Nociceptin inhibits acquisition of amphetamine-induced place preference and sensitization to stereotypy in rats

Nociceptin (also called orphanin FQ), a 17-amino-acid peptide, is the natural ligand of the nociceptin opioid peptide (NOP) receptor. This peptide shows similarities, in its structure, to opioid peptides, mainly to dynorphin A. However, unlike opioid peptides, it does not produce a conditioned place preference or aversion but inhibits rewarding effect of drugs of abuse. The present study was designed to examine the ability of nociceptin to block the acquisition of amphetamine-induced place preference, and the development of amphetamine-induced sensitization to stereotypy in rats. Our experiments indicated that repeated administration of nociceptin at increasing doses during conditioning significantly attenuated the reinforcing effect of amphetamine in conditioned place preference paradigm. Nociceptin did not change the acute effect of amphetamine-induced stereotypy but prevented the development of sensitization to stereotypy measured on the challenge day. Our results suggest the involvement of nociceptin in long-lasting neuronal adaptation after repeated amphetamine treatment.     

Effect of imipramine on the expression and acquisition of morphine-induced conditioned place preference in mice

The effect of imipramine and alpha-adrenoceptor agonists and antagonists on the acquisition or expression of morphine-induced conditioned place preference (CPP) was studied in mice. An unbiased CPP paradigm was used to study the effect of the agents. In the first set of experiments, the drugs were used during the development of CPP by morphine or they were used alone in order to see if they induce CPP or conditioned place aversion (CPA). Our data showed that intraperitoneal injection of morphine sulphate (2.5-10 mg/kg) induced CPP in mice. Imipramine (0.5-2.5 mg/kg), phenylephrine (0.5-2 mg/kg), yohimbine (0.5-2 mg/kg) or prazosin (0.1-1 mg/kg) did not influence CPP, but clonidine (0.002-0.05 mg/kg) induced CPA. Yohimbine increased, while clonidine and prazosin reversed, morphine-induced CPP. Phenylephrine did not influence the CPP induced by morphine. In the second set of experiments, when the drugs were used before testing on Day 6, in order to test their effects on the expression of morphine-induced CPP, imipramine (0.5-5 mg/kg) reversed morphine-induced CPP and this reversal was blocked by naloxone (2 mg/kg). Clonidine and prazosin reversed, while yohimbine decreased morphine-induced CPP. Phenylephrine did not alter the morphine response. Furthermore, yohimbine and prazosin reversed the imipramine effect. None of the drugs influenced locomotion. However, prazosin or yohimbine in combination with morphine altered locomotor activity during the acquisition of CPP. Yohimbine by itself increased locomotion. It is concluded that imipramine can induce CPA through an opioid receptor mechanism and alpha-adrenoceptor agents may influence morphine CPP.     

Transient inactivation of the nucleus accumbens reduces both the expression and acquisition of morphine-induced conditioned place preference in rats

In the present study, the effects of transient inhibition of the shell and core parts of the nucleus accumbens by lidocaine on the expression and acquisition of morphine-induced conditioned place preference in male Wistar rats were investigated. In addition, the number of bouts of sniffing, rearing, and compartment crossing was scored. Lidocaine hydrochloride was injected into different parts of the nucleus accumbens 5 min before each morphine session for the transient inhibition of particular anatomical regions. Subcutaneous (s.c.) injection of morphine (2.5 and 5 mg/kg) induced place preference. Transient inhibition of the left and/or right side of the shell part of nucleus accumbens reduced morphine place conditioning. However, when both sides of the nucleus were inhibited, inhibition was weaker when compared to the results when only one side was inhibited. Also, the number of compartment crossings in these animals reduced significantly. Nevertheless, the number of rearing occurrences was reduced only when both sides of the shell part of the nucleus accumbens were inhibited. In contrast, the number of sniffing bouts increased in all three groups. The results for the core part of the nucleus accumbens also indicated that place preference was inhibited after transient inhibition of the left, right, and both sides. However, although the number of total compartment crossings was reduced in all experimental groups, the reduction was not statistically significant. The data obtained was similar to the number of rearings, yet the number of sniffing bouts increased in the experimental groups compared to the control. In conclusion, these results confirmed the involvement of the left and right sides and core and shell parts of the nucleus accumbens in morphine place conditioning.     

