Roles of 5-HT3 and opioid receptors in the ethanol-induced place preference in rats exposed to conditioned fear stress.

The effect of the selective 5-HT3 receptor antagonist ondansetron on the ethanol-induced place preference in rats exposed to conditioned fear stress, which stimulates the release of endogenous opioid peptides (beta-endorphin and enkephalins), was investigated using the conditioned place preference paradigm. In addition, we also examined the effect of ondansetron on the ethanol-induced place preference enhanced by the administration of mu- and delta-opioid receptor agonists (exogenous opioids). The administration of ethanol (300 mg/kg, i.p.) induced a significant place preference in rats exposed to conditioned fear stress. Pretreatment with ondansetron (0.01 and 0.1 mg/kg, s.c.) effectively attenuated this ethanol-induced place preference. When the mu-opioid receptor agonist morphine (0.1 mg/kg, s.c.) or the selective delta-opioid receptor agonist 2-methyl-4a(alpha)-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a(alpha)-octah ydroquinolino [2,3,3-g] isoquinoline (TAN-67; 20 mg/kg, s.c.) was administered in combination with 75 mg/kg ethanol (which tended to produce a place preference), the ethanol-induced place preference was significantly enhanced. The selective mu-opioid receptor antagonist beta-funaltrexamine at a dose of 10 mg/kg significantly attenuated the enhancement of the ethanol-induced place preference produced by morphine. Ondansetron (0.1 mg/kg, s.c.) also significantly attenuated the enhancement of the ethanol-induced place preference produced by morphine. Furthermore, the selective delta-opioid receptor antagonist naltrindole at a dose of 3 mg/kg significantly attenuated the enhancement of the ethanol-induced place preference produced by TAN-67. Ondansetron (0.1 mg/kg, s.c.) slightly, but significantly, attenuated the enhancement of the ethanol-induced place preference produced by TAN-67. These results suggest that 5-HT3 receptors may be involved in the rewarding mechanism of ethanol under psychological stress, and may play an important role in the rewarding effect of ethanol through the activation of mu- and delta-opioid receptors.     

Dopamine-dependent responses to cocaine depend on corticotropin-releasing factor receptor subtypes

The effects on locomotor response to cocaine challenge, acquisition of cocaine conditioned place preference and cocaine-induced dopamine (DA) release in nucleus accumbens and ventral tegmental area by the non-specific corticotropin-releasing factor (CRF) receptors antagonist alpha-helical CRF, the selective CRF receptor subtype 1 antagonist CP-154,526 and the selective CRF receptor subtype 2 antagonist anti-sauvagine-30 (AS-30) were investigated in rats. Both alpha-helical CRF (10 microg, i.c.v.) and CP-154,526 (3 microg, i.c.v.) decreased the cocaine-induced distance travelled, whereas AS-30 (3 microg, i.c.v.) did not show such an effect. The CRF receptor antagonists also have significant effects on stereotype counts induced by cocaine injection, in which the alpha-helical CRF or CP-154,526 but not AS-30 did significantly reduce the stereotype counts. alpha-Helical CRF (10 microg) prior to each injection of cocaine blocked cocaine conditioned place preference with no significant difference observed in the time spent in the drug-paired side between post- and pre-training and both 1 and 3 microg CP-154,526 also had significant inhibitory effects on cocaine-induced place preference. However, pre-treatment with an i.c.v. infusion of AS-30 (1 or 3 microg) prior to each injection of cocaine did not affect the acquisition of conditioned place preference. The alpha-helical CRF and CP-154,526 reduced extracellular DA levels of nucleus accumbens and ventral tegmental area in response to the injection of cocaine. However, both alpha-helical CRF and CP-154,526 did not modify extracellular DA levels under basal conditions. In contrast, the i.c.v. infusion of AS-30 had no effects on either the basal DA or the cocaine-induced increase in DA release in nucleus accumbens and ventral tegmental area. These findings demonstrate that activation of the CRF receptor is involved in behavioral and neurochemical effects of cocaine challenge and cocaine reward and that the role of CRF receptor subtypes 1 and 2 in cocaine-induced locomotion, reward and DA release is not identical. The CRF receptor subtype 1 is largely responsible for the action of the CRF system on cocaine locomotion and reward. These results suggest that the CRF receptor antagonist, particularly the CRF receptor subtype 1 antagonist, might be of some value in the treatment of cocaine addiction and cocaine-related behavioral disorders.     

