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.     

NMDA receptors of dorsal hippocampus are involved in the acquisition, but not in the expression of morphine-induced place preference

In the present study, involvement of the N-methyl-d-aspartate (NMDA) receptors of the CA1 region of dorsal hippocampus (intra-CA1) in the acquisition or expression of morphine-induced conditioned place preference in rats was studied. Male Wistar rats were used in these experiments. NMDA-receptor agonist (NMDA) and antagonist (MK-801) were injected into the CA1 region of the dorsal hippocampus (intra-CA1) and morphine was injected subcutaneously. An unbiased conditioned place preference paradigm was used to study the effect of these agents. In the first set of experiments, the drugs were used during the development of conditioned place preference by morphine or they were used alone in order to see if they induce conditioned place preference or conditioned place aversion. Our data showed that subcutaneous (s.c.) injection of morphine sulphate (2.5-10 mg/kg) induced conditioned place preference in rat. NMDA (0.1-1 microg/rat) or MK-801 (1-4 microg/rat) did not induce conditioned place preference or conditioned place aversion. Intra-CA1 administration of different doses of NMDA (0.1-1 microg/rat) increased, while MK-801 (1-4 microg/rat) decreased morphine-induced place preference. MK-801 reversed the effect of NMDA on morphine response. In the second set of experiments, when the drugs were used before testing on Day 5, in order to test their effects on the expression of morphine (7.5 mg/kg)-induced place preference, intra-CA1 administration of NMDA or MK-801 did not alter the morphine response. None of the drugs influenced locomotion. It is concluded that NMDA receptor of the CA1 region of hippocampus are involved in the acquisition but not expression of morphine-induced place preference.     

Naloxone enhances the expression of morphine-induced conditioned place preference

The present study examined the effects of naloxone on acquisition and expression of morphine-induced conditioned place preference (CPP). Three groups of rats were given morphine (5 mg/kg, SC), both morphine and naloxone (1 mg/kg, SC), or saline paired with a distinctive environment. On alternating days they were given saline paired with another distinctive environment. After four exposures to each environment, the animals were given a preference test in which they had access to both environments simultaneously while under the influence of either naloxone (1 mg/kg, SC) or saline. Morphine-conditioned animals showed CPP evident as an increased amount of time spent in the drug-associated environment relative to saline controls. Rats given both naloxone and morphine during conditioning, and saline on the test day, did not show CPP. In contrast, morphine-conditioned animals given naloxone on the test day showed stronger CPP than morphine-conditioned animals given saline. These findings indicate that naloxone blocks the acquisition, but enhances the expression of morphine-induced CPP. In a separate experiment, the effects of naloxone on locomotor activity were determined during the CPP test. The results indicated that naloxone decreased locomotor activity. In morphine-conditioned animals only, naloxone also produced an increase in the amount of time per entry in the drug-associated environment. The results suggest that naloxone may enhance morphine-induced CPP by decreasing locomotor activity that may otherwise compete with expression of CPP.     

Blockade of morphine-induced place preference by diazepam in mice

The effects of diazepam on morphine-induced place preference were examined in mice. Pretreatment with diazepam (2 mg/kg i.p.) 30 min prior to morphine injection significantly abolished the morphine (5 mg/kg s.c.)-induced place preference, and this effect of diazepam was antagonized by pretreatment with flumazenil. In addition, pretreatment with diazepam prevented the morphine (5 mg/kg s.c.)-induced increase in dopamine turnover in the limbic forebrain. These results suggest that pretreatment with diazepam may suppress the rewarding effects of morphine.     

