At present, the problem of drug addiction treatment mainly lies in the high relapse rate of drug addicts. Addictive drugs will bring users a strong sense of euphoria and promote drug seeking. Once the drug is withdrawn, there will be withdrawal symptoms such as strong negative emotions and uncomfortable physical reactions. The recurrence of context-induced withdrawal memory is an important reason for drug relapse. Our previous study has shown increased c-Fos expression in prelimbic cortex (PrL) neurons projecting to paraventricular nucleus of the thalamus (PVT) (PrL^-PVT) during conditioned context-induced retrieval of morphine withdrawal memory. However, whether PrL^-PVT neurons are involved in withdrawal memory retrieval and the underlying molecular mechanisms remain unknown. In this study, we used conditioned place aversion (CPA) model combined with in vivo calcium signal recording, chemogenetics and nucleus drug injection methods to investigate the role and molecular mechanism of PrL^-PVT neurons in retrieval of morphine withdrawal memory. The results showed that the calcium signals of PrL^-PVT neurons were significantly enhanced by withdrawal-related context; Inhibition of PrL^-PVT neurons blocked the conditioned context-induced morphine withdrawal memory retrieval; Activation of PrL^-PVT neurons caused animals to escape from the context; After the inhibition of NMDA receptors in the PrL, withdrawal-related context failed to increase c-Fos and Arc expressions in PrL^-PVT neurons. The above results suggest that NMDA receptors in PrL^-PVT neurons are associated with retrieval of morphine withdrawal memory. This study is of great significance for further understanding the neural circuit mechanism of withdrawal memory retrieval as well as the intervention and prevention of drug relapse.
Animals ; Substance Withdrawal Syndrome/physiopathology* ; Morphine/adverse effects* ; Neurons/physiology* ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Male ; Rats ; Paraventricular Hypothalamic Nucleus/metabolism* ; Memory ; Rats, Sprague-Dawley ; Morphine Dependence/physiopathology* ; Midline Thalamic Nuclei/physiology* ; Neural Pathways/metabolism*

OBJECTIVETo study the changes of cognitive attention-related brain function in the heroin addicts before and after electro-acupuncture (EA) intervention for exploring the concerned neuro-mechanism of addictive relapse and the central action role of EA intervention.

METHODSAdopting event-related potential (ERP) technique, the ERP at 64 electrode spots in 10 heroin addicts (test group) were recorded before and after EA intervention with dot-probe experimental form during implementing cognitive task on positive emotional clue (PEC), negative emotional clues (NEC), and heroin-related clue (HRC). The P200 amplitude components on the selected observation points (Fz, Cz, and Pz) were analyzed and compared with those obtained from 10 healthy subjects as the control.

RESULTSBefore EA, the ERP of attention on HRC in the test group was higher than that on PEC and NEC (P<0.05) and significantly higher than that in the control group (P<0.05); after EA, the P200 amplitude of attention on HRC at Cz and Pz was significantly lowered (P<0.05) and that on PEC at Fz was significantly elevated (P<0.05). After EA, the P200 amplitude at Pz was ranked as NEC > PEC > HRC, but in the control group, it showed PEC > HRC at all three observation points and PEC > NEC at Pz.

CONCLUSIONHeroin addicts show attention bias to HRC, which could be significantly reduced by EA intervention, illustrating that EA could effectively inhibit the attention bias to heroin and so might have potential for lowering the relapse rate.

Adult ; Attention ; Case-Control Studies ; Cognition ; Electroacupuncture ; Evoked Potentials ; Heroin Dependence ; physiopathology ; therapy ; Humans ; Male ; Substance Withdrawal Syndrome ; physiopathology ; therapy

OBJECTIVETo investigate the effects of clobenpropit and histidine on reinstatement of morphine-induced conditioned place preference (CPP) in rats.

METHODSThe persistence, extinction and reinstatement of morphine-induced CPP were established.In clobenpropit group three different doses of clobenpropit (2, 5 and 10 microg/rat, i.c.v.) were administered 15 min after morphine (1 mg/kg, i.p.) was injected. In histidine group histidine (100, 200, 500 mg/kg) was given 1 h prior to morphine treatment (1 mg/kg i.p).

RESULTThe CPP was reinstated by priming injection of 1 mg/kg morphine. Clobenpropit (5, 10 microg/rat) significantly inhabited the reinstatement by a priming dose of morphine-induced CPP compared with the morphine control group; histidine (100, 200, 500 mg/kg) significantly inhibited the reinstatement in a dose-dependent manner.

CONCLUSIONClobenpropit and histidine inhibit the revival of morphine-induced CPP in a dose dependent manner, indicating that endogenous histamine may inhibit relapse of morphine to some extent.