Clozapine attenuates cocaine conditioned place preference

Clozapine, an atypical neuroleptic, has dopamine and serotonin antagonist actions that suggest its potential as a cocaine abuse pharmacotherapy. Yet, self-administration and discriminative stimulus studies in animals have reported both an enhancement and a partial blockade of cocaine's behavioral effects with clozapine. The present study examines further the effects of clozapine on cocaine conditioned place preference. Clozapine (10 mg/kg, s.c.) treatment significantly attenuated the development of cocaine (10mg/kg, i.p.) conditioned place preference. These results, coupled with research that shows clozapine has limited extrapyramidal side effects, suggest that it should be considered as a pharmacotherapy for cocaine abuse.     

Enhancing effects of morphine on methamphetamine-induced reinforcing behavior and its association with dopamine release and metabolism in mice

Polydrug abuse has become a significant problem worldwide, and the combined use of methamphetamine (MA) and morphine (M) is now highly prevalent among addicts. In the present study, we investigated the neurobehavioral effects of repeated treatment regimens of these drugs (i.p. administration of 0.75 mg/kg/day MA, 5 mg/kg/day M, and their combination for five consecutive days followed by once weekly for five consecutive weeks) in mice. In addition, we used an in vivo microdialysis technique to study the changes in extracellular concentrations of dopamine (DA) and its metabolites in the mouse striatum after challenge administration of these drugs. The results showed that systemic M increased MA-induced conditioned place preference (CPP), as revealed by higher CPP values which were also maintained for a longer duration compared with those induced by an identical dose of MA or M alone. Subsequent to challenge with combined MA and M, mice exhibited an increase in stereotyped behavior, which appeared to be associated with an elevation of extracellular concentration of DA in the striatum. Our findings suggest that M not only produces synergistic effects on MA-induced CPP, but also interacts with MA to induce stereotyped behavioral sensitization which is mediated by an increase in DA outflow in the striatum. These findings provide insight into the behavioral and neurochemical basis responsible for the combined abuse liability of MA and M.     

Effects of the non-competitive NMDA receptor antagonist ketamine on morphine-induced place preference in mice

The effects of ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, on morphine-induced place preference were examined in mice. Morphine (1-5 mg/kg, s.c.) produced a dose-related place preference in mice. Ketamine alone (3, 10 mg/kg, i.p.), like dizocilpine alone (0.2 mg/ kg, i.p.), also produced a preference for the drug-associated place. Pretreatment with ketamine (10 mg/ kg, i.p.) or dizocilpine (0.1 and 0.2 mg/kg, i.p) suppressed the place preference produced by morphine in a dose-dependent manner. These findings provide the first demonstration that ketamine alone produces a place preference using the conditioned place preference (CPP) paradigm, but that mice treated with ketamine combined with morphine show neither a morphine- nor a ketamine-induced place preference.     

GABA(B) receptor agonist baclofen attenuates the development and expression of d-methamphetamine-induced place preference in rats

The present study investigated the effect of systemic administration of the GABA(B) receptor agonist, baclofen, on the development and expression of d-methamphetamine (d-MA)-induced place preference in male Wistar rats. Using a biased and 8-day schedule of conditioning, it was found that administration of d-MA (0.5 mg/kg, i.p.) produced significant place preference. The administration of baclofen (2.5 and 5.0 mg/kg, i.p.) 30 min prior to the exposure to d-MA attenuated the development of d-MA-induced place preference (p<0.05). In addition, when it was acutely administered 30 min prior to the testing session of an already established d-MA place preference, baclofen (1.25-5.0 mg/kg, i.p.) attenuated the expression of this conditioned response in a dose-dependent manner. These results showed that baclofen suppressed the rewarding effect produced by d-MA and may be potentially effective in the treatment of methamphetamine dependence and craving.     

Adrenalectomy potentiates the morphinebut not cocaine-induced place preference in rats

The conditioned place preference paradigm is commonly used to study the reinforcing properties of various drugs. In the present study, the effect of adrenalectomy (ADX) on the morphine-induced place preference was examined in rats. Morphine produced a significant preference for the drug-associated place in sham-operated (sham) and ADX rats. In sham rats, only the highest dose of morphine (8 mg/kg, i.p.) produced a significant preference, while in ADX rats, lower doses of morphine (1 and 2 mg/kg, i.p.) produced a significant preference for the drug-associated place. Furthermore, the morphine-induced place preference was blocked by the dopamine D₁ antagonist SCH23390 in both sham and ADX rats. On the other hand, the cocaineinduced place preference was not affected by ADX. In the present study, we found that ADX potentiates the reinforcing effect induced by morphine, but not that induced by cocaine, which suggests that the enhancement by ADX may be due to a change in opioid receptors, morphine metabolism and/or some other cause, but not to a change in dopamine receptors.     