Brief exposure to a mild stressor enhances morphine-conditioned place preference in male rats

Rationale Exposure to moderate tail shock [3, 0.75 s, 1 mA, 20 s interstimulus interval (ISI)] can enhance pain reactivity (hyperalgesia) in rats. This hyperalgesia reflects an unconditioned response that transfers across contexts and is associated with enhanced Pavlovian fear conditioning to aversive unconditioned stimuli (US). It is possible that moderate shock also enhances learning about appetitive stimuli such as a reinforcing drug.Objectives The present study examined the effect of moderate shock exposure on unconditioned psychomotor activation and appetitive conditioning using a morphine place-preference task.Methods During training, rats were given moderate shock or restraint and then received subcutaneous morphine at one of four doses (0.0, 0.2, 1.0, or 5.0 mg/kg) and were transferred to a conditioning apparatus. Five hours later, animals were given discrimination training in a different context. Animals received 2 days of training, each separated by a day of testing for preference. To test the impact of shock on psychomotor activation, subjects were given shock or restraint and one of two doses of morphine (0.0 mg/kg or 5.0 mg/kg) and placed in a box to monitor activity.Results Vehicle-treated shocked rats showed a conditioned place aversion. Subjects that received morphine showed a dose-dependent place preference that was facilitated by moderate shock exposure. Shock also enhanced the motor activation produced by morphine.Conclusions These results indicate that the affective state produced by moderate shock has a negative valence that is sufficient to support a conditioned place aversion. This state is associated with a general sensitization that enhances processing of appetitive US.     

Effects of dopamine receptor antagonists on the acquisition of ethanol-induced conditioned place preference in mice

Rationale

Studies support differential roles of dopamine receptor subfamilies in the rewarding and reinforcing properties of drugs of abuse, including ethanol. However, the roles these receptor subfamilies play in ethanol reward are not fully delineated.

Objective

To examine the roles of dopamine receptor subfamilies in the acquisition of ethanol-induced conditioned place preference (CPP), we pretreated animals systemically with antagonist drugs selective for dopamine D1-like (SCH-23390) and D2-like (raclopride) receptors prior to ethanol conditioning trials.

Methods

Effects of raclopride (0–1.2 mg/kg) and SCH-23390 (0–0.3 mg/kg) on the acquisition of ethanol-induced CPP were examined in DBA/2J mice (experiments 1 and 2). Based on significant effects of SCH-23390, we then determined if SCH-23390 (0.3 mg/kg) produced a place preference on its own (experiment 3). To evaluate whether SCH-23390 impaired learning, we used a conditioned place aversion (CPA) paradigm and pretreated animals with SCH-23390 (0–0.3 mg/kg) before conditioning sessions with LiCl (experiment 4).

Results

Whereas raclopride (0–1.2 mg/kg) did not affect acquisition, SCH-23390 (0.1–0.3 mg/kg) impaired the development of ethanol-induced CPP. SCH-23390 (0.3 mg/kg) did not produce place preference when tested alone and SCH-23390 (0.1–0.3 mg/kg) did not perturb the acquisition of LiCl-induced CPA.

Conclusions

Our results support a role for dopamine D1-like but not D2-like receptors in ethanol’s unconditioned rewarding effect as indexed by CPP. Blockade of D1-like receptors did not affect aversive learning in this procedure.     

Effects of beta-funaltrexamine and naloxonazine on single-trial morphine-conditioned place preference and locomotor activity

The current study assessed the ability of the selective irreversible mu-opioid receptor antagonists beta-funaltrexamine (betaFNA) and naloxonazine (NALZ) to alter the locomotor and rewarding effects of a single intravenous injection of morphine using the conditioned place preference (CPP) model. In the first experiment, rats were conditioned with a single injection of morphine (10 mg/kg iv) paired with one compartment of a CPP apparatus and then were tested for CPP at either 1 or 7 days after conditioning. Rats showed hypoactivity following acute morphine on the conditioning trial and showed CPP when tested either 1 or 7 days later. In the next experiments, rats were pretreated with betaFNA (20 mg/kg sc, 20 h before conditioning), NALZ (15 or 30 mg/kg sc, 24 h before conditioning) or saline and then were conditioned with a single injection of morphine (10 mg/kg iv) or saline. Pretreatment with NALZ alone, but not betaFNA, significantly decreased locomotor activity; neither antagonist alone produced a significant shift in preference for either compartment of the CPP apparatus. Pretreatment with either betaFNA or NALZ blocked completely morphine-induced hypoactivity, but neither antagonist had a significant effect on morphine CPP. These results indicate that mu-opioid receptors are more critically involved in acute morphine-induced hypoactivity than in acute morphine reward.     

