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.     

Reactivation of morphine conditioned place preference by drug priming: role of environmental cues and sensitization

RATIONALE: Relapse is a major characteristic of drug addiction and remains the primary problem in treating drug abuse. Despite a great deal of research, the exact factors that determine renewed drug-seeking and persistent craving for them remain unclear. OBJECTIVE: The present study was designed to evaluate the role of environmental cues and behavioral sensitization in reactivation of place preference following long-term extinction of morphine conditioned place preference (CPP) in rats. METHODS: After being injected with morphine and saline alternately for 6 days to induce morphine CPP, the rats were subjected to extinction of conditioning for 21 days. The rats were then administered various doses of morphine, heroin, or cocaine and confined in the previous drug- or saline-paired compartment. CPP was determined. Some rats were treated with scopolamine or naloxone prior to administration of these three drugs. RESULTS: Morphine CPP disappeared following a 21-day extinction. A single injection of morphine, heroin, or cocaine evoked place preference for the previous drug-paired side. However, place preference for the previous vehicle-paired side was induced after the animals received a single injection of morphine, heroin or cocaine and confined to the previous vehicle-paired compartment. Administration of naloxone prior to drug treatment significantly attenuated the place preference induced by morphine or heroin, but had no significant effect on the place preference elicited by cocaine. Administration of the cholinergic antagonist scopolamine before morphine, heroin and cocaine inhibited the expression of place preference. CONCLUSIONS: Environment-related cues and behavioral sensitization play critical roles in the incentive motivation underlying drug-seeking behaviors.     

Blockade of cue- and drug-induced reinstatement of morphine-induced conditioned place preference with intermittent sucrose intake

Sucrose intake has been suggested to alter the expression of morphine-induced conditioned place preference (CPP). To date, the potential effects of sucrose intake on the extinction and drug-induced reinstatement of CPP have not been determined. In the present study, sucrose solution (15%) was given prior to, during, and following the acquisition of morphine-induced CPP. Place preference was subsequently assessed during expression, extinction, and morphine-induced reinstatement. The results showed that the sucrose solution given prior to place conditioning training transiently suppressed the expression of morphine CPP. Sucrose solution given during place conditioning training had no effects on the expression, extinction, and reinstatement of CPP. When the sucrose solution was given following the acquisition of morphine CPP, the extinction of morphine CPP was accelerated, and morphine-induced reinstatement was profoundly inhibited. The above results demonstrated that sucrose intake could differentially affect the expression, extinction, and reinstatement of morphine-induced CPP, depending on the interference schedules. Our findings suggest that offering non-drug rewards could be a valuable approach to maintain abstinence and preventing relapse in drug addicts.     

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.     

Reinstatement of nicotine-conditioned place preference by drug priming: effects of calcium channel antagonists

Reinstatement of drug-seeking behaviour in animals is relevant to drug relapse in humans. In the present study, we used the conditioned place preference paradigm to investigate the establishment, extinction, reinstatement and cross-reinstatement of nicotine-induced place conditioning in rats. Nicotine produced a place preference to the initially less-preferred compartment paired with its injections during conditioning (0.5 mg/kg, i.p., three drug sessions). Once established, nicotine place preference was extinguished by repeated training. Following this extinction phase, the reinstatement of place conditioning was investigated. For this purpose, nicotine-experienced rats were challenged with nicotine (0.5 mg/kg, i.p.) or morphine (10 mg/kg, i.p.). These priming injections of both drugs renewed a marked preference for the compartment previously paired with nicotine. In the second step, we examined the influence of the calcium channel antagonists, nimodipine (10 and 20 mg/kg, i.p.) and flunarizine (5 and 10 mg/kg, i.p.), on the reinstatement of nicotine-conditioned place preference induced by priming doses of nicotine and morphine. It was shown that the calcium channel blockers dose dependently attenuated the reinstatement of nicotine place preference induced by both drugs. These findings support the hypothesis that similar neural calcium-dependent mechanisms are involved in nicotine- and morphine-induced reinstatement. Finally, the conditioned place preference paradigm appears to be a useful tool for studies of the relapse of drug-seeking behaviour in laboratory animals.     