粉防己碱对小鼠吗啡位置偏爱效应的影响(英文)

利用条件性位置偏爱实验研究钙拮抗剂粉防己碱对小鼠吗啡奖赏效应的影响 .实验采用有倾向性程序 .吗啡 ( 5mg· kg-1,sc,每日 1次 ,5d)引起小鼠显著的位置偏爱效应 .在训练阶段每天 sc吗啡前 30 min预先给予粉防己碱 ( 1 0 ,2 0和 40 mg·kg-1,ip)可剂量依赖性地抑制吗啡引起的小鼠位置偏爱效应 .而粉防己碱 ( 1 0 ,2 0和 40 mg· kg-1,ip)只在测试前 30 min给药 1次 ,不影响吗啡已形成的小鼠位置偏爱 .结果说明粉防己碱能有效地抑制吗啡偏爱效应的获得 ,但不影响其表达 .     

左旋四氢巴马汀对吗啡条件性位置偏爱的影响

目的探讨不同剂量的左旋四氢巴马汀(lTetrahydropalmatine,lTHP)对吗啡诱导的条件性位置偏爱(CPP)的影响以及自身能否产生CPP效应。方法本实验采用倾向性实验程序,①对♂SD大鼠sc吗啡(5.00mg·kg-1)或生理盐水(NS)训练8d,d9测定大鼠对伴药侧的偏爱效应或测试前40minipNS或不同剂量的lTHP(1.25～5.00mg·kg-1),观察这些预处理对该效应的影响;②测量不同剂量的lTHP(1.25～5.00mg·kg-1)慢性用药(每天1次,ip)对CPP效应消退的影响;③测试ipNS或lTHP(1.25～5.00mg·kg-1)能否诱导大鼠对伴药侧产生偏爱(方法同吗啡)。结果5.00mg·kg-1吗啡诱导大鼠对伴药盒产生明显的CPP;测试前ip2.50mg·kg-1或5.00mg·kg-1的lTHP明显降低吗啡诱导的CPP效应的表达(P<0.05),其慢性给药明显加速吗啡CPP效应的消退;3个剂量的lTHP均不能诱导大鼠形成CPP。结论lTHP能抑制吗啡的奖赏效应,可在吗啡成瘾的治疗中发挥一定的作用。     

The influence of central administration of dopaminergic and cholinergic agents on morphine-induced amnesia in morphine-sensitized mice

In the present study, effects of intracerebroventricular (i.c.v.) injections of dopaminergic and cholinergic agents on morphine-induced amnesia in morphine-sensitized mice were investigated by using a one-trial passive avoidance task. Amnesia induced by pre-training morphine was significantly reversed in morphine-sensitized mice, which had previously received once daily injections of morphine (20 and 30 mg/kg, s.c.) for 3 days. Three daily injections of SKF 38393 (1, 2 and 4 g/mouse, i.c.v.) or SCH 23390 (0.25, 0.5, 0.75 and 1 g/mouse, i.c.v.) before morphine, and during morphine-sensitization, decreased and increased the amnesia induced by pre-training morphine respectively. Three daily injections of quinpirole (0.3, 1 and 3 g/mouse, i.c.v.) or sulpiride (0.03, 0.1, 0.3 and 1 g/mouse, i.c.v.) before morphine, also decreased and increased the amnesia induced by pre-training morphine respectively. Morphine-sensitized mice received similar injections of cholinergic agents. Three daily injections of physostigmine (1, 3 and 5 g/mouse, i.c.v.) or atropine (1, 4 and 7 g/mouse, i.c.v.) before morphine, and during morphine-sensitization, decreased and increased the amnesia induced by pre-training morphine respectively. Three daily injections of nicotine (0.75, 1 and 2 g/mouse, i.c.v.) or mecamylamine (1, 3 and 6 g/mouse, i.c.v.) before morphine, also decreased and increased the amnesia induced by pre-training morphine respectively. The results suggest that morphine sensitization affects the impairment of memory formation and thus it is postulated that central dopaminergic and cholinergic systems may play an important role in this effect.     

