Morphine-induced place conditioning is not confounded by drug-induced alterations in locomotor activity

The influence of locomotor activity and environmental familiarity upon the reinforcing effects of morphine was examined in an unbiased place preference conditioning procedure. Groups of rats were trained to associate one distinctive environment with morphine and another with saline. One group was made tolerant to the locomotor activity effects of morphine by the SC administration of morphine (5.0 mg/kg/12 hr) for four days prior to conditioning. The other group received injections of saline. Administration of morphine, at doses which decreased locomotor activity, resulted in marked preferences for the drug-associated place in saline-treated rats. In contrast, chronic morphine treatment resulted in tolerance to the sedative effects of morphine and an abolition of the morphine-induced place preference. These results indicate that in the place conditioning procedure, measures of reinforcement are not confounded by drug-induced increases in activity.     

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.     

The role of alpha-adrenoceptor mechanism(s) in morphine-induced conditioned place preference in female mice

It has been shown that the alpha-adrenergic system is involved in some effects of opioids, including analgesia and reward. Gender differences also exist between males and females in response to alpha-adrenergic agents. This study was designed to determine the effects of alpha-adrenoceptor agonists and antagonists on the acquisition or expression of morphine-induced conditioned place preference (CPP) in female mice. The experiments showed that subcutaneous injections of morphine (0.5-8 mg/kg) induced CPP in a dose-dependent manner in mice. Intrapritoneal administration of the alpha-1-adrenoceptor agonist, phenylephrine (0.03, 0.1 and 0.3 mg/kg), and alpha-2 adrenoceptor agonist, clonidine (0.0001, 0.0005 and 0.001 mg/kg), as well as alpha-1-adrenoceptor antagonist, prazosin (0.01, 0.05 and 0.1 mg/kg) or alpha-2 adrenoceptor antagonist, yohimbine (0.005, 0.01 and 0.05 mg/kg) did not induce motivational effects and also did not alter locomotor activity in the animals. In the second set of experiments, the drugs were used before testing on Day 5, to test their effects on the expression of morphine-induced CPP. Intrapritoneal administration of phenylephrine and clonidine decreased the expression of morphine-induced CPP. In contrast, after application of prazosin or yohimbine, the expression of morphine-induced CPP was increased. Administration of lower (0.03 mg/kg) and higher doses of phenylephrine (0.1 and 0.3 mg/kg) during acquisition of morphine CPP decreased and increased the morphine CPP, respectively. Similarly, the administration of prazosin and clonidine decreased while yohimbine increased the morphine CPP. It may be concluded that alpha-adrenoceptor mechanism(s) influence morphine-induced CPP in female mice.     

GABA(A) receptors of hippocampal CA1 regions are involved in the acquisition and expression of morphine-induced place preference.

In the present study, the effects of bilateral intra-hippocampal CA1 (intra-CA1) injections of GABA(A) receptor agonist and/or antagonist on the acquisition and expression of morphine-induced place preference in male Wistar rats have been investigated. The conditioning treatments with subcutaneous (s.c.) injections of different doses of morphine (0.5-7.5 mg/kg) induced a conditioned place preference (CPP) for the drug-associated place in a dose-dependent manner. Intra-CA1 administration of the GABA(A) receptor agonist, muscimol (0.25, 0.5 and 1 microg/rat) significantly inhibited the morphine (5 mg/kg, s.c.)-induced CPP. Intra-CA1 injections of different doses of the GABA(A) receptor antagonist, bicuculline (0.25, 0.5 and 1 microg/rat), in combination with an ineffective dose of morphine (0.5 mg/kg, s.c.) elicited a significant CPP. However, muscimol or bicuculline by themselves did not elicit any effect on place conditioning. Furthermore, the muscimol-induced inhibition of morphine response was reversed by bicuculline (1 microg/rat, intra-CA1) administration. On the other hand, the bilateral intra-CA1 injections of muscimol (0.25, 0.5 and 1 microg/rat) or bicuculline (0.5, 1 and 2 microg/rat) significantly decreased the expression of morphine-induced CPP. Intra-CA1 administration of different doses of muscimol or bicuculline had no effect on locomotor activity in the testing phase. Our data indicated that the GABA(A) receptors of the hippocampal CA1 regions may play an important role in the acquisition and expression of morphine-induced place preference.     

