[show abstract][hide abstract] ABSTRACT: A single exposure to drugs of abuse produces an NMDAR (N-methyl-D-aspartate receptor)-dependent synaptic potentiation at excitatory synapses of dopamine (DA) neurons in the ventral tegmental area (VTA) of the midbrain. All addictive drugs can increase DA concentrations in projection areas of the midbrain, including the hippocampus. Hippocampal DA release subsequently modulates hippocampal plasticity and drug-associated memories. Using in vivo electrophysiological recording techniques in anesthetized rats, we show that systemic injection of morphine induced hippocampal synaptic potentiation in a dose-dependent manner. Intra-VTA but not intra-hippocampus injection of morphine evoked this potentiation. Local hippocampal dopamine D1 receptors (D1R) are required in the morphine-induced synaptic potentiation and conditioned place preference (CPP). Moreover, both NMDAR activation in the VTA and VTA/hippocampus dopaminergic connections are essential for the morphine-evoked potentiation and CPP. These findings suggest that NMDAR signalings in the midbrain play a key role in regulating dopamine-mediated hippocampal synaptic plasticity underlying drug-induced associative memory.
[show abstract][hide abstract] ABSTRACT: Evidence suggests that the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP dependent protein kinase (PKG) signaling pathway plays a key role in memory processing, but the actual participation of this signaling cascade in the hippocampal CA1 during morphine-induced reward memory remains unknown. In this study, we investigated the role of the NO/sGC/PKG signaling pathway in the CA1 on morphine-induced reward memory using a conditioned place preference (CPP) paradigm. We found that rats receiving an intraperitoneal (i.p.) injection of 4mg/kg morphine exhibited CPP, whereas rats treated with only 0.2mg/kg morphine failed to produce CPP. Intra-CA1 injection of the neuronal NO synthase (nNOS) inhibitor 7-NI, the sGC inhibitor ODQ or the PKG inhibitor Rp-8-Br-PET-cGMPS had no effect on the acquisition of CPP by 4mg/kg morphine. Intra-CA1 injection of 7-NI blocked the consolidation of CPP induced by 4mg/kg morphine, and this amnesic effect of 7-NI was mimicked by ODQ and Rp-8-Br-PET-cGMPS. Intra-CA1 injection of the NOS substrate L-arg or the sGC activator YC-1 with an ineffective dose of morphine (0.2mg/kg, i.p.) elicited CPP. This response induced by L-arg or YC-1 was reversed by pre-microinjection of Rp-8-Br-PET-cGMPS in the CA1. These results indicated that the activation of the NO/sGC/PKG signaling pathway in the CA1 is necessary for the consolidation of morphine-related reward memory.
Neurobiology of Learning and Memory 07/2012; 98(2):130-8. · 3.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: Learned associations between the rewarding effect of addictive drugs and drug-paired contexts resist extinction and contribute to the high rate of relapse observed in drug addicts. Although it has been shown that extracellular signal-regulated kinase 1/2 (ERK1/2) activity in the nucleus accumbens (NAc) is modulated by the primary rewarding effect of opiates, little is known as to its role in the morphine-associated contextual memory. In the present study, we investigated the ERK1/2 activity indicated by phosphorylated ERK1/2 (pERK1/2) levels in rats using a morphine-induced conditioned place preference (CPP) procedure. Our results showed that, in rats that had undergone morphine conditioning, after testing (expression phase) pERK1/2 in the NAc shell but not the NAc core or the adjacent caudate putamen was specifically increased. pERK1/2 levels in several other parts of the brain involved in drug-seeking, such as the medial prefrontal cortex, dorsal hippocampus, and basolateral amygdala, showed no significant changes. A significant positive correlation was observed between the elevated pERK1/2 level in the NAc shell and the degree of conditioned preference for morphine-associated contexts. Bilateral injection of an inhibitor of ERK activation into the NAc shell attenuated ERK1/2 phosphorylation and prevented the expression of morphine CPP, but injections into the core did not. Selective inhibition of NR2B-containing NMDA receptor in the NAc shell by ifenprodil prevented CPP expression and down-regulated local ERK1/2 phosphorylation. These findings collectively suggest that recall of morphine-associated contextual memory depends specifically upon ERK1/2 activation in the NAc shell and that ERK1/2 phosphorylation is regulated by the upstream NR2B-containing NMDA receptor.