Nicotine-induced conditioned place preference in adolescent rats

A number of clinical reports have noted that women are more vulnerable to tobacco abuse than men, and adolescent females are especially vulnerable to nicotine addiction. Conditioned place preference (CPP) is a widely used technique for determining the rewarding effects of drugs with abuse potential in animal models. Several studies have reported that nicotine was ineffective in eliciting CPP in rats; while others have observed conditioned place aversion (CPA) rather than preference for nicotine. One recent investigation established CPP in adolescent female rats, however at a reasonably high dose; while a second reported dose dependence of nicotine-induced CPP in male but not female rats. The present study was designed to determine the lowest dose necessary to induce CPP to nicotine in adolescent female rats. Nicotine-induced CPP was obtained at a subcutaneous dose of 0.03 mg/kg (salt content) using a biased conditioning paradigm. Higher doses produced aversion and lower doses provided no rewarding or aversive effects. CPP persisted for at least 3 weeks following conditioning in the absence of further nicotine treatment. In contrast with results from adolescent human females and males, age-matched male rats also evidenced CPP at this very low dose of nicotine. These results indicate that even a low dose of nicotine is reinforcing and addicting in both adolescent male and female rats and brings into question the suggestion that nicotine induces greater addicting capacity in adolescent girls than boys.     

The effects of nitric oxide on the acquisition and expression of nicotine-induced conditioned place preference in mice

In the present study, the possible role of nitric oxide on the conditioned place preference (CPP) induced by nicotine in mice was investigated. Intraperitoneal (i.p.) injections of nicotine (1 mg/kg) and the nitric oxide (NO) precursor, L-arginine (200 and 500 mg/kg), produced significant place preference. However, injection of mecamylamine (0.05 and 0.1 mg/kg; i.p.) or the NO synthase (NOS) inhibitor, L-Nitro-amino-methyl-ester, L-NAME (5-20 mg/kg; i.p.), had no effect. Ineffective doses of nicotine in combination with ineffective doses of L-arginine produced significant place preference. Administration of L-arginine (50, 100 and 150 mg/kg; i.p.) on the test day reduced the expression of nicotine-induced place preference. Nicotine injection (0.25, 0.5 and 0.75 mg/kg) on the test day reduced the expression of place preference induced by L-arginine, while both mecamylamine (0.05 and 0.1 mg/kg) and L-NAME (5, 10 and 20 mg/kg) inhibited the acquisition of place preference induced by nicotine (1 mg/kg) and L-arginine (200 mg/kg). Moreover, neither of the antagonists reduced the expression of nicotine- or L-arginine-induced place preference. It is suggested that nitric oxide may play an important role in nicotine-induced place preference.     

Role of withdrawal in reinstatement of morphine-conditioned place preference

Rationale Relapse is a major characteristic of drug addiction and the primary problem in treating drug abuse. Based on the negative reinforcement view of addiction, in which the motivation to take drugs is thought to result from the desire to avoid the aversive effect of drug withdrawal, it has been theorized that withdrawal symptoms play a major role in the maintenance of and relapse to drug taking. However, the role of withdrawal in relapse has not yet been systemically investigated in the reinstatement model. Objectives Using a conditioned place preference (CPP) paradigm, we examined the role of different morphine withdrawal states (spontaneous withdrawal, naloxone-precipitated withdrawal, and conditioned withdrawal) in relapse to drug seeking. Methods Rats alternately received morphine (10 mg/kg, s.c.) and saline for 8 days to acquire the CPP. The morphine CPP disappeared after a 2-week extinction phase of saline-paired training. Rats were then chronically administered morphine to induce physical dependence. The different withdrawal states were induced and their roles in the reinstatement of extinguished CPP were assessed. During conditioned withdrawal, trunk blood samples were taken and the corticosterone level was measured by radioimmunoassay. To examine the role of corticotropin-releasing factor (CRF) receptor antagonist on conditioned-withdrawal-induced reinstatement of CPP, different doses of α-helical CRF (0.1 and 1 μg, i.c.v.) were administered 30 min prior to the CPP testing. Results The results show that morphine spontaneous withdrawal and naloxone-precipitated morphine withdrawal were ineffective in reinstating morphine CPP. However, the withdrawal cues significantly elicited the reinstatement of CPP and increased corticosterone level. Moreover, pretreatment with the CRF receptor antagonist α-helical CRF (1 μg, i.c.v.) significantly attenuated the effects of withdrawal cues on reinstatement of CPP and corticosterone levels. Conclusion These findings demonstrate that the cues associated with previous drug withdrawal play a major role in drug relapse and that activation of the CRF receptor is involved in conditioned-withdrawal-induced reinstatement. The present study suggests that CRF receptor antagonists might be of value in the treatment and prevention of relapse to drug seeking after long-term abstinence. Xin Ge and Wen Yue contributed equally to this work.     