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.     

Chronic naltrexone supersensitizes the reinforcing and locomotor-activating effects of morphine

Rats were implanted for 10 days with a slow-release naltrexone pellet and then the pellet was removed. Sham-control animals were treated similarly, except no pellet was implanted. One day after pellet removal or sham treatment, animals were assessed for morphine-induced conditioned place preference (CPP) or locomotor activity. CPP was evident in sham animals following two conditioning trials using 5 mg/kg subcutaneous morphine (Experiment 1) and following one conditioning trial using 8 mg/kg intravenous morphine (Experiment 2). Animals conditioned while implanted with a naltrexone pellet showed no morphine-induced CPP. More important, one day after pellet removal, naltrexone-pretreated animals given one conditioning trial with 5 mg/kg intravenous morphine displayed a greater preference for morphine-associated cues relative to sham animals given morphine (Experiment 3 and 4). This single IV morphine dose was insufficient to produce CPP in sham animals, suggesting that naltrexone-induced supersensitization may only be evident at a morphine dose below the reinforcing threshold in control animals. Further, chronic naltrexone potentiated the locomotor-activating effect of 2 mg/kg subcutaneous morphine but not of either 1 or 5 mg/kg morphine (Experiment 5). Behavioral supersensitization assessed by morphine-induced locomotor activation was transient, as it was evident one day, but not either three or 10 days following pellet removal (Experiment 6). These results confirm the functional significance of opiate receptor up-regulation following chronic opioid blockade.     

Involvement of dopamine D2 receptors of the central amygdala on the acquisition and expression of morphine-induced place preference in rat

In the present study, the effects of intra-central amygdala (CeA) injections of dopamine (DA) D2-like 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 (0.5-10 mg/kg) produced a dose-dependent conditioned place preference (CPP). Using a 3-day schedule of conditioning, it was found that the DA D2/D3 receptor agonist, quinpirole (0.3-3 microg/rat), or the DA D2 receptor antagonist, sulpiride (0.04-5 microg/rat), did not produce a significant place preference or place aversion. Intra-CeA administration of quinpirole (0.3 and 1 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited a significant CPP. On the other hand, quinpirole (0.3 microg/rat) injection into the CeA induced CPP in combination with the lower doses of morphine (0.5 and 2.5 mg/kg), but decreased the response of higher dose (7.5 mg/kg) of morphine. This response of quinpirole was attenuated by sulpiride (0.2 microg/rat). Sulpiride by itself (0.04-5 microg/rat) reduced the acquisition of morphine (7.5 mg/kg)-induced place preference. The administration of the higher dose of sulpiride (1 and 5 microg/rat) or the higher dose of quinpirole (3 microg/rat) during acquisition decreased the locomotor activity of the animals on the testing days. The injection of the low dose of quinpirole (0.3 microg/rat) on the test day reduced the expression of morphine-induced CPP, but the high dose of quinpirole (3 microg/rat) potentiated this expression. The administration of sulpiride (5 microg/rat) attenuated the quinpirole response. The injection of sulpiride (1 and 5 microg/rat) abolished the expression of morphine-induced CPP. It is concluded that the CeA DA D2-like receptors may play an active role in morphine reward.     