Animals ; Conditioning, Operant ; drug effects ; Histidine ; metabolism ; Imidazoles ; pharmacology ; Male ; Morphine Dependence ; physiopathology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, Cell Surface ; antagonists & inhibitors ; Substance Withdrawal Syndrome ; physiopathology ; Thiourea ; analogs & derivatives ; pharmacology

Nicotine, the primary psychoactive component of tobacco products, produces diverse neurophysiological, motivational, and behavioral effects through several brain regions and neurochemical pathways. Various neurotransmitter systems have been explored to understand the mechanisms behind nicotine tolerance, dependence, and withdrawal. Recent evidence suggests that glutamate neurotransmission has an important role in this phenomenon. The aim of the present review is to discuss preclinical findings concerning the role of N-methyl-D-aspartate (NMDA) receptor neurotransmission in mediating the behavioral effects of nicotine, tolerance, sensitization, dependence, and withdrawal. Based on preclinical findings, it is hypothesized that NMDA receptors mediate the common adaptive processes that are involved in the development, maintenance, and expression of nicotine addiction. Modulation of glutamatergic neurotransmission with NMDA receptor antagonists may prove to be useful in alleviating the symptoms of nicotine abstinence and facilitate tobacco-smoking cessation.
Animals ; Dizocilpine Maleate/pharmacology ; Drug Tolerance ; Excitatory Amino Acid Antagonists/*pharmacology ; Humans ; Nicotine/*administration & dosage ; Receptors, N-Methyl-D-Aspartate/*antagonists & inhibitors/physiology ; Substance Withdrawal Syndrome/physiopathology/prevention & control ; Tobacco Use Disorder/physiopathology/*prevention & control

In order to identify ceftriaxone and its analogs whether has the function of anti-tolerance of morphine and study the dose-effect relation of ceftriaxone in mice, hot plate method to measure pain threshold of mouse and naloxone withdrawal models were carried out and compared with normal saline group. Ceftriaxone and cefotaxime had the effect of anti-tolerance and anti-dependence of morphine notably. And ceftriaxone has the effect of anti-tolerance of morphine in a dose dependent manner.
Animals ; Anti-Bacterial Agents ; pharmacology ; Cefotaxime ; pharmacology ; Ceftriaxone ; pharmacology ; Dose-Response Relationship, Drug ; Drug Tolerance ; Female ; Mice ; Morphine ; pharmacology ; Morphine Dependence ; prevention & control ; Pain Threshold ; drug effects ; Random Allocation ; Substance Withdrawal Syndrome ; physiopathology

AIMTo determine whether testosterone is involved in morphine withdrawal syndrome (WS).

METHODSIn order to induce dependency, rats were treated with subcutaneous injection of morphine (days 1-2, 5 mg/kg; days 3-5, 7.5 mg/kg; days 6-8, 10 mg/kg), and after the last dose of morphine (day 8) WS was induced by intraperitoneal injection of naloxone (1 mg/kg). Wet dog shake (WDS), abdomen writhing (AW), and jumps (J) were recorded as indicators of WS.

RESULTSThe severity of WDS, AW, and J in male rats was greater than that in females. Accordingly, in 4-week castrated and flutamide-treated (10 mg/kg/day for 8 days, i.p.) male rats, WDS, AW, and J were significantly decreased compared to male control rats. Testosterone replacement therapy (10 mg/kg/day for 8 days, i.m.) in 4-week castrated rats restored the severity of WDS, AW, and J behaviors to the level of non-castrated male rats, whereas testosterone potentiated the WDS behavior in non-castrated male rats.

CONCLUSIONIt can be concluded that testosterone might be effectively involved in morphine WS.

Androgen Antagonists ; pharmacology ; Androgens ; pharmacology ; physiology ; Animals ; Behavior, Animal ; Female ; Flutamide ; pharmacology ; Male ; Morphine ; pharmacology ; Morphine Dependence ; physiopathology ; Naloxone ; pharmacology ; Narcotic Antagonists ; pharmacology ; Narcotics ; pharmacology ; Orchiectomy ; Rats ; Rats, Wistar ; Severity of Illness Index ; Substance Withdrawal Syndrome ; physiopathology ; Testosterone ; pharmacology ; physiology

Aged ; Humans ; Male ; Neuroleptic Malignant Syndrome ; etiology ; physiopathology ; Parkinson Disease ; drug therapy ; Substance Withdrawal Syndrome