Effects of a lipopolysaccharide from Pantoea agglomerans on the cocaine-induced place preference

A lipopolysaccharide from Pantoea agglomerans (LPSp) was purified, and its effect on the cocaine-induced place preference was examined in rats. Cocaine (4 mg/kg, i.p.) produced a significant place preference. Administration of LPSp (5 – 1000 μg/kg, i.p.) alone resulted in neither preference nor aversion for either the drug- or saline-associated place. However, pretreatment with LPSp (500 and 1000 μg/kg, i.p.) abolished the place preference that had been induced by cocaine. Furthermore, treatment with LPSp (500 μg/kg, i.p.) abolished cocaine (20 mg/kg, i.p.)-induced locomotor enhancement in mice. These results suggest that while LPSp itself may possess neither reinforcing nor locomotor enhancing effects, it blocks both the reinforcing and the locomotor enhancing effects of cocaine. Therefore, LPSp might be useful in pharmacotherapy for prevention of recurrent cocaine abuse.     

Dansyl-PQRamide, a possible neuropeptide FF receptor antagonist, induces conditioned place preference

Neuropeptide FF (NPFF) is an endogenous anti-opioid peptide. NPFF could potentiate the naloxone-precipitated morphine withdrawal syndromes in morphine-dependent rats, indicating the possible involvement of the endogenous NPFF system in opioid analgesia and dependence. The present study was performed to examine the effects of dansyl-PQRamide (dns-PQRa), a putative NPFF antagonist, on conditioned place preference (CPP), in addition, its interaction with the opioid system. Two CPP experiments were conducted. First, rats were treated with dns-PQRa (4-13 mg/kg, i.p.) and paired with the non-preferred compartment while the vehicle was paired with the preferred compartment. Second, similar to experiment 1 except naloxone (1 mg/kg, i.p.) was given 10 min prior to each dns-PQRa administration. The post-drug place preference was examined after 4 alternative pairings. Another group of animals after repetitive dns-PQRa treatments were analyzed for levels of neurotransmitters in discrete brain areas. Dns-PQRa (4-13 mg/kg, i.p.) induced a significant dose-dependent CPP. The dns-PQRa-induced CPP was completely blocked by pretreatment with 1 mg/kg i.p. naloxone, while naloxone alone did not induce any place aversion. The chronic dns-PQRa-treated (13 mg/kg, i.p., b.i.d.) rats caused a significant increase in 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid in the olfactory tubercle compared to the vehicle-treated controls. There was also an increase in the turnover of serotonin in the olfactory tubercle, nucleus accumbens and medial prefrontal cortex. These results suggest that blockade of the NPFF system produces rewarding, possibly via an inhibition of the anti-opioid action of NPFF. These results also reveal a close relationship between NPFF, drug rewarding and the dopaminergic and serotoninergic neurons in the mesolimbic system.     

Conditional Knockout of NMDA Receptors in Dopamine Neurons Prevents Nicotine-Conditioned Place Preference

Nicotine from smoking tobacco produces one of the most common forms of addictive behavior and has major societal and health consequences. It is known that nicotine triggers tobacco addiction by activating nicotine acetylcholine receptors (nAChRs) in the midbrain dopaminergic reward system, primarily via the ventral tegmental area. Heterogeneity of cell populations in the region has made it difficult for pharmacology-based analyses to precisely assess the functional significance of glutamatergic inputs to dopamine neurons in nicotine addiction. By generating dopamine neuron-specific NR1 knockout mice using cre/loxP-mediated method, we demonstrate that genetic inactivation of the NMDA receptors in ventral tegmental area dopamine neurons selectively prevents nicotine-conditioned place preference. Interestingly, the mutant mice exhibit normal performances in the conditioned place aversion induced by aversive air puffs. Therefore, this selective effect on addictive drug-induced reinforcement behavior suggests that NMDA receptors in the dopamine neurons are critical for the development of nicotine addiction.     