Brain research bulletin 07/2012; 89(1-2):22-30. · 2.18 Impact Factor
[show abstract][hide abstract] ABSTRACT: Electroacupuncture (EA) has been clinically applied for treating different medical conditions, such as pain, strain, and immune diseases. Low- and high-frequency EAs have distinct therapeutic effects in clinical practice and experimental studies. However, the molecular mechanism of this difference remains obscure. The arcuate nucleus (Arc) is a critical region of the hypothalamus and is responsible for the effect of EA stimulation to remote acupoints. Gene expression profiling provides a powerful tool with which to explore the basis of physiopathological responses to external stimulus. In this study, using cDNA microarray, we investigated gene expressions in the rat Arc region induced by low-frequency (2-Hz) and high-frequency (100-Hz) EAs to two remote acupoints, zusanli (ST36) and sanyinjiao (SP6). We have found that more genes were differentially regulated by 2-Hz EA than 100-Hz EA (154 vs. 66 regulated genes/ESTs) in Arc, especially those related to neurogenesis, which was confirmed by qRT-PCR. These results demonstrate that the expression level of genes in the Arc region could be effectively regulated by low-frequency EA, compared with high-frequency EA, helping to uncover the mechanisms of the therapeutic effects of the low-frequency EA. Our results also indicate different-frequency EAs are spatially specific.
Journal of Neuroscience Research 03/2012; 90(7):1464-73. · 2.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: Our previous study demonstrated that morphine dose- and time-dependently elevated dopamine (DA) concentrations in the nucleus accumbens (NAc) during the expression of morphine-induced conditioned place preference (CPP) in rats. However, still unknown are how DA concentrations dynamically change during the morphine-induced CPP test and whether tyrosine hydroxylase (TH) activity in the ventral tegmental area (VTA) plays a vital role in this process. In the present study, we measured dynamic changes in TH and phosphorylated TH serine 40 (pTH Ser(40)) and pTH Ser(31) proteins in the VTA, and DA concentrations in the NAc at 5 min intervals during a 30 min morphine-induced CPP test. Rats that underwent morphine-induced CPP training significantly preferred the morphine-paired chamber during the CPP expression test, an effect that lasted at least 30 min in the drug-free state. DA concentrations in the NAc markedly increased at 15 min when the rats were returned to the CPP boxes to assess the expression of preference for the previously drug-paired chamber. DA concentrations then declined 2 h after the CPP test. TH and pTH Ser(40) levels, but not pTH Ser(31) levels, in the VTA were enhanced during the CPP test. These results indicated that TH and the phosphorylation of TH Ser(40) in the VTA may be responsible for DA synthesis and release in the NAc during the behavioral expression of conditioned reward elicited by a drug-associated context.
Neurochemical Research 03/2012; 37(7):1482-9. · 2.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: Activity-regulated cytoskeleton-associated protein (Arc), also known as activity-regulated gene 3.1 (Arg3.1), is an immediate early gene whose mRNA is selectively targeted to recently activated synaptic sites, where it is translated and enriched. This unique feature suggests a role for Arc/Arg3.1 in coupling synaptic activity to protein synthesis, leading to synaptic plasticity. Although the Arc/Arg3.1 gene has been shown to be induced by a variety of abused drugs and its protein has been implicated in diverse forms of long-term memory, relatively little is known about its role in drug-induced reward memory. In this study, we investigated the potential role of Arc/Arg3.1 protein expression in reward-related associative learning and memory using morphine-induced conditioned place preference (CPP) in rats. We found that (1) intraperitoneal (i.p.) injection of morphine (10mg/kg) increased Arc/Arg3.1 protein levels after 2h in the NAc core but not in the NAc shell. (2) In CPP experiments, Arc/Arg3.1 protein was increased in the NAc shell of rats following both morphine conditioning and the CPP expression test compared to rats that received the conditioning without the test or those that did not receive morphine conditioning. (3) Microinjection of Arc/Arg3.1 antisense oligodeoxynucleotide (AS) into the NAc core inhibited the acquisition, expression and reinstatement of morphine CPP; however, intra-NAc shell infusions of the AS only blocked the expression of CPP. These findings suggest that expression of the Arc/Arg3.1 protein in the NAc core is required for the acquisition, context-induced retrieval and reinstatement of morphine-associated reward memory, whereas Arc/Arg3.1 protein expression in the NAc shell is only critical for the context-induced retrieval of memory. As a result, Arc/Arg3.1 may be a potential therapeutic target for the prevention of drug abuse or the relapse of drug use.