Drug addiction is considered as a chronic, recurrent brain disease characterized by relapse. Repeated exposure to certain drugs, such as morphine, can produce deleterious sequelae, such as drug dependence, tolerance and compulsive drug seeking. In the present study, we investigated the dependence and psychological craving for morphine in rats using the conditioned place preference (CPP) paradigm. On the other hand, to study the effect of morphine on hippocampal sensory gating (N40), double click auditory-evoked potential was recorded during the chronic morphine administration, withdrawal and re-exposure to morphine in rats. The rats in morphine group received a course of morphine (10 mg/kg, i.p.) injection for 12 d, followed by 12 d of withdrawal, 1 d of re-exposure to morphine (2.5 mg/kg, i.p.) and 2 d of the second withdrawal. The rats in the control group were treated in the same way except that saline was applied instead of morphine. CPP test demonstrated that the method of drug administration in the present study induced dependence and psychological craving for morphine in rats. The results in the double click auditory-evoked potential experiment showed that during the chronic morphine administration, hippocampal N40 gating was damaged. In the initial 2 d of the first withdrawal hippocampal N40 gating in morphine group was reduced compared with that in the control group and it was significantly greater on the 3rd day, and then recovered gradually to the normal level from day 4 to day 12. After re-exposure to morphine, hippocampal N40 gating in morphine group was significantly reduced compared with that in the control group, and it remained at a lower level during the following 2 d, suggesting that hippocampal N40 gating in rats was more sensitive to morphine during re-exposure. Our results suggest that long-term repeated morphine administration and re-exposure to morphine disrupt hippocampal N40 gating, and that the effect of morphine addiction on the brain is possibly long-term.
Animals ; Conditioning (Psychology) ; drug effects ; Evoked Potentials, Auditory ; drug effects ; Hippocampus ; physiopathology ; Male ; Morphine ; pharmacology ; Morphine Dependence ; physiopathology ; Rats ; Rats, Sprague-Dawley ; Substance Withdrawal Syndrome ; physiopathology

Craving of drug addicts for drugs is the most important factor that causes relapse. On-line, objective and quantificational measurement of craving is of certain value in predicting relapse and drug-seeking behavior of addicts. Some common methods used to measure craving are reviewed and their shortcomings are analyzed. Aiming at characteristics, analysis methods, typical application of electroencephalography (EEG) and characteristics of craving, we have a discussion about the possibility of using EEG to measure craving. In addition, some related problems and difficulties are probed. These analyses are helpful to the study of craving.
Behavior, Addictive ; diagnosis ; physiopathology ; psychology ; Electroencephalography ; Humans ; Self Disclosure ; Sensitivity and Specificity ; Substance Withdrawal Syndrome ; diagnosis

Extracellular signal-regulated kinase (ERK), a mitogen-activated protein kinase (MAPK), transduces a broad range of extracellular stimuli into diverse intracellular responses. It has been reported that ERK is involved in the modulation of nociceptive information and central sensitization produced by intense noxious stimuli or peripheral tissue inflammation. Our previous studies showed that the spinal neurons sensitization was involved in morphine withdrawal response. This study was to investigate the role of the spinal ERK in morphine dependence and naloxone-precipitated withdrawal response. To set up morphine-dependent model, rats were subcutaneously injected with morphine (twice a day, for 5 d). The dose of morphine was 10 mg/kg on the first day and was increased by 10 mg/kg each day. On day 6, 4 h after the injection of morphine (50 mg/kg), morphine withdrawal syndrome was precipitated by an injection of naloxone (4 mg/kg, i.p.). Using anti-phospho-ERK (pERK) antibody, the time course of pERK expression was detected by Western blot. U0126, a mitogen-activated protein kinase kinase (MEK) inhibitor, or phosphorothioate-modified antisense oligonucleotides (ODN) was intrathecally injected 30 min or 36, 24 and 12 h before naloxone-precipitated withdrawal. The scores of morphine withdrawal symptom and morphine withdrawal-induced allodynia were observed. One hour after naloxone-precipitated withdrawal, pERK expression in the spinal dorsal horn was assessed by immunohistochemical analysis and Western blot was used to detect the expression of cytosolic and nuclear fraction of pERK in the rat spinal cord. The results showed that the expression of cytosolic and nuclear fraction of pERK, not non-phospho-ERK, in the spinal cord was gradually increased following the injection of morphine. When morphine withdrawal was precipitated with naloxone, the expression of the spinal pERK further increased. Intrathecal administration of U0126 or antisense ODN against ERK decreased the scores of morphine withdrawal, attenuated morphine withdrawal-induced allodynia and also inhibited the increase of pERK expression in the spinal cord of morphine withdrawal rats. These results suggest that activation of the spinal ERK is involved in morphine-dependent and naloxone-precipitated withdrawal response.
Animals ; Extracellular Signal-Regulated MAP Kinases ; metabolism ; Male ; Morphine Dependence ; enzymology ; physiopathology ; Naloxone ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord ; enzymology ; Substance Withdrawal Syndrome ; enzymology ; physiopathology