Repeated administration of dopaminergic agents in the dorsal hippocampus and morphine-induced place preference

The aim of the present experiments was to investigate whether repeated intra-hippocampal CA1 (intra-CA1) administration of dopaminergic agents can affect morphine-induced conditioned place preference (CPP). Effects of repeated intra-CA1 injections of dopamine (DA) receptor agonists and antagonists on morphine-induced CPP in rats were investigated using an unbiased 3-day schedule of place conditioning. Animals receiving once-daily subcutaneous (s.c.) injections of morphine (1-9 mg/kg) or saline (1.0 ml/kg, s.c.) showed a significant place preference in a dose-dependent manner: the maximum response was observed with 3 mg/kg morphine. Three days' intra-CA1 injections of apomorphine (0.25-1 microg/rat) followed by 5 days free of the drug, significantly decreased morphine CPP (1 and 3 mg/kg, s.c.). Moreover, pre-treatment with the highest dose of apomorphine (1 microg/rat) altered the effect of morphine to an aversive response. The morphine (1 and 3 mg/kg) CPP was also significantly decreased in animals that previously received three intra-CA1 injections of SKF 38393 (2-9 microg/rat), quinpirole (1-3 microg/rat) or sulpiride (1-3 microg/rat), and significantly increased in animals that had previously received three intra-CA1 injections of SCH 23390 (0.02 microg/rat). The 3-day pre-treatment with apomorphine, SKF 38393 or quinpirole reduced locomotor activity in the test session, while SCH 23390 and sulpiride did not have any influence on locomotor activity. It is concluded that repeated injections of DA receptor agents in the dorsal hippocampus, followed by 5 days free of the drugs, can affect morphine reward.     

Social stress is as effective as physical stress in reinstating morphine-induced place preference in mice

Rationale Relapse to drug-seeking in abstinent heroin addicts and reinstatement in experimental animals are observed when exposed to drug-associated stimuli or cues, the drug itself, and stressful events. It has been shown that footshock-induced stress increases the rewarding effects of opiates, delays extinction, and induces the reinstatement of drug-seeking. However, the effects of social stress on the reinstatement of opiate-seeking after extinction has not been studied.Objectives The role of physical (restraint and tail pinch) and social (social defeat) stressors on the reinstatement of morphine-induced conditioned place preference (CPP) was evaluated.Methods Adult male OF1 mice were conditioned with 10, 20, or 40 mg/kg of morphine or saline. Only morphine-conditioned animals acquired CPP. All mice underwent extinction sessions until the CPP was extinguished. Then, the effects of physical or social stress on the reinstatement of CPP were evaluated. Morphine- and saline-conditioned animals were exposed to the respective stressor or control stress condition immediately or 15 min before reinstatement tests. In experiment 1, animals underwent restraint for 15 min. In experiment 2, animals were exposed to tail pinch or placed in a cage without any manipulation for 15 min. In experiment 3, animals performed an agonistic encounter with an isolated or anosmic mouse or were placed in a cage without any social contact or manipulation.Results Restraint, tail pinch, and social defeat in an agonistic encounter with an isolated mouse produce the reinstatement of CPP in morphine-conditioned animals.Conclusions These data demonstrate that social stress is as effective as physical stress in reinstating morphine-seeking.     

Morphine conditioned reward is inhibited by MPEP,the mGluR5 antagonist

In the present study we examined the effect of MPEP [2-methyl-6-(phenylethynyl)-pyridine] a potent, selective and systemically active metabotropic glutamate receptor (mGluR) type I (subtype mGluR5) antagonist on conditioned morphine reward in mice. In an unbiased version of conditioned place preference (CPP) paradigm, single conditioning with 10 mg/kg of morphine produced reliable place preference. MPEP at 30, but not 10 mg/kg significantly inhibited the acquisition as well as expression of morphine-induced CPP, but it neither produced place preference or aversion, nor affected locomotor activity of mice. Effects of MPEP on learning and memory were studied in the elevated plus maze model of spatial learning. In contrast to 0.1 mg/kg of MK-801, which inhibited the acquisition of this task, 30 mg/kg of MPEP affected neither learning nor memory retrieval. These data suggest that mGluR5 may be involved in conditioned morphine reward.     