Concentration-dependent conditioned place preference to inhaled toluene vapors in rats

OBJECTIVES: Toluene is present in many commercial products and is subject to abuse by inhalation. The goal of this study was to extend previous reports indicating that rats will exhibit a positive conditioned place preference to inhaled toluene vapors and to determine the dose-response relationship for inhaled toluene in terms of exposure concentration and number of exposures. For the conditioned place preference experiments rats were exposed to toluene vapors at concentrations of 800, 2000, 3000 or 5000 ppm in one compartment of a three-compartment box. RESULTS: Following six conditioning sessions with toluene, a significant place preference was obtained at 2000 and 3000 ppm, but not at 800 or 5000 ppm. Extending the number of toluene pairings at the 2000 and 3000 ppm concentration to 12 significantly enhanced the place preference compared to that at six pairings. CONCLUSIONS: These experiments extend our previous finding that rats will show a conditioned place preference to inhaled toluene, and indicate that a reinforcing "dose" of toluene depends on both the concentration and number of pairings.     

Effects of nicotine and epibatidine on locomotor activity and conditioned place preference in rats

We studied the effects of nicotine and epibatidine given s.c. acutely and repeatedly, on locomotor activity and conditioned place preference (CPP) in rats. Nicotine at 0.5 mg/kg immediately and at 0.8 mg/kg after a delay increased the locomotor activity and its locomotor stimulant effects were greatly sensitized (about fourfold) when it was given repeatedly. Acute epibatidine at 0.6 and 3.0 microg/kg increased the activity modestly after a delay. When given repeatedly epibatidine's stimulant effects, mainly those at 3.0 microg/kg, were somewhat sensitized (less than twofold). Nicotine at 0.5 and 0.8 mg/kg produced CPP in rats in a biased paradigm. Epibatidine elicited CPP at very low dose (0.1 microg/kg), but at 0.3 or 0.6 microg/kg it induced neither preference nor aversion and at the 3.0 microg/kg dose it was aversive. Both acutely and after the repeated administration, epibatidine enhanced the locomotor activity of rats clearly less than nicotine agreeing with its previously reported lesser effects on accumbal dopamine output. Thus, while nicotine elicits CPP at doses (0.5 and 0.8 mg/kg) equal to those that increase accumbal dopamine output and locomotor activity, epibatidine seems to be aversive at the dose (3.0 microg/kg) that enhances accumbal dopamine output and increases locomotor activity.     

Effects of oxazepam on methamphetamine-induced conditioned place preference

Our laboratory has been investigating the role for the hypothalamo-pituitary-adrenal (HPA) axis and benzodiazepines in the behavioral effects of cocaine for several years now. The following represents our initial investigation of the influence of benzodiazepines on methamphetamine reward using conditioned place preference. In these experiments, methamphetamine (0.5 mg/kg ip) resulted in a robust conditioned place preference that was attenuated when the rats were pretreated with oxazepam (10 mg/kg ip) on the day of preference testing. These data suggest a potential role for benzodiazepines in the behavioral effects of methamphetamine. Additional research will be necessary to determine if the nature of these effects is similar with what has been observed with cocaine.     

Effects of carnosine on morphine- induced conditioned place preference in Sprague -Dawley rats

Carnosine （ - alanyl - L - histidine）, a natural occurring dipeptide, presents in muscle and brain of mammals in high concentrations. Carnosine serves as a reservoir for histidine, which is a precursor of histamine. The study was to investigate the effects of carnosine on reward - seeking behavior were in Sprague - Dawley rats, The model of CPP was used to assess the rewarding effect of morphine. The levels of histidine, histamine, dopamine （DA） and 3, 4 - dihydroxyphenylacetic acid （DOPAC） in rat brain were measured with high - performance liquid chromatography. I. p. injection of earnosine （200, 500, 1000mg/kg. ） significantly inhibited morphine - induced conditioned place preference in a dose - dependent manner. Carnosine （ 1000mg/kg, i. p. ） caused a significant increase of histidine and histamine levels it, the ventral tegmental area （VTA） and nucleus accumbens （NAc）. In addition, carnosine significantly decreased DA and levels as well as DOPAC/DA ratios in the VTA and NAc. These results indicate that carnosine can inhibit the development of morphineinduced reward -seeking behavior, and its inhibition may be mediated by histaminergic pathway. The study suggests that carnosine may be approached as a novel therapeutic agents for drug addiction instead of histamine.     