Behavioural brain research 09/2011; 223(1):182-91. · 3.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: Drug addiction, as well as learning and memory, share common mechanisms in terms of neural circuits and intracellular signaling pathways. In the present study, the role of N-methyl-D-aspartate (NMDA) receptors, particularly those containing NR2B subunits, in morphine-induced conditioned place preference (CPP) and Morris water maze (MWM) learning and memory task was investigated. CPP was used as a paradigm for assessing the rewarding effect of morphine, and MWM was used to measure spatial learning and memory in male Sprague-Dawley rats. We found that ifenprodil, an antagonist highly selective for NR2B-containing NMDA receptors, dose-dependently blocked the development, maintenance and reinstatement of morphine-induced CPP, without evident impairment of the acquisition and retrieval of spatial memory in the MWM task. However, the consolidation of spatial memory was disrupted by a high dose (10 mg/kg) of ifenprodil. These results clearly demonstrate that NR2B-containing NMDA receptors are actively involved in addiction memory induced by morphine conditioning, but not in the acquisition and retrieval of spatial learning and memory. In conclusion, NR2B-containing NMDA receptors can be considered potential targets for the treatment of opiate addiction.
Neurochemical Research 03/2011; 36(3):383-91. · 2.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: In a previous paper we reported that electroacupuncture (EA) could suppress opioid withdrawal syndrome and increase the appetite, sleep, and body weight in heroin addicts or morphine dependent animals. Considering that opioids were known to inhibit immune function, the present study was designed to observe whether EA could modulate the immune status of morphine dependent and withdrawal mice. We found that chronic morphine-induced decrease of splenic T lymphocyte proliferation and IL-2 production can be significantly raised by 2 Hz EA, and the fluctuation of CD4(+)/CD8(+) ratio was also run to the baseline level by the EA. These findings indicated that chronic morphine exposure-induced immune dysfunction in mice could be normalized by 2 Hz EA.
Evidence-based Complementary and Alternative Medicine 01/2011; 2011:424092. · 1.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: Alleviating opiate withdrawal syndrome in addicts is a critical precondition to break away from drug and further to prevent reuse. Electroacupuncture (EA) was claimed to be effective for alleviating withdrawal syndrome, but the optimal protocol remained unclear. In the present study we found that (1) 100 Hz EA administered 12-24h after the last morphine injection suppressed the withdrawal syndrome in rats, multiple sessions of EA were more effective than single session, with the after-effect lasting for at least 7 days. (2) A down-regulation of preprodynorphin (PPD) mRNA level was observed in spinal cord, PAG and hypothalamus 60 h after the last morphine injection, which could be reversed by multiple sessions, but not a single session of EA. (3) Accompanied with the decrease of PPD mRNA level, there was an up-regulation of p-CREB in the three CNS regions, which was abolished by 100 Hz EA treatment. The findings suggest that down-regulation of p-CREB and acceleration of dynorphin synthesis in spinal cord, PAG and hypothalamus may be implicated in the cumulative effect of multiple 100Hz EA treatment for opioid detoxification.
[show abstract][hide abstract] ABSTRACT: To assess the efficacy of transcutaneous electrical acupoint stimulation (TEAS) in preventing the relapse of detoxified heroin users in a period of 12 months.
A total of 164 rehabilitating heroin users in Shanghai area were recruited after compulsory detoxification treatment for a period ranging from 3 months to 3 years. The TEAS was executed by the device named Han's acupoint nerve stimulator (HANS). The patients were treated with HANS for at least 3 months. All the subjects were then followed up for one year and relapse was monitored by monthly heroin/morphine urinalysis.
Of 164 rehabilitating former heroin addicts, 53 remained drug-free at the end of 12 months observation period as judged by negative urinalysis while 35 become relapsed as documented by positive urine tests. The rest 76 dropped off due to various reasons and were all counted into the category of "relapsed". Thus, our data indicated 32.3% rehabilitating heroin users could stay sober for at least one year, which is significantly higher than the existing reports that less than 5% detoxified abusers would stay drug free for one year with no further intervention. No obvious correlation was found between the susceptibility of relapse and the duration of compulsory detoxification.
Compared to the existing literatures, our results indicate that HANS could produce a marked decrease of the relapse rate of rehabilitating heroin users after compulsory detoxification.