Reducing endocannabinoid metabolism with the fatty acid amide hydrolase inhibitor, URB597, fails to modify reinstatement of morphine-induced conditioned floor preference and naloxone-precipitated morphine withdrawal-induced conditioned floor avoidance

The potential of the fatty acid amide hydrolase (FAAH) inhibitor, URB597, to modify drug prime-induced reinstatement of morphine-induced conditioned floor preference or naloxone-precipitated morphine withdrawal-induced conditioned floor avoidance was evaluated. In Experiment 1, morphine-induced conditioned floor preference was established across 4 conditioning trials. Following extinction training (4 trials), rats were pretreated with URB597 or vehicle prior to a morphine prime or a saline prime. Morphine reinstated the previously extinguished floor preference, but URB597 did not modify the strength of the reinstated preference. In Experiment 2, naloxone-precipitated morphine withdrawal-induced conditioned floor avoidance was established across 2 conditioning trials. Following extinction training (14 trials), rats were pretreated with URB597 or vehicle prior to a saline prime or a morphine withdrawal prime. The morphine withdrawal prime reinstated the previously extinguished floor avoidance, but URB597 did not modify the strength of reinstated avoidance. These results suggest that under the conditions in which URB597 promotes extinction (e.g., Manwell et al. (2009)) it does not interfere with drug-induced reinstatement of either conditioned floor preference or avoidance. That is, although activation of the endocannabinoid (eCB) system promotes extinction of aversive learning, it may not prevent reinstatement of that aversion by re-exposure to the aversive treatment.     

Role of the cholinergic system in the rat basolateral amygdala on morphine-induced conditioned place preference

The effects of intra-basolateral amygdala (intra-BLA) injections of physostigmine, atropine, nicotine and/or mecamylamine on morphine-induced conditioned place preference (CPP) in rats was investigated by using an unbiased 3-day schedule of place conditioning design. Animals that received 3 daily injections of morphine (0.5-10 mg/kg) subcutaneously (s.c.) or saline (1.0 ml/kg, s.c.) showed a significant preference for compartment paired with morphine. The maximum response was observed with 7.5 mg/kg of the opioid. Administration of the anticholinesterase drug, physostigmine (1, 3 and 5 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited a significant CPP. Injections of antimuscarinic receptor agent, atropine (1, 4 and 7 microg/rat) dose-dependently inhibited the morphine (7.5 mg/kg)-induced place preference. The injections of nicotine (0.75, 1 and 2 microg/rat) potentiated the morphine (0.5 mg/kg)-induced place preference, while the nicotinic receptor antagonist, mecamylamine (1, 3 and 6 microg/rat) dose-dependently inhibited the morphine (7.5 mg/kg)-induced place preference. Furthermore, administration of atropine (7 microg/rat) but not mecamylamine (6 microg/rat) reduced the response induced by different doses of physostigmine plus morphine. Moreover, mecamylamine (6 microg/rat) but not atropine (7 microg/rat) reduced the response induced by different doses of nicotine plus morphine. It is concluded that the muscarinic and nicotinic receptor mechanisms in the BLA may be involved in the acquisition of morphine-induced place preference.     

Role of nitric oxide in the rat hippocampal CA1 area on morphine-induced conditioned place preference

Effects of intrahippocampal CA1 injections of L-arginine, a nitric oxide (NO) precursor, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, on morphine-induced conditioned place preference in male Wistar rats were investigated. Animals received subcutaneous (s.c.) injections of saline (1.0 ml/kg) or morphine (0.5-7.5 mg/kg) once daily for 3 days to induce conditioned place preference. The administration of L-arginine (0.3, 1.0, and 3.0 microg/rat), but not L-NAME (0.3, 1.0, and 3.0, microg/rat), prior to administration of morphine (5.0 mg/kg) during acquisition of morphine-induced conditioned place preference increased morphine-induced conditioned place preference, but the interaction between the response to morphine and/or L-arginine was not statistically significant. The response to L-arginine was blocked by L-NAME pre-administration. L-Arginine or L-NAME by itself did not induce conditioned place preference. The administration of L-arginine but not L-NAME, 1 min before conditioned place preference testing, increased the expression of morphine-induced conditioned place preference. Pre-administration of L-NAME blocked the L-arginine response. It is concluded that NO in the rat hippocampal CA1 area may be involved in morphine-induced conditioned place preference.     