Morphine Dependence is Attenuated by Treatment of 3,4,5-Trimethoxy Cinnamic Acid in Mice and Rats

The effect of 3, 4, 5-trimethoxy cinnamic acid (TMCA) against morphine-induced dependence in mice and rats was investigated. Mice were pretreated with TMCA and then morphine was injected intraperitoneally; whereas rats were treated with TMCA (i.p.) and infused with morphine into the lateral ventricle of brain. Naloxone-induced morphine withdrawal syndrome and conditioned place preference test were performed. Moreover, western blotting and immunohistochemistry were used to measure protein expressions. Number of naloxone-precipitated jumps and conditioned place preference score in mice were attenuated by TMCA. Likewise, TMCA attenuated morphine dependent behavioral patterns such as diarrhea, grooming, penis licking, rearing, teeth chattering, and vocalization in rats. Moreover, the expression levels of pNR1and pERK in the frontal cortex of mice and cultured cortical neurons were diminished by TMCA. In the striatum, pERK expression was attenuated despite unaltered expression of pNR1 and NR1. Interestingly, morphine-induced elevations of FosB/ΔFosB⁺ cells were suppressed by TMCA (50, 100 mg/kg) in the nucleus accumbens sub-shell region of mice. In conclusion, TMCA could be considered as potential therapeutic agent against morphine-induced dependence.

     

眼镜蛇毒细胞毒素CTXn的致死毒性及药物依赖性研究

目的研究眼镜蛇毒细胞毒素CTXn的致死毒性和药物依赖性,评价其安全性。方法检测CTXn的LD50和对肝细胞色素P450含量的影响,采用大鼠催促戒断模型、自然戒断模型及大鼠条件性位置偏爱模型检测CTXn的药物依赖性。结果 CTXn的LD50为19.61 mg/kg,长期给药对肝细胞色素P450含量无影响。在催促戒断试验中,大鼠连续腹腔注射不同剂量CTXn(0.5、1.0、2.0 mg/kg)10天后经纳洛酮催促,未出现戒断症状及体重下降现象;在大鼠自然戒断试验中,CTXn连续给药21天,停药后大鼠没有出现戒断反应及体重下降现象;在大鼠条件性位置偏爱试验中,CTXn不同剂量组分别连续用药15天后,大鼠在伴药盒的逗留时间均无明显延长,不形成条件性位置偏爱。结论 CTXn毒性较小,长期给药对肝脏药物代谢功能无影响。且不具有身体依赖性及精神依赖性,有潜在的药物开发价值。     

Synaptic neurotransmission depression in ventral tegmental dopamine neurons and cannabinoid-associated addictive learning

Drug addiction is an association of compulsive drug use with long-term associative learning/memory. Multiple forms of learning/memory are primarily subserved by activity- or experience-dependent synaptic long-term potentiation (LTP) and long-term depression (LTD). Recent studies suggest LTP expression in locally activated glutamate synapses onto dopamine neurons (local Glu-DA synapses) of the midbrain ventral tegmental area (VTA) following a single or chronic exposure to many drugs of abuse, whereas a single exposure to cannabinoid did not significantly affect synaptic plasticity at these synapses. It is unknown whether chronic exposure of cannabis (marijuana or cannabinoids), the most commonly used illicit drug worldwide, induce LTP or LTD at these synapses. More importantly, whether such alterations in VTA synaptic plasticity causatively contribute to drug addictive behavior has not previously been addressed. Here we show in rats that chronic cannabinoid exposure activates VTA cannabinoid CB1 receptors to induce transient neurotransmission depression at VTA local Glu-DA synapses through activation of NMDA receptors and subsequent endocytosis of AMPA receptor GluR2 subunits. A GluR2-derived peptide blocks cannabinoid-induced VTA synaptic depression and conditioned place preference, i.e., learning to associate drug exposure with environmental cues. These data not only provide the first evidence, to our knowledge, that NMDA receptor-dependent synaptic depression at VTA dopamine circuitry requires GluR2 endocytosis, but also suggest an essential contribution of such synaptic depression to cannabinoid-associated addictive learning, in addition to pointing to novel pharmacological strategies for the treatment of cannabis addiction.     

Attenuation of morphine dependence and withdrawal in rats by venlafaxine, a serotonin and noradrenaline reuptake inhibitor.