Endogenous histamine inhibits the development of morphine-induced conditioned place preference

AIM: The conditioned place preference (CPP) paradigm was used to investigate the effects of endogenous histamine on the processes leading to morphine-induced reward-seeking behavior in Sprague-Dawley rats. METHODS: The model of CPP was used to assess the rewarding effect of morphine. The levels of histamine, glutamate, gamma-aminobutyric acid (GABA), dopamine (DA) and 3, 4-dihydroxyphenylacetic acid (DOPAC) in rat brains were measured with high-performance liquid chromatography. Immunohistochemistry technique was used to observe the morphological changes of neurons. RESULTS: Intraperitoneal injection of morphine (2, 5 or 10 mg/kg) induced the development of CPP in a dose-dependent manner. In addition, morphine administrations (10 mg/kg) decreased the histamine content and reduced the number and size of histaminergic neurons in the tubero-mammillary nucleus (TM), as well as markedly increasing the DOPAC/DA ratios in the ventral tegmental area (VTA) and nucleus accumbens (NAc). Intraperitoneal injection of histidine (50, 100 or 200 mg/kg) dose-dependently inhibited the development of morphine-induced CPP. Bilateral lesions of the TM, which decreased the histamine levels in the VTA and NAc, potentiated the development of CPP induced by morphine (1 mg/kg, a dose that produced no appreciable effect when given alone) and increased the DOPAC/DA ratios in the VTA and NAc, but did not change the glutamate or GABA levels in these nuclei. Histidine reversed the effects of the TM lesions. CONCLUSION: These results indicate that endogenous histamine plays a role in inhibiting the development of morphine-induced reward-seeking behavior, and the inhibition may involve the modulation of dopaminergic activity.     

Cross-reinstatement by cocaine and amphetamine of morphine-induced place preference in mice

The cross-reinstatement by psychostimulants of a conditioned place preference (CPP) induced by morphine was evaluated in mice. In Experiment 1, we examined the effects of a single dose of cocaine and amphetamine on a previously extinguished morphine CPP. After acquisition of CPP induced by morphine (40 mg/kg), animals underwent daily extinction sessions of 15 min duration until the CPP was extinguished. Subsequently, animals received a non-contingent injection of cocaine (25 mg/kg) or amphetamine (4 mg/kg), which produced the reinstatement of the extinguished morphine-induced CPP. In Experiment 2, we evaluated the reinstating effects of several priming doses of cocaine (Experiment 2A) or amphetamine (Experiment 2B). As in the first experiment, after conditioning with morphine (40 mg/kg), mice underwent daily 15 min extinction sessions. When the preference was no longer evident, we tested the effects of cocaine (0, 6.25, 12.5, 25 and 50 mg/kg) and amphetamine (0, 0.5, 1, 2 and 4 mg/kg) on the reinstatement of CPP. Doses from 12.5 mg/kg of cocaine upward and doses from 1 mg/kg of amphetamine upward effectively reinstated CPP. Our results demonstrate cross-reinstatement with psychostimulants and opiates, suggesting that in abstinent individuals, drug exposure can produce craving for the previously abused drug and relapse.     

Estrogen pretreatment modulates morphine-induced conditioned place preference in ovariectomized mice

Estrogen is known to modulate the neurotransmission in the brain. The main aim of this study was to investigate the effects of estrogen on the rewarding properties of morphine using conditioned place preference (CPP) paradigm in adult female mice. The possible rewarding effect of estrogen was also examined in ovariectomized mice. Following a 6-day conditioning procedure, sham operated animals showed a significant preference towards the side previously paired with a range of morphine doses (2, 5 and 10—but not 20—mg/kg, SC). However, ovariectomized mice showed decreased CPP compared to gonadally intact mice with a right shift in their morphine dose-response curve. These effects were reversed by chronic daily administration of estradiol benzoate (EB; 20 µg/kg, SC). Furthermore, in ovariectomized mice, EB per se was able to induce CPP. In conclusion, our findings indicate that estradiol has a facilitating effect on morphine reward while its deficiency increases the threshold dose of morphine to induce CPP.     