Influence of nitric oxide on morphine-induced conditioned place preference in the rat central amygdala

Effects of intra-central amygdala injections of L-arginine, a nitric oxide (NO) precursor, and N(G)-nitro-L-arginine methyl ester (L-NAME), a NO synthase (NOS) inhibitor, on morphine-induced conditioned place preference in rats were investigated by using an unbiased 3-day schedule of place conditioning design. Animals receiving once daily injections of morphine (0.5-7.5 mg/kg, subcutaneously, s.c.) or saline (1.0 ml/kg, s.c.) showed a significant place preference in a dose-dependent manner. The maximum response was observed with 5.0 mg/kg of the opioid. Co-administration of morphine (5.0 mg/kg) with L-arginine (0.3, 1.0 and 3.0 microg/rat), but not with L-NAME (0.3, 1.0 and 3.0 microg/rat), during the acquisition of morphine-induced conditioned place preference increased morphine-induced conditioned place preference. The response to L-arginine was blocked by L-NAME preadministration. L-arginine and L-NAME by themselves did not induce conditioned place preference. When L-arginine or L-NAME at 0.3-3.0 microg/rat was administered 1 min before conditioned place preference testing, L-arginine but not L-NAME caused an increase in the expression of morphine-induced conditioned place preference, the effect that was blocked by L-NAME preadministration. A dose of L-arginine (0.3 microg/rat), but not L-NAME, during expression of morphine-induced conditioned place preference produced an increase in locomotion compared with that in the control group. It may be concluded that an increase in the NO levels in the central amygdala may have an effect on the acquisition and expression of morphine-induced conditioned place preference.     

不同给药时间间隔对吗啡诱导的条件性位置偏爱的影响

目的:比较两种不同给药时间间隔的实验方案对大鼠吗啡条件性位置偏爱(CPP)的影响。方法:采用三箱式非平衡设计的CPP装置,在实验方案1中,吗啡组大鼠注射吗啡(10 mg.kg-1.d-1,ip)后放入伴药箱50 min,间隔6 h后注射同等剂量的生理盐水后放入非伴药箱50 min,共12 d,检测期检测13 d。实验方案2中,奇数天给吗啡组大鼠注射吗啡(10 mg.kg-1,ip),偶数天注射同等剂量的生理盐水,共8 d,在检测期不定期地把大鼠放入到CPP箱中进行检测。结果:两种实验方案的吗啡组大鼠在伴药箱停留的时间均明显多于生理盐水对照组(P<0.01,P<0.01);自然戒断后,实验方案1和实验方案2中吗啡组大鼠的CPP维持分别为5 d和42 d。结论:两种实验方案均能有效建立大鼠吗啡CPP模型,而实验方案2更经济、省时,可提高实验效率。     

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.     

Effects of bupropion on the reinstatement of nicotine-induced conditioned place preference by drug priming in rats

Nicotine is one of the most widely consumed psychoactive drugs, and its consumption is currently associated with other drugs of abuse, such as opioids. The aim of the present study was to evaluate the efficacy of the atypical antidepressant drug bupropion (5, 10 and 20 mg/kg, ip) in blocking the reinstatement of nicotine-induced conditioned place preference (CPP) provoked by nicotine and morphine. It was shown that nicotine produced a place preference to the initially less-preferred compartment paired with its injections during conditioning (0.175 mg/kg, ip, free base, three drug sessions). Once established, nicotine-induced CPP was extinguished by repeated testing. Following this extinction phase, the reinstatement of CPP was investigated. Nicotine-experienced rats were challenged with nicotine (0.175 mg/kg, ip) or morphine (10 mg/kg, ip). These priming injections of both drugs induced a marked preference for the compartment previously paired with nicotine. Our results demonstrated that bupropion (10 and 20 mg/kg) attenuated the nicotine-induced reinstatement of nicotine-conditioned response. Moreover, bupropion (5 and 10 mg/kg) diminished the morphine-induced reinstatement of nicotine-conditioned response. The results of our studies suggest that bupropion may offer an interesting approach to the relapse-prevention pharmacotherapy of addiction, including nicotinism and polydrug abuse.     