The effects of venlafaxine, a novel serotonin and adrenaline reuptake inhibitor, on the morphine withdrawal and activation of morphine conditioned place preference (CPP), were investigated in rats. Our results showed that the most morphine withdrawal signs, including jumping, writhing, shakes, exploring, lacrimation, piloerection, irritability, and diarrhea, were attenuated by pretreatment with 10 or 20 mg/kg venlafaxine. To investigate the effects of venlafaxine on relapse to opiate dependence, the morphine CPP was used and a dopamine D2 antagonist sulpiride was selected as a control drug. The morphine CPP disappeared following a 28-day drug-free period and appeared again after given a single injection of 1 mg/kg morphine. Acute treatment with sulpiride (25 or 50 mg/kg, i.p.) 30 min prior to 1 mg/kg morphine injection significantly blocked the reacquisition of CPP, while venlafaxine (10 or 20 mg/kg, i.p.) did not show significant effect. However, chronic treatment with venlafaxine (5 or 10 mg/kg, i.p. twice, daily, for seven consecutive days) significantly attenuated the reacquisition of morphine CPP, whereas chronic treatment with sulpiride (10 or 20 mg/kg, i.p.) have no significant effect. Our results demonstrated for the first time that venlafaxine strongly attenuates morphine withdrawal and morphine-induced reaquisition of     

Effect of rhynchophylline on conditioned place preference on expression of NR2B in methamphetamine-dependent mice

Objective

To study the effect of rhynchophylline on N-methyl d-aspartate receptor subtype 2B subunit in hippocampus of Methamphetamine-induced conditioned place preference (CPP) mice.

Methods

Place preference mice models were established by methamphetamine; the expression of NR2B was observed by immunohistochemistry technique and Western blot.

Results

Methamphetamine (4 mg/kg)-induced place preference mice model was successfully established; ketamine (15 mg/kg), rhynchophylline (40 mg/kg) and rhynchophylline (80 mg/kg) can eliminate place preference; Immunohistochemistry showed that the number of NR2B-positive neurons in hippocampus was increased in the methamphetamine model group, whereas less NR2B-positive neurons were found in the ketamine group, low and high dosage rhynchophylline group. Western blot showed that the expression of NR2B protein was significantly increased in the model group, whereas less expression was found in the ketamine group, low and high dosage rhynchophylline group.

Conclusions

NR2B plays an important role in the formation of methamphetamine-induced place preference in mice. Rhynchophylline reversed the expression of NR2B in the hippocampus demonstrates the potential effect of mediates methamphetamine induced rewarding effect.     

Nociceptin differentially affects morphine-induced dopamine release from the nucleus accumbens and nucleus caudate in rats

The effects induced by nociceptin on morphine-induced release of dopamine (DA), 3,4-dihydroxyphenilacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens and nucleus caudate were studied in rats by microdialysis with electrochemical detection. Nociceptin administered intracerebroventricularly (i.c.v.) at doses of 2, 5 and 10 nmol/rat changed neither DA nor metabolites release in the shell of the nucleus accumbens or in the nucleus caudate. Morphine administered intraperitoneally (i.p.) (2, 5, and 10 mg/kg) increased DA and metabolites release more in the shell of the nucleus accumbens than in the nucleus caudate. When nociceptin (5 or 10 nmol) was administered 15 min before morphine (5 or 10 mg/kg), it significantly reduced morphine-induced DA and metabolites release in the shell of the nucleus accumbens, whereas only a slight, nonsignificant reduction was observed in the nucleus caudate. Our data indicate that nociceptin may regulate the stimulating action associated with morphine-induced DA release more in the nucleus accumbens than in the nucleus caudate, and are consistent with recent observations that nociceptin reversed ethanol- and morphine-induced conditioned place preference. Therefore, the nociceptin-induced reduction of DA release stimulated by morphine in the nucleus accumbens, and the results obtained with nociceptin in the conditioned place preference procedure suggest a role for nociceptin in the modulation of the behavioral and neurochemical effects of abuse drugs.     

The conditioned place preference paradigm in rats: effect of bupropion

The effect of bupropion in the conditioned place preference paradigm in rats is described. In doses between 10 and 50 mg/kg i.p. bupropion increased the time rats spent in a shuttle box compartment conditioned to this compound. This effect of bupropion was not blocked by pretreatment of the animals with 0.1 mg/kg i.p. haloperidol or 50 mg/kg i.p. sulpiride. The same doses of the neuroleptics did, however, attenuate locomotor hyperactivity induced by bupropion. Bupropion thus seems to belong to the group of CNS stimulants whose effect in the conditioned place preference paradigm is not blocked by neuroleptics.     