Effects of scopolamine and ketamine on reconsolidation of morphine conditioned place preference in rats

Persistent memory associated with addictive drugs contributes to the relapse of drug abuse. The current study was conducted to examine the effects of scopolamine and ketamine on reconsolidation of morphine-induced conditioned place preference (CPP). In experiment 1, after morphine CPP was acquired, rats were injected with ketamine (60 mg/kg, intraperitoneally) and scopolamine (2 mg/kg, intraperitoneally), respectively, after reexposure to an earlier morphine-paired context or in their home cages. The CPP was reassessed 24 and 48 h after reexposure. An additional group of rats received saline following reexposure to the earlier morphine-paired context. In experiment 2, two groups of rats were only given saline during the CPP training and subsequent administration of ketamine or scopolamine during the reexposure. In experiment 1, rats failed to exhibit morphine CPP when ketamine and scopolamine were administered only after reexposure to a morphine-paired context. CPP was not abolished by ketamine or scopolamine administration in the animals' home cages. Also, the animals receiving only saline injections showed strong morphine CPP 24 h after a short exposure to the morphine-paired context. In experiment 2, ketamine or scopolamine treatment alone did not induce CPP or aversion. Administration of scopolamine and ketamine, after reexposure to a drug-paired context, resulted in the disruption of morphine CPP, suggesting the potential effects of scopolamine and ketamine in disrupting memory associated with environmental cues and addictive drugs.     

Effects of periadolescent versus adult cocaine exposure on cocaine conditioned place preference and motor sensitization in mice

Rationale Age of initial exposure to addictive substances is inversely proportional to risk of developing drug dependence. There is debate, however, as to whether intake at a young age causes dependency or whether young people who experiment with addictive substances are predisposed to dependency by other factors.Objectives We tested the relationship between cocaine exposure at two different ages in mice and the development of subsequent drug-seeking behavior to test for age-specific exposure effects.Methods We performed dose-response analysis of cocaine conditioned place preference (CPP) and locomotor activity in periadolescent and adult C57Bl/6J mice. In addition, we pretreated periadolescent and adult C57Bl/6J mice with cocaine or saline in the home cage or a drug-associated context, and then examined their behavior in a biased CPP procedure in adulthood.Results Dose-response relationships were similar between the two age groups. In the pretreatment experiments, we observed locomotor sensitization during the pretreatment in periadolescent but not adult mice. We also observed an enhanced aversion to the non-preferred side of the chamber in periadolescent mice compared to adult mice, which was alleviated by cocaine association with that side. Third, we observed that after further conditioning in adulthood, there were no pretreatment-specific effects.Conclusions Our results are consistent with a vulnerable brain hypothesis for responses to cocaine based on our findings that periadolescent mice exhibit greater locomotor sensitization to cocaine, and greater baseline anxiety responses that are alleviated by cocaine exposure compared to adult mice.     

Agmatine attenuates methamphetamine-induced conditioned place preference in rats

The polyamine agmatine modulates a variety of behavioral effects including the abuse-related effects of opioids and has been proposed as a potential medication candidate for the treatment of opioid abuse. However, little is known of the effects of agmatine on the abuse-related effects of other drugs of abuse. This study examined the effects of agmatine on the rewarding effects of methamphetamine in rats using a conditioned place preference paradigm. Methamphetamine (0.1-1.0mg/kg) dose-dependently increased the time spent in methamphetamine-paired side (place preference). Agmatine, at doses that did not produce place preference or aversion (10-32mg/kg), significantly decreased the development of methamphetamine-induced place preference when agmatine was administered in combination with methamphetamine during place conditioning. Agmatine also significantly decreased the expression of methamphetamine-induced place preference when an acute injection of agmatine was given immediately before test session. These doses of agmatine do not alter the motor activity in rats, suggesting that the observed attenuation of methamphetamine-induced place preference was not due to general behavioral disruption. Together, these data suggests that agmatine attenuates the rewarding effects of methamphetamine and may be able to modulate the abuse liability of methamphetamine.     