Inhibition of the morphine-induced rewarding effect by direct activation of spinal protein kinase C in mice

Rationale We previously demonstrated that the morphine-induced rewarding effect was attenuated under a neuropathic pain-like state following partial sciatic nerve ligation in rodents. Furthermore, the up-regulation of protein kinase C (PKC) activity in the spinal cord is considered to be the key factor for induction of hyperalgesia following sciatic nerve ligation. However, little direct evidence is available for the involvement of activated PKC in the spinal cord in reduction of rewarding effects induced by morphine under chronic pain-like state.Objective The present study was to investigate whether direct activation of spinal PKC by intrathecal (IT) administration of a specific PKC activator, phorbol 12,13-dibutyrate (PDBu) could produce hyperalgesia and suppress the place preference induced by morphine in mice.Method The morphine-induced rewarding effect was investigated using the conditioned place preference method. Conditioning sessions (three for morphine, three for saline) were started 24 h after IT injection of PDBu or saline and conducted once daily for 6 days. On the day after the final conditioning session, a post-conditioning test was performed.Results IT-administered PDBu produced a long-lasting thermal hyperalgesia. Under these conditions, the place preference induced by morphine was abolished by a single IT pretreatment with PDBu. The effect was reversed by concomitant IT treatment with the specific PKC inhibitor Ro-32-0432. In contrast, IT-administered PDBu failed to affect the hyperlocomotion and supraspinal antinociception induced by morphine.Conclusion The present findings suggest that activated PKC in the spinal cord with chronic pain-like hyperalgesia may play a substantial role in the suppression of the morphine-induced rewarding effect in mice with chronic pain-like hyperalgesia.     

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.     

Fenamate-induced enhancement of heterologously expressed HERG currents in Xenopus oocytes

In the present study, the effects of intra-nucleus accumbens injection of L-arginine, a nitric oxide (NO) precursor, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on morphine-induced conditioned place preference in male Wistar rats were investigated. Our data showed that subcutaneous (s.c.) injection of morphine sulphate (0.5-10 mg/kg) significantly increased the time spent in the drug-paired compartment in a dose-dependent manner. Intra-accumbens administration of L-arginine (0.03 and 0.05 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited significant conditioned place preference, while intra-accumbens administration of L-NAME (0.3, 0.1 and 1 microg/rat) decreased the acquisition of conditioned place preference induced by morphine (7.5 mg/kg). The response to different doses of L-arginine was decreased by L-NAME (0.03 microg/rat). L-Arginine and L-NAME by themselves did not elicit any effect on place conditioning. Intra-accumbens administration of L-arginine but not L-NAME significantly decreased the expression of morphine (7.5 mg/kg)-induced place preference. The attenuation of already established morphine-induced place preference on the test day by L-arginine was inhibited by L-NAME. The results indicate that NO may be involved in the acquisition and expression of morphine-induced place preference.     

Further studies on nicotine-induced conditioned place preference in the rat

Rats received subcutaneous (SC) injections of either nicotine (NIC, 0.001 to 2.0 mg/kg) or saline (SAL, 1 ml/kg) immediately prior to conditioning sessions in a conditioned place preference (CPP) paradigm. NIC was paired for 3 conditioning sessions with one environment of a 3 compartment CPP apparatus; SAL was paired with another environment. The animals were then tested for place preference by determining the proportion of time spent in each compartment during a 15 min test session. A dose-response curve was obtained for the place conditioning effect of nicotine as measured by its ability to alter baseline preferences calculated from control rats. NIC's place preference, but not place aversion, effect was linearly correlated with respect to dosage within the range of 0.1 to 0.8 mg/kg. NIC, 0.8 mg/kg, induced a place preference when it was administered immediately prior to conditioning sessions, but not when administered 20, 60 or 120 min prior to the sessions. Three repeated conditioning and testing cycles, or the daily administration of NIC for 2 weeks between conditioning and testing cycles had little or no effect on NIC place conditioning. Lobeline (2, 10 and 20 mg/kg) or cotinine (1 to 50 mg/kg) failed to condition a place preference. NIC, 0.1 or 1.2 mg/kg SC, administered to rat pups on postnatal days 5 through 8, did not alter subsequent place preference (induced by 0.8 mg/kg of NIC) measured at approximately 40 and 70 days of age. Periodic measurements of spontaneous motor activity, forelimb grip strength and negative geotaxis were unaltered by the perinatal exposure to nicotine.     