Inhibition of the cyclooxygenase pathway attenuates morphine-induced conditioned place preference in mice

Prostanoids are shown to be important lipid mediators, not only in periphery but also in the brain, where they appear to modulate synaptic transmission. Recent studies have demonstrated that cyclooxygenase (COX) pathway might modulate the neurotransmission of gamma-aminobutyric acid and dopamine in the central nervous system. In this study, we have evaluated the effects of indomethacin (a non-selective COX inhibitor) and celecoxib (a selective COX-2 inhibitor) on the acquisition of morphine-induced conditioned place preference (CPP) in male Swiss mice. Our data shows that morphine (2.5-7.5 mg/kg) induces place preference conditioning in a dose-dependent manner. Celecoxib (0.01-5 mg/kg) and indomethacin (1 mg/kg) fail to produce a significant CPP or conditioned place aversion (CPA); however, higher doses of celecoxib (10 mg/kg) and indomethacin (5 mg/kg) induce CPA. Co-administration of celecoxib (0.5-5 mg/kg) or indomethacin (1-5 mg/kg) with morphine during the conditioning phase, blocked the acquisition of morphine CPP. These results indicate that the reward properties of morphine can be modulated by inhibiting COX activity in mice.     

Alpha-2 agonists decrease expression of morphine-induced conditioned place preference

Opioidergic system can interact with different transmission such as dopaminergic and adrenergic system. It has been shown that alpha-adrenergic system is involved in some effects of opioid including reward. In this study, alpha-2 agonists were used before testing on day 6 to evaluate their effects on the expression of morphine-induced conditioned place preference (CPP). Our results showed that intraperitoneal (i.p.) injections of morphine (5 mg/kg) induced CPP. Administration of alpha(2)-agonists clonidine (0.01, 0.02 and 0.04 mg/kg, i.p.), tizanidine (0.1, 0.2 and 0.4 mg/kg, i.p.) and xylazine (2.5, 5 and 10 mg/kg, i.p.) decreases the expression of morphine-induced CPP. Yohimbine (0.5 mg/kg, i.p.) reversed the inhibitory effect of alpha(2)-agonists. The comparison of potency of inhibitory effect of three agonists showed that ID(50) values for clonidine, tizanidine and xylazine were 0.013, 0.32 and 1.86 mg/kg respectively. Therefore, it is concluded that alpha(2)-agonists decrease the morphine-induced CPP in mice and clonidine is more potent than tizanidine and xylazine. The relative potency of clonidine with respect to tizanidine and xylazine was 30 and 180 respectively.     

Repeated testing attenuates conditioned place preference with cocaine

Cocaine-treated rats acquired a preference for cocaine-associated contextual stimuli (CS) relative to saline-injected control rats. However, when animals were given repeated tests for conditioned place preference intermittent between conditioning trials, they displayed an attenuation in strength of conditioning. This attenuation was not due to pharmacologic tolerance (Experiment 1), but rather reflected a disruption in learning due to exposure to the CS alone (Experiment 2). Like other examples of classical conditioning, the strength of the conditioned response (CR) as assessed by the conditioned place preference model may be influenced by partial reinforcement.     

Intra-hippocampal inhibition of protein kinase AII attenuates morphine-induced conditioned place preference

Morphine and other drugs of abuse modulate protein kinase A (PKA) signaling within the mesolimbic reward pathway. Using a balanced conditioned place preference (CPP) paradigm, we studied the possible involvement of protein kinase AII (PKA II) on the acquisition, expression and consolidation of morphine place conditioning in male Wistar rats. Subcutaneous administration of various doses of morphine sulfate (1-9 mg/kg) induced CPP in a dose-dependent manner. H-89, a selective PKA II inhibitor, was administered into CA1 region of the hippocampus at 1, 2.5 and 5 microM/rat. Using a 3-day schedule of conditioning, it was found that the H-89 did not produce a significant place preference or place aversion. H-89 (1, 2.5 and 5 microM/rat) significantly reduced the time spent by rats in the morphine compartment when given immediately after each conditioning session (consolidation), whereas it had no effect when administered before morphine during the conditioning phase (acquisition) or before testing for place preference in the absence of morphine (expression). It is concluded that the PKA II may play an active role in the consolidation of reward-related memory of morphine in CA1 region of the hippocampus.     