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

Aripiprazole is an atypical antipsychotic drug primarily characterized by partial agonist activity at dopamine (DA) D₂ receptors and serotonin-1A (5-hydroxytryptamine, 5-HT_1A) receptors and minimal side effects. Based on its pharmacological profile, including stabilization of mesocorticolimbic DA activity (a pathway implicated in drug addiction), we investigated the effects of aripiprazole on relapse to morphine seeking in rats. In experiment 1, rats underwent morphine-induced conditioned place preference (CPP) training with alternate injections of morphine (5 mg/kg, s.c.) and saline (1 ml/kg, s.c.) for 8 consecutive days. To examine the effect of aripiprazole on the expression of morphine-induced CPP, rats received aripiprazole (0, 0.03, 0.1, and 0.3 mg/kg, i.p.) 30 min before testing for the expression of CPP. In experiment 2, rats underwent the same CPP training as in experiment 1 and subsequent extinction training. To examine the effect of aripiprazole on reinstatement of morphine-induced CPP, rats received aripiprazole 30 min before testing for reinstatement of CPP. In experiment 3, to assess the effects of aripiprazole on locomotor activity, aripiprazole was administered 30 min before testing for locomotor activity. Aripiprazole significantly decreased the reinstatement of CPP induced by a priming injection of morphine but had no effect on the expression of morphine-induced CPP or locomotor activity. The D₂ and 5-HT_1A partial agonist and 5-HT_2A antagonist properties of aripiprazole likely account for the blockade of relapse to drug seeking. These findings suggest that aripiprazole may have therapeutic value for reducing craving and preventing relapse to drug seeking.     

Dopamine D<Subscript>3</Subscript> receptor ligands modulate the acquisition of morphine-conditioned place preference

Rationale The dopamine D₃ receptor has been shown to mediate conditioned effects of psychostimulants such as cocaine. The present work was aimed at determining whether drugs acting at D₃ receptors alter acquisition of conditioned effects of opiates.Methods We have used the conditioned place preference (CPP) in mice, which permits the measurement of approach behaviour to environmental stimuli previously paired with drug effects. To assess the interaction of morphine and D₃ receptor ligands during acquisition of CPP, we have used a particular procedure, in which the animals were given the choice between compartments associated with either morphine alone or the combination of morphine with the tested agent.Results D₃ receptor agonists (7-OH-DPAT, quinelorane, BP 897) did not induce, alone, a significant CPP but, all of them, at the doses tested, and notably BP 897, a highly selective partial agonist, significantly enhanced acquisition of morphine-induced CPP when administered together with morphine at each conditioning session. PNU-99194A, a D₃ receptor-preferring antagonist, induced a CPP itself at the dose of 10 mg/kg but not at 5 or 15 mg/kg and impaired significantly at 10 and 15 mg/kg the morphine-induced CPP. In contrast, BP 897 did not alter morphine-induced analgesia, an unconditioned effect of this drug.Conclusions These results suggest the stimulation of D₃ receptors has no rewarding effect per se, but may synergize upon opiate-induced dopamine release with stimulation of other dopamine receptor subtypes to enhance approach behaviour to morphine-associated environment.     

Effects of the NMDA/glycine receptor antagonist, L-701,324, on morphine- and cocaine-induced place preference.

Effects of the novel NMDA/glycine receptor antagonist, L-701,324, on morphine- and cocaine-induced conditioned place preference (CPP) were examined in male Wistar rats. After determination of initial preference, animals were conditioned with morphine (5 mg/kg, i.p.) or cocaine (5 mg/kg, i.p.) for 3 conditioning trials, alone or in combination of these drugs with L-701,324 (2.5 mg/kg and 5 mg/kg, p.o.). L-701,324 prevented acquisition of the place preference produced by morphine and cocaine. Administration of L-701,324 on the test day attenuated the expression of morphine-induced CPP, whereas it had no effect on cocaine CPP. When L-701,324 was given alone it did not affect dependent variables (i.e. time spent in non-preferred compartment) suggesting that L-701,324 did not display any reinforcing properties by itself. Our current data suggest that glycine site on the NMDA receptor complex may be involved in the mediation of the rewarding effects of drugs of abuse.     