Reconditioning of drug-related cues: a potential contributor to relapse after drug reexposure

To investigate the process of relapse to drug seeking caused by reexposure to drugs, we studied the consequences of recurring instances of stimuli–drug associations using heroin conditioned place preference (CPP) in rats. After original conditioning and extinction, rats received either a single compartment–heroin pairing (reconditioning) or were primed with heroin and tested for reinstatement of CPP. It was found that the session of reconditioning, but not the session of reinstatement, caused the reappearance of a preference for the heroin-paired compartment on a test given 24 h later, in drug-free conditions. The effect of reconditioning was found to be dependent on heroin doses, and was not seen when heroin injections were given outside the conditioning environment. Furthermore, a single session of reconditioning elevated heroin seeking even on a test given 96 h later. Finally, heroin seeking was found to be significantly elevated on a test given 28 days after the last extinction session whether animals received 1 or 3 reconditioning sessions. These results suggest that the motivational value of cues associated with heroin is not eliminated by extinction and, importantly, that these cues can rapidly regain their ability to promote drug seeking behavior if they are re-associated with the effect of heroin.     

Effect of cyclosporin A on morphine-induced place conditioning in mice: involvement of nitric oxide

Cyclosporin A is shown to attenuate antinociceptive effects of morphine, development and expression of morphine-induced tolerance and dependency via nitric oxide (NO) pathway. In the present study, the effect of systemic cyclosporin A on morphine-induced conditioned place preference (CPP) and the probable involvement of nitric oxide were assessed in mice. Our data showed that administration of morphine (1, 2.5, 5, 7.5, 10 mg/kg) significantly increased the time spent in the drug-paired compartment in a dose-dependent manner. The maximum response was obtained with 5 mg/kg of morphine. Cyclosporin A (5, 10 mg/kg) and N(G)-nitro-L-arginine methyl ester (L-NAME; 2.5, 5, 10 mg/kg), a nonselective nitric oxide synthase (NOS) inhibitor, did not induce either conditioned place preference or conditioned place aversion (CPA), while cyclosporin A (20 mg/kg) induced CPA. Both cyclosporin A (10, 20 mg/kg) and L-NAME (5, 10 mg/kg), in combination with morphine (5 mg/kg) during conditioning, significantly suppressed acquisition of morphine-induced place preference. Lower and per se noneffective doses of Cyclosporin A (1, 2.5, 5 mg/kg) and L-NAME (2.5 mg/kg), when coadministered, exerted a significant potentiating effect on the attenuation of morphine-induced place preference. Aminoguanidine (50, 100 mg/kg), the specific inducible nitric oxide synthase (iNOS) inhibitor, whether alone or in combination with cyclosporin A failed to show this inhibitory effect on morphine-induced place preference. In conclusion, decreasing nitric oxide production through inhibiting constitutive nitric oxide synthase may be a mechanism through which cyclosporin A attenuates morphine-induced place preference.     

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.     

Morphine preexposure facilitates morphine place preference and attenuates morphine taste aversion

Repeated morphine preexposure has been reported to enhance measures of morphine reward (conditioned place preference; CPP) and attenuate measures of morphine aversion (conditioned taste aversion; CTA). These effects are generally independently assessed, limiting the ability to determine if the enhancing and attenuating effects of morphine exposure are mediated by a common factor. To assess any potential relationship between these two effects, the present study examined the impact of morphine preexposure on these motivational properties of morphine using a combined CTA/CPP procedure in which the same animals receive concurrent taste and place conditioning. Specifically, male Sprague-Dawley rats were preexposed to morphine [5 mg/kg; subcutaneously (sc)] or equivolume drug vehicle. Following preexposure, animals were given saccharin to drink and injected with morphine sulfate (1 or 5 mg/kg sc) or drug vehicle (CTA). Immediately thereafter, they were placed on one side of a two-compartment chamber (CPP). On the next day, they were given water followed by injections of the drug's vehicle and then placed in the other compartment. There were four such conditioning cycles after each of which a CTA and CPP test were given. While preexposure to morphine attenuated morphine-induced CTAs, morphine-induced CPPs were enhanced within the same animals. These effects of morphine preexposure were dose- and time-dependent and parallel. These data indicate that the attenuating and sensitizing effects of morphine preexposure on taste aversions and place preferences, respectively, could be mediated by a common mechanism, although other possibilities for these effects of morphine preexposure remain.