[show abstract][hide abstract] ABSTRACT: It is generally believed that temporary moderate stress to a living organism has protective and adaptive effects, but little is known about the responses of CNS to the moderate stresses at molecular level. This study aims to investigate the gene expression changes induced by moderate stress in CNS stress- and nociception-related regions of rats. Moderate restraint was applied to rats for 50 min and cDNA microarrays were used to detect the differential gene expression in different CNS regions. Transcriptome profiling analysis showed that at acute stage stress-related genes were up-regulated in arcuate nucleus; fight-or-flight behavior-related genes were up-regulated in periaqueductal gray, while nitric oxide and GABA signal transmission-related genes were up-regulated in spinal dorsal horn. In addition, immune-related genes were broadly regulated, especially at the late stage. These results suggested that specific genes of certain gene ontology categories were spatiotemporally regulated in specific CNS regions related to relevant functions under moderate external stimuli at acute stage, while immune response was broadly regulated at the late stage. The co-regulated genes among the three different CNS regions may play general roles in CNS when exposed to moderate stress. Furthermore, these results will help to elucidate the physiological processes involved in moderate stress in CNS.
Journal of Neurochemistry 03/2010; 113(6):1436-46. · 3.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: Sleep disturbance is considered as an important symptom of acute and protracted opiate withdrawal. Current results suggest that sleep disturbance may be taken as a predictor of relapse. Appropriate sleep enhancement therapy will be in favor of the retention in treatment for opiate addicts. Our previous studies have shown that electroacupuncture (EA) is effective in suppressing morphine withdrawal syndrome. The aim of the present study is to investigate the effect of 2 and 100 Hz EA on the sleep disturbance during morphine withdrawal. Rats were made dependent on morphine by repeated morphine injections (escalating doses of 5-80 mg kg(-1), subcutaneously, twice a day) for 5 days. EA of 2 or 100 Hz was given twice a day for 3 days, starting at 48 h after the last morphine injection. Electroencephalogram and electromyogram were monitored at the end of the first and the last EA treatments, respectively. Results showed that non-rapid eye movement (NREM) sleep, REM sleep and total sleep time decreased dramatically, while the sleep latency prolonged significantly during acute morphine withdrawal. Both 2 and 100 Hz EA produced a significant increase in NREM sleep, REM sleep and total sleep time. It was suggested that EA could be a potential treatment for sleep disturbance during morphine withdrawal.
Evidence-based Complementary and Alternative Medicine 10/2009; 2011:361054. · 1.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: Our previous studies have demonstrated that morphine-induced conditioned place preference (CPP) can be inhibited by 2 Hz electroacupuncture (EA). This inhibition can be blocked by either the opioid receptor antagonist naloxone (i.p.) or lesion in the nucleus accumbens (NAc), providing evidence that endogenous opioid system in the NAc mediates the effects of EA. Here we report that 1) A single session of 2 Hz EA produced a significant increase of the content of enkephalin in the NAc of morphine-induced CPP rats, and this effect was stronger in three consecutive sessions of EA; 2) Intracerebroventricular injection of the mu-opioid receptor antagonist CTAP or delta-opioid receptor antagonist NTI, but not kappa-opioid receptor antagonist nor-BNI, dose-dependently reversed the inhibitory effects of 2 Hz EA on the expression of morphine-induced CPP; 3) Three consecutive sessions of 2 Hz EA up-regulated the mRNA level of preproenkephalin in the NAc of morphine-induced CPP rats. The results suggest that the inhibitory effects of 2 Hz EA on the expression of the morphine CPP is mediated by mu- and delta-, but not kappa-opioid receptor, possibly via accelerating both the release and synthesis of enkephalin in the NAc. These findings support the possibility of using 2 Hz EA for the treatment of opiate addiction.
[show abstract][hide abstract] ABSTRACT: The dopamine (DA) projections from the ventral tegmental area to the nucleus accumbens (NAc) are the key component of the brain reward circuitry. The encoded information by DA in reward-related memory within this circuit during opiate reinforcement requires further clarification. The present study was designed to explore the correlations between morphine dose, retention of morphine-induced conditioned place preference (CPP), morphine-induced changes in levels of DA and its metabolites in the NAc in expression and retention of CPP in Sprague-Dawley male rats. A dose-effect curve for morphine-induced CPP (0.01-10 mg/kg, i.p.) was obtained using 4-day conditioning sessions followed by a CPP test; the retention of morphine CPP was measured with CPP tests after the development of CPP. We found a dose-dependent effect of morphine (from 0.01 to 10.0 mg/kg, i.p.) on both the magnitude and the retention of CPP. During the retention of morphine-induced CPP, a morphine-dose- and time-dependent elevation of DA and its metabolites was observed in the NAc. These changes were absent if the same dose of morphine was injected outside of the conditioning environment (i.e., in the home cage). These results suggest that that the long-lasting elevation of DA and its metabolites in the NAc is attributable mainly to drug-associated context, rather than the residual effect of morphine.