皮质酮对吗啡条件性位置偏爱及条件性精神运动获得的影响

目的 :研究皮质酮作用下吗啡条件性位置偏爱 (CPP)及条件性精神运动的变化趋势及其可能机制 ,为探讨应激、环境线索诱发复吸的机制提供基础。方法 :32只♂SD大鼠分成 4组。训练 2d ,1次药物匹配训练 (吗啡 2mg·kg- 1 ,皮质酮 5mg·kg- 1 ,ip ,提前 2 0min注射 ) ,1次生理盐水训练。观察训练前后大鼠在伴药侧停留的时间 ,急性给药后的运动及条件性精神运动的变化。结果 :(1)吗啡组训练后在伴药侧停留的时间显著长于对照组 (P <0 0 1) ,皮质酮吗啡组、皮质酮组与对照组比较差异无显著性 (P >0 0 5 ) ;(2 )在 5 0、6 0min时皮质酮吗啡组的急性精神运动显著大于吗啡组和对照组 (P <0 0 1) ;(3)皮质酮吗啡组大鼠的条件性精神运动显著大于对照组、吗啡组 (P <0 0 1,P <0 0 5 )。结论 :5mg·kg- 1 的皮质酮显著抑制吗啡CPP的获得 ,但促进吗啡条件性精神运动的获得以及急性精神运动。CPP与条件性精神运动获得的机制可能存在差异     

Morphine sex-dependently induced place conditioning in adult Wistar rats

The present study was conducted to investigate the potential sex-differences in morphine-induced conditioned place preference. A 3-day unbiased conditioning procedure was used to establish conditioned place preference in adult male and female Wistar rats (weighing 200-250 g). The effect of morphine on locomotor activity of subjects was also studied. Naloxone (0.5-2 mg/kg, i.p.), a selective antagonist of mu-opioid receptor or sulpiride (0.5-2 mg/kg, s.c.), a selective antagonist of dopamine D(2) receptor was administered, during conditioning, to indicate the receptor-mediated mechanisms governing upon possible sex-differences to the opioid response. Results show that morphine (0.5-10 mg/kg, s.c.) differently produced a significant place preference in female and male Wistar rats. Although, the opioid maximum response in both sexes was observed at 7.5 mg/kg, but, it was found that female rats acquired conditioned place preference at a lower dose (0.5 mg/kg, s.c.) of morphine compared to male rats. Moreover, the increase in morphine-induced response at higher doses (5-10 mg/kg, s.c.) was more pronounced in females than the males, indicating that female Wistar rats are more sensitive to the place conditioning induced by morphine. Also, the females were more sensitive to locomotor activation induced by morphine at least at one dose (7.5 mg/kg). Animals' body-weight at 10 mg/kg of opioid was increased, the effect that was not dependent to sex. The results also demonstrate that naloxone (1 and 2 mg/kg, i.p.) induced a significant place preference in two sexes with no significant effect on animals' locomotor activity. The antagonist in males but not in females showed a significant effect on animals' body-weight. Naloxone (0.5-2 mg/kg, i.p.) prior-administration to morphine, during conditioning, attenuated the opioid response in two sexes. The attenuation of the morphine response was more pronounced in males than the other sex at the higher dose (2 mg/kg) of the antagonist. In addition, the preadministration of naloxone, during morphine conditioning, both attenuated the drug-induced hyperactivity in females and decreased the animals' body-weight, albeit more effectively in females than the males. Sulpiride injections (1 and 2 mg/kg s.c.), during the conditioning period, induced a significant aversion in males but not in females with no significant effect either on locomotor activity or body-weight in both sexes. When sulpiride (0.5-2 mg/kg, s.c.), during conditioning, was morphine pre-injected, the antagonist at higher doses significantly attenuated the opioid response in males, reflecting the involvement of dopamine D(2) receptor in sex-dependent morphine-conditioned place preference. Prior-injections of sulpiride to morphine produced a significant effect on locomotor activity of females. The effect of the antagonist preinjections on body-weight was also observed in males. Present results indicate sex-differences both in reinforcing and locomotor activity effects of morphine in Wistar rats.     