Importance of GluA1 subunit-containing AMPA glutamate receptors for morphine state-dependency

In state-dependency, information retrieval is most efficient when the animal is in the same state as it was during the information acquisition. State-dependency has been implicated in a variety of learning and memory processes, but its mechanisms remain to be resolved. Here, mice deficient in AMPA-type glutamate receptor GluA1 subunits were first conditioned to morphine (10 or 20 mg/kg s.c. during eight sessions over four days) using an unbiased procedure, followed by testing for conditioned place preference at morphine states that were the same as or different from the one the mice were conditioned to. In GluA1 wildtype littermate mice the same-state morphine dose produced the greatest expression of place preference, while in the knockout mice no place preference was then detected. Both wildtype and knockout mice expressed moderate morphine-induced place preference when not at the morphine state (saline treatment at the test); in this case, place preference was weaker than that in the same-state test in wildtype mice. No correlation between place preference scores and locomotor activity during testing was found. Additionally, as compared to the controls, the knockout mice showed unchanged sensitization to morphine, morphine drug discrimination and brain regional μ-opioid receptor signal transduction at the G-protein level. However, the knockout mice failed to show increased AMPA/NMDA receptor current ratios in the ventral tegmental area dopamine neurons of midbrain slices after a single injection of morphine (10 mg/kg, s.c., sliced prepared 24 h afterwards), in contrast to the wildtype mice. The results indicate impaired drug-induced state-dependency in GluA1 knockout mice, correlating with impaired opioid-induced glutamate receptor neuroplasticity.     

Cocaine-induced alterations in nucleus accumbens ionotropic glutamate receptor subunits in human and non-human primates

Chronic cocaine and withdrawal induce significant alterations in nucleus accumbens (NAc) glutamatergic function in humans and rodent models of cocaine addiction. Dysregulation of glutamatergic function of the prefrontal cortical-NAc pathway has been proposed as a critical substrate for unmanageable drug seeking. Previously, we demonstrated significant up-regulation of NMDA, (+/-)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptor subunit mRNAs and protein levels in the ventral tegmental area (VTA), but not the substantia nigra, of cocaine overdose victims (COD). The present study was undertaken to examine the extent of altered ionotropic glutamate receptor (iGluR) subunit expression in the NAc and the putamen in cocaine overdose victims. Results revealed statistically significant increases in the NAc, but not in the putamen, of NMDA receptor subunit (NR)1 and glutamate receptor subunit (GluR)2/3 wit trends in GluR1 and GluR5 in COD. These results extend our previous finding and indicate pathway-specific alterations in iGluRs in COD. In order to determine that changes were related to cocaine intake and not to other factors in the COD victims, we examined the effects of cocaine intravenous self-administration in rhesus monkeys for 18 months (unit dose of 0.1 mg/kg/injection and daily drug intake of 0.5 mg/kg/session). Total drug intake for the group of four monkeys was 37.9 +/- 4.6 mg/kg. Statistically significant elevations were observed for NR1, GluR1, GluR2/3 and GluR5 (p < 0.05) and a trend towards increased NR1 phosphorylated at serine 896 (p = 0.07) in the NAc but not putamen of monkeys self-administering cocaine compared with controls. These results extend previous results by demonstrating an up-regulation of NR1, GluR2/3 and GluR5 in the NAc and suggest these alterations are pathway specific. Furthermore, these changes may mediate persistent drug intake and craving in the human cocaine abuser.     

基于NR2B基因探讨疏肝与补肾法对吗啡精神依赖的调节作用及机制

目的：探讨补肾法与舒肝法对大鼠吗啡精神依赖的调节作用及机制。方法：使用盐酸吗啡建立大鼠精神依赖模型（conditioned place preference,CPP）,采用Obersiver5．0行为学软件分析大鼠的CPP效应,并利用RealtimePCR方法测定伏核和前额叶皮质内NR2B亚基的mRNA含量。结果：与对照组相比,模型组大鼠在白侧累积停留时间极显著长于对照组（P〈0．01）,同时伏核与前额叶皮质中NR2B的mRNA水平也显著升高（P〈0．01和P〈0．05）;与模型组相比,补肾组和舒肝组大鼠在白侧的累积停留时间显著下调（P〈0．05）,疏肝组NR2B的mRNA也显著下降（P〈0．05）,而补肾组变化不显著。结论：①补肾法与舒肝法对吗啡引起的精神依赖均有调节作用。②舒肝法的作用机制可能在于通过影响伏核和前额叶皮质中NR2B亚基的mRNA表达进一步调节精神依赖的相关神经通路。③补肾法的作用机制与NR2B亚基的mRNA表达关系不密切,其调节的具体机制尚有待研究。