular zone of the dentate gyrus. Surprisingly, there was no difference in the expression of cocaine-induced CPP. These results suggest that the existing neural network, rather than potential new neural circuits mediated by adult neurogenesis, is sufficient for the acquisition of cocaine-induced CPP.     

Peripubertal stress of male,but not female rats increases morphine-induced conditioned place preference and locomotion in adulthood

Animal studies demonstrate that peripubertal social stress markedly increases the risk for subsequent substance use in adulthood. However, whether non-social stress has a similar long-term impact is not clear, and whether male and female animals show different sensitivity to peripubertal non-social stress has not been examined. In the present study, we addressed these issues by introducing two non-social stressors (elevated platform and predator odor 2,5-Dihydro-2,4,5-trimethylthiazoline) to male and female Wistar rats during adolescence (postnatal days 28–30, 34, 36, 40, and 42), then tested reward-related behaviors during adulthood, including morphine-induced conditioned place preference (CPP, 1 mg/kg morphine or 5 mg/kg morphine) and hyperlocomotor activity (5 mg/kg morphine). We found that adult male rats, but not females who were exposed to peripubertal non-social stressors showed enhanced morphine-induced CPP. Moreover, morphine-induced increase in locomotor activity was also significantly increased in adult male rats, but not in females. These results indicate that peripubertal exposure to repeated non-social stress may enhance sensitivity to the rewarding effects of opioids in adulthood in a sex-dependent manner, with males being even more sensitive than females in this regard.     

Expression of morphine-conditioned place preference is more vulnerable than naloxone-conditioned place aversion to disruption by nociceptin in mice

The opioid peptide nociceptin (orphanin FQ) suppresses the incentive and rewarding properties of drugs. Thus, targeting the nociceptin system may be beneficial in treating drug addiction. The effects of nociceptin (0–1.5 nmol intracerebroventricular) on the expression of morphine- (6 mg/kg subcutaneous) and naloxone-(6 mg/kg subcutaneous) induced place conditioning were examined in mice. Whereas doses of 0.5 nmol nociceptin and above disrupted expression of morphine-conditioned place preference (CPP), naloxone-conditioned place aversion (CPA) remained intact at all doses of nociceptin tested. Doses of 0.5 nmol nociceptin and above suppressed locomotion, though this appeared unrelated to the expression of place conditioning. These results suggest that nociceptin more potently blocks the ability of reward-associated cues than aversion-associated cues to influence behavioral biases.     

18-Methoxycoronaridine blocks acquisition but enhances reinstatement of a cocaine place preference

The iboga alkaloid congener, 18-methoxycoronaridine (18-MC), decreases self-administration of multiple drugs of abuse. Here, in a biased procedure, we investigated whether 18-MC would have a similar effect on the acquisition, expression and reinstatement of a cocaine conditioned place preference (CPP) in male Sprague-Dawley rats. While 18-MC attenuated acquisition of a cocaine CPP, it had no effect on CPP expression, and enhanced the reinstatement of cocaine CPP following extinction. Our results are consistent with those obtained using ibogaine, but reinforce the notion that acquisition, expression and reinstatement of a CPP likely involve separate mechanisms.