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.     

Involvement of insular muscarinic cholinergic receptors in morphine-induced conditioned place preference in rats

Rationale

Drug addiction represents a pathological usurpation of neural processes involved in learning and memory. Retrieval of drug-related memories can result in drug craving and relapse. Recently, the insula was identified as part of the neuronal circuit responsible for the processing of drug memory; however, its precise role remains unclear.

Objective

To investigate the involvement of insular muscarinic acetylcholine receptors (mAChRs) in the processing of drug memory.

Method

The morphine-induced conditioned place preference (CPP) was used to assess drug memory. All rats were first trained with morphine to establish the CPP. Sub-groups of these rats were used for contextual cue-induced CPP reinstatement. Other sub-groups of rats underwent extinction of the CPP, and 5 m/kg morphine was used for priming-induced CPP reinstatement. Microinjection of mAChR antagonists or agonists into the insula was performed prior to the CPP tests in order to evaluate their effect on CPP expression.

Results

Insular microinjections of the nonselective mAChR antagonist, scopolamine, and the M₁ antagonist, pirenzepine, significantly inhibited CPP expression in both contextual cue- and priming-induced CPP reinstatement; the M₁ agonist, MCN-A-343, and the M₄ antagonist, tropicamide, enhanced CPP expression. The M₄ agonist, LY2033298, inhibited CPP expression. The M₂ antagonist, methoctramine, and M₃ antagonist, 4-DAMP, had no effect on CPP expression.

Conclusion

Our results demonstrate that insular mAChRs play a role in the processing of drug memory. M₁ and M₄ mAChRs work paradoxically; M₁ activation and M₄ inhibition attenuate the expression of drug memory, while M₁ inhibition and M₄ activation augment the expression of drug memory.     

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.     

A Scutellaria baicalensis radix water extract inhibits morphine-induced conditioned place preference

Context: Scutellaria baicalensis Georgi (Lamiaceae) has been used as a traditional herbal preparation for the treatment of neuropsychiatric disorders in Asian countries for centuries.

Objective: To evaluate the effects of S. baicalensis on morphine-induced drug dependence in rats.

Materials and methods: In order to evaluate the effect of S. baicalensis and baicalin on morphine-induced dependence-like behavior, a water extract of S. baicalensis [500?mg/kg, intraperitoneally (i.p.)] or baicalin (50?mg/kg, i.p., a flavonoid found in S. baicalensis) was administered prior to morphine injection [5 and 2.5?mg/kg, respectively, subcutaneously (s.c.)] to rats for 8 and 4?d, respectively. Morphine-induced conditioned place preference was assessed by measuring the time spent in a drug-paired chamber. The effect of S. baicalensis on dopamine receptor supersensitivity (locomotor activity) and dopamine agonist-induced climbing behavior due to a single apomorphine treatment (2?mg/kg, s.c.) was also measured.

Results: At 50?mg/kg, a water extract of S. baicalensis decreased morphine (5?mg/kg)-induced conditioned place preference by 86% in rats. Apomorphine (2?mg/kg)-induced locomotor activity (dopamine receptor supersensitivity) in rats and climbing behavior in mice were attenuated after pretreatment with 500?mg/kg of S. baicalensis water extract by 41% and 56%, respectively. In addition, baicalin-reduced morphine-induced conditioned places preference by 86% in rats at 50?mg/kg.

Discussion and conclusion: These results suggest that S. baicalensis can ameliorate drug addiction-related behavior through functional regulation of dopamine receptors.