Rewarding and aversive effects of morphine: Temporal and pharmacological properties

To assess morphine-induced location preferences and flavor aversions, rats were administered morphine sulfate (10 mg/kg, IP) either immediately before (Experiment 1) or immediately after (Experiment 2) confinement for 20 min in one side of a shuttlebox with access to a flavored solution. On control trials the rats were administered saline and confined for 20 min on the opposite side with a differently flavored solution. In subsequent choice tests, it was found that morphine injections before confinement produced a preference for the side associated with morphine and indifference to the flavors, whereas morphine injections after confinement produced an aversion to the flavor paired with morphine and indifference to the sides. Experiments 3 and 4, using a procedure similar to that of Experiment 1, showed that naloxone (1 mg/kg, IP) blocked the morphine-induced side preference, although given alone it was without effect in this test.     

Morphine-induced place conditioning in Fischer and Lewis rats: acquisition and dose-response in a fully biased procedure

The Fischer (F344) and Lewis (LEW) rat strains differ on a variety of behavioral assays examining the effects of morphine, with many of the differences observed during acquisition of behavioral responses. The results of these studies and others examining endogenous physiology and the biochemical effects of morphine suggest that F344 rats are more sensitive to morphine than LEW rats. However, LEW animals have shown greater conditioned place preferences (CPP) to 4 mg/kg than F344 rats. CPP is a popular assay of drug reward in which acquisition of the preference can be measured across multiple conditioning cycles, yet this aspect of CPP has not been assessed in F344 and LEW rats. As part of an ongoing effort to fully characterize the conditioned rewarding effects of abused drugs in these strains, the present study assessed the effects of 0, 1, 4 and 10 mg/kg subcutaneous (SC) morphine in adult male F344 and LEW rats (n=12/strain/dose). A fully biased place conditioning procedure was employed where morphine's effects were paired with the initially non-preferred chamber on Day 1, saline was paired with the preferred chamber on Day 2 and drug-free access to the entire apparatus was allowed on Day 3. This conditioning and testing regimen was repeated for four consecutive cycles. The F344 animals acquired CPP at 1 mg/kg only; this effect emerged after only two conditioning cycles. LEW rats never acquired a CPP at any dose tested. Peak blood morphine levels following SC injections of 1, 4 or 10 mg/kg revealed no significant strain or dose effects. These behavioral data are consistent with the hypothesis that F344 rats are more sensitive to the rewarding effects of morphine than LEW rats. Additional implications for the Fischer-Lewis model of drug abuse and the utility of CPP acquisition procedures are discussed.     

Involvement of dopamine receptors of the dorsal hippocampus on the acquisition and expression of morphine-induced place preference in rats