Clonidine produces a conditioned place preference in rats

The possibility that the -adrenergic agonist clonidine can act as a reinforcing agent was investigated using the conditioned place preference paradigm. Using two different variants of this method we were able to demonstrate reinforcing properties of clonidine at doses of 200 and 400 g/kg. These results are consistent with those obtained by other investigators using the self-administration technique, and support the view that adrenergic mechanisms may be involved in reinforcement.     

Dimenhydrinate produces a conditioned place preference in rats

Dimenhydrinate (DMH; trade names Gravol and Dramamine) is a compound of diphenhydramine (DP) and 8-chlorotheophylline in equimolar ratios. DMH has been reported to be abused by humans for its euphoric and hallucinogenic properties but few studies have evaluated its reinforcing effects in animals. To evaluate the hypothesis that DMH and its constituents DP and 8-chlorotheophylline are rewarding in animals, rats were tested for conditioned place preference (CPP). The paradigm consisted of pre-exposure (three 15-min sessions of access to both sides of the chamber), conditioning [eight 30-min pairings of one side with drug (four sessions) and, on alternate days, the other side with vehicle (four sessions)] and test phases (three 15-min sessions of access to both sides of the chamber). Significant preferences for the drug-paired location were found on test session one after conditioning with 60.0, but not 25.0, 40.0 or 50.0 mg/kg of DMH, and after conditioning with 37.8 but not 27.0 or 32.4 mg/kg of DP. No preference was found after conditioning with 23.0, 27.6 or 32.2 mg/kg of 8-chlorotheophylline. All three drugs stimulated locomotor activity during conditioning sessions and DMH and DP showed sensitization over conditioning sessions. DMH doses that showed sensitization (25.0 and 40.0 mg/kg) were lower than the dose (60.0 mg/kg) that produced a CPP revealing a dissociation of locomotor stimulating versus rewarding effects. Results reveal that DMH and DP have rewarding properties, although the molar equivalent dose-response curve for DP appeared to be further to the right than that for DMH. Future investigations into the neurotransmitter systems modulating this effect are awaited.     

Sexual experience and conditioned place preference in male rats

We have previously shown that sexual behavior induces a reward state, as evaluated by conditioned place preference (CPP), only when males or females are able to control the rate of sexual interaction. In the present experiment, we evaluated if male rats that are repeatedly tested in a situation in which they are not able to control the sexual interaction eventually develop CPP. Three groups of sexually na?ve male rats were used. One group never mated. A second group was tested once a week for 10 consecutive weeks in a chamber in which they controlled the rate of the sexual interaction. The third group was mated for the same number of weeks in a chamber in which the female, but not the male, controlled mating. The three groups were then tested for CPP. Only the group able to control the sexual interaction developed CPP. The group that had no control over the rate of the sexual interaction did not develop CPP even after 10 tests in which they consistently displayed sexual behavior. These results suggest that an estrous female and/or sexual behavior are powerful incentives that maintain mating even if the rewarding properties of the incentive are reduced.     

Inhibitory effects of paeonol on morphine-induced locomotor sensitization and conditioned place preference in mice

The inhibitory effects of paeonol, a major compound of Paeoniae radix, on the development of locomotor sensitization, conditioned place preference (CPP) and dopamine receptor supersensitivity induced by the repeated administration of morphine were investigated through behavioral experiments. A single administration of morphine produces hyperlocomotion. Repeated administration of morphine develops sensitization (reverse tolerance), a progressive enhancement of locomotion, which is used as a model for studying the drug-induced drug-seeking behaviors, and CPP, which is used as a model for studying drug reinforcement. Paeonol inhibited morphine-induced hyperlocomotion, sensitization and CPP. In addition, paeonol inhibited the development of postsynaptic dopamine receptors supersensitivity, which may be an underlying common mechanism that mediates the morphine-induced dopaminergic behaviors such as sensitization and CPP. Apomorphine (a dopamine agonist)-induced climbing behaviors also were inhibited by a single direct administration of paeonol. These results provide evidence that paeonol exerts anti-dopaminergic activity, and it is suggested that paeonol may be useful for the prevention and therapy of these adverse actions of morphine.