Behavioural brain research 07/2009; 204(1):192-9. · 3.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: Chronic morphine administration decreases the size of dopamine (DA) neurons in the ventral tegmental area (VTA). These transient morphological changes are accompanied by a reduced sensitivity of morphine-induced conditioned place preference (CPP) after chronic exposure to the drug. In this study we examined alterations in the firing rate of DAergic neurons by means of extracellular recording following chronic morphine exposure and applied 100 Hz electroacupuncture (EA) treatment to reverse the reduced firing rate of these neurons. In the first set of experiments we show that in rats, which received chronic morphine treatment for 14 days, a small dose of morphine was not able to induce a CPP response anymore. However, the sensitivity to morphine was reinstated by consecutive EA treatment for 10 days. The electrophysiological response of VTA DA neurons to morphine was markedly reduced in chronic morphine-treated rats compared to saline-treated controls. A substantial recovery of the reactivity of VTA DA neurons to morphine was observed in rats that received 100 Hz EA for 10 days. Our findings suggest that 100 Hz EA is a potential therapy for the treatment of opiate addiction by normalizing the activity of VTA DA neurons.
[show abstract][hide abstract] ABSTRACT: The past decade has witnessed an impressive accumulation of evidence indicating that the excitatory amino acid glutamate and its receptors, in particular the N-methyl-D-aspartate (NMDA) receptor subtype, play an important role in drug addiction. Various lines of research using animal models of drug addiction have demonstrated that drug-induced craving is accompanied by significant upregulation of NR2B subunit expression. Furthermore, selective blockade of NR2B-containing NMDA receptors in the striatum, especially in the nucleus accumbens (NAc) can inhibit drug craving and reinstatement. The purpose of this review is to examine the role of striatal NMDA receptors in drug addiction. After a brief description of glutamatergic innervation and NMDA receptor subunit distribution in the striatum, we discuss potential mechanisms to explain the role of striatal NMDA receptors in drug addiction by elucidating signaling cascades involved in the regulation of subunit expression and redistribution, phosphorylation of receptor subunits, as well as activation of intracellular signals triggered by drug experience. Understanding the mechanisms regulating striatal NMDA receptor changes in drug addiction will provide more specific and rational targets to counteract the deleterious effects of drug addiction.
International Review of Neurobiology 01/2009; 89:131-46. · 1.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Over the last three decades there has been an increasing interest in acupuncture treatment of substance abuse around the world. Three important steps can be identified in this field. Dr. H. L. Wen of Hong Kong was the first (1973) to report that acupuncture at 4 body points and 2 ear points combined with electrical stimulation can relieve opiate withdrawal signs in the addicts. The second major step was made by Dr. M. Smith in New York, the head of the National Acupuncture Detoxification Association (NADA) of the U.S.A., who finalized a protocol (1985), using only ear points without electrical stimulation for the treatment of drug abuse. The recent advance in this field was made by Prof. J. S. Han and his colleagues in Neuroscience Research Institute of the Peking University, Beijing, who characterized a protocol (1992- ), using electrical stimulation of identified frequencies on body points to ameliorate heroin withdrawal signs and prevent relapse to heroin use. In this review, the efficacy of acupuncture and related techniques for the treatment of drug dependence in experimental settings and clinical practice will be reviewed, and the possible mechanisms underlying this effect be discussed.
Sheng li ke xue jin zhan [Progress in physiology] 11/2008; 39(4):325-30.
[show abstract][hide abstract] ABSTRACT: Electroacupuncture (EA) has been shown to modify the effects of various drugs of abuse, including alcohol. Inbred P rats were trained to drink alcohol voluntarily and then subjected to two periods of alcohol deprivation lasting 3 days. During the second deprivation, the rats received either EA or sham EA. The rats were pretreated with naltrexone (5 mg/kg) or saline 30 min before each of the EA or sham EA sessions. Approximately 6 h after the last naltrexone or saline treatment, the alcohol tubes were returned and alcohol and water intakes were recorded later at 2, 4, 6, and 24 h. Only EA led to a decrease in alcohol intake, which was most prominent at 6 and 24 h, and this inhibitory effect of EA was blocked by naltrexone, suggesting that activation of the endogenous opiate system may be responsible for EA's effects on alcohol intake in the alcohol-dependent iP rats.
Neurochemical Research 10/2008; 33(10):2166-70. · 2.13 Impact Factor