In the present study, the effects of bilateral intrahippocampal CA1 injections of dopamine receptor agonists and antagonists on the acquisition and expression of morphine-induced place preference were examined in male Wistar rats. Subcutaneous administration of different doses of morphine sulphate (0.5-10 mg/kg) produced a conditioned place preference (CPP) dose-dependently. Using a 3-day schedule of conditioning, it was found that dopamine D1 receptor agonist, SKF 38393 (0.01-1 microg/rat), dopamine D1 receptor antagonist, SCH 23390 (0.25-1 microg/rat), dopamine D(2/3) receptor agonist, quinpirole (0.3-3 microg/rat) or dopamine D2 receptor antagonist, sulpiride (0.04-5 microg/rat) did not produce significant place preference. The administration of SKF 38393 (1 microg/rat) significantly potentiated the acquisition of morphine (0.5 and 2.5 mg/kg)-induced place preference. This potentiation was reversed by SCH 23390 (1 microg/rat) pretreatment. Quinpirole injection (0.3 microg/rat) induced CPP in combination with the lower doses of morphine but decreased the response of the higher doses of morphine. These responses of quinpirole were reversed by sulpiride (5 microg/rat) pretreatment. SCH 23390 or sulpiride reduced the acquisition of morphine (7.5 mg/kg)-induced place preference. The administration of sulpiride, but not other drugs, during acquisition showed an increase in the locomotor activity on the testing days. SKF 38393, SCH 23390 or sulpiride, but not quinpirole when used before testing, reduced the expression of morphine-induced place preference. Sulpiride, but not other drugs, increased locomotion when used before testing. It is concluded that dorsal hippocampal dopamine receptors may play an active role in morphine reward.     

Effects of diazepam on conditioned place preference induced by morphine or amphetamine in the rat

RATIONALE: The drug-abuse literature suggests that benzodiazepines may be preferentially abused in conjunction with opioids rather than stimulants. OBJECTIVE: To investigate possible effects of diazepam on the reinforcing effects of morphine and amphetamine. METHODS: The effects of diazepam (0.5, 1 or 2 mg/kg) on the formation and expression of conditioned place preferences (CPP) induced by morphine sulphate (0.3, 0.8, 2 and 8 mg/kg) or D-amphetamine (0.4, 0.8, 2 or 2.5 mg/kg) were studied in an unbiased CPP paradigm. The action of diazepam (1 mg/kg) on conditioned and unconditioned locomotion induced by morphine (2 mg/kg) or amphetamine (2 mg/kg) was assessed. RESULTS: Rats that received conditioning injections of morphine in one environment displayed a preference for this environment. Pre-testing injections of diazepam did not alter the magnitude of this CPP. When diazepam was given with morphine during training, rats displayed a CPP for the environment paired with the two drugs. Injections of amphetamine in one environment also induced a preference for this environment. However, pre-testing injections of diazepam blocked the expression of amphetamine-induced CPP, and co-injections of diazepam blocked the formation of amphetamine CPP. Diazepam itself did not produce a CPP nor did it alter spontaneous place preferences. Diazepam equally blocked both morphine and amphetamine unconditioned and conditioned locomotor hyperactivity. This indicates that its effects on morphine and amphetamine CPP were not due to a differential effect on locomotion. CONCLUSIONS: Diazepam interferes with the reinforcing properties of amphetamines but not of morphine. The reinforcing effects of morphine and amphetamine are pharmacologically dissociable.     

Calmodulin inhibitor trifluoperazine attenuates the development and expression of morphine-induced conditioned place preference in rats

The effect of trifluoperazine, a calmodulin inhibitor, on morphine-induced conditioned place preference was examined in rats. Morphine (5, 10 mg/kg, i.p.) produced significant place preference for the drug-associated place. Trifluoperazine significantly suppressed the development as well as the expression of morphine-induced place preference in a dose-dependent manner, but it neither produced place preference or aversion, nor affected locomotor activity. Injection of 0.5 and 1.0 mg/kg apomorphine, a dopamine receptor agonist, did not alter the inhibition by trifluoperazine of morphine-induced place preference. Verapamil, at the dose that failed to change the place preference induced by morphine, enhanced the inhibition by trifluoperazine of morphine-induced place preference. These findings provide the first demonstration that trifluoperazine attenuates morphine-induced conditioned place preference in rats. The action of trifluoperazine might be produced through its inhibition of calmodulin, but is probably not related to dopamine receptor blockade.