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 Once the drug is withdrawn, there will be withdrawal symptoms such as strong negative emotions and uncomfortable physical reactions.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 correlation between EEG characteristics of medial prefrontal cortex (mPFC) and drug-seeking behavior of rats with morphine dependent place preference under shuttling condition.

METHODSForty rats were randomly divided into four groups (n = 10): morphine PL group, NS PL group, morphine IL group and NS IL group. After embeding the electrode in prelimbic (PL) or infralimbic (IL) cortex of each group by brain stereotaxic operation, the model of morphine dependent conditioned place preference (CPP) in rats was established. The differences of EEG wave percentage in mPFC were telemetered and analyzed when rats shuttled before and after the model.

RESULTSAfter the model, the withdrawal symptoms were evident in morphine PL and IL group, and the activity time and distance in white box were increased obviously. Compared with control group, after the model, the EEG in morphine PL group showed that: when the rats shuttled to white box, 8 wave decreased obviously, P wave increased obviously. When the rats shuttled to black box, brain waves showed opposite changes. The EEG in morphine IL group showed that: when the rats shuttled to white box, a wave increased obviously, P and a wave decreased obviously. When the rats shuttled to black box, the brain wave had no significant differences compared with control group.

CONCLUSIONThe EEG changes are different in PL and IL cortex of morphine CPP rats under shuttling condition, and the EEG changes are also different when rats shuttling to white or black box. There is possibly different mechanism, when different drug-seeking environmental cues caused EEG changes in different regions of mPFC.

Animals ; Conditioning (Psychology) ; Cues ; Drug-Seeking Behavior ; Electroencephalography ; Morphine Dependence ; physiopathology ; Prefrontal Cortex ; physiopathology ; Rats ; Telemetry

Eighty-three of 114 original articles and abstracts of research published by neuropsychiatrists of Chosun Chongdokbu Hospital (the Japanese colonial government hospital in Korea) and Keijo (Seoul) Imperial University Hospital during the Japanese colonial period (1910-1945) in journals including Shinkeigaku-zassi (Neurologia), Seishin-shinkei-gaku zassi (Psychiatria Et Neurologia Japonica), and The Journal of Chosun (Korea) Medical Association were reviewed. Most articles were on clinical research based on descriptive and biological psychiatry while only 4 articles were on dynamic psychiatry, probably because Japanese pioneers in psychiatry had introduced German psychiatry into Japan during the 1880s. The first paper was written by Dr. Shim Ho-sub. Professor Kubo of Keijo (Seoul) Imperial University published most articles, followed by Dr. Hikari, Dr. Hattori, and Dr. Sugihara. There were more articles on symptomatic psychosis and morphine addiction, followed by general paralysis, schizophrenia, neurological diseases, narcolepsy, epilepsy, and neurasthenia. The meaningful articles even for today were comparative studies between Japanese and Koreans and articles on opioid use disorder in Korea. Authors reported a markedly lower rate of psychotic inpatients in the population of Koreans compared with Japanese. Japanese researchers argued that, because of simpleness in social life in Korea and less violence or excitement in symptoms, Korean mental patients could be cared for by family or members of the community, or be treated by shamanism rather than bringing them to a public mental hospital, and poverty also prohibited hospital care. Finding of higher ratio of schizophrenia to manic-depressive psychosis among Koreans than Japanese was discussed in relation to delayed cultural development of Korea compared to Japan. In addition, traditional customs prohibiting marriage between relatives in Korea was related to low prevalence of manic-depressive psychosis, local endemic malaria was related to low prevalence of general paresis, and poor general hygiene was related to high prevalence of epilepsy. Unclear (undifferentiated) form of psychotic symptoms including hallucination and delusion was reported in more Koreans than Japanese. Also Korean patients showed a more atypical form in diagnosis. Authors added that they had found no culture-specific mental illness in Korea. However, no Korean psychiatrists were included as author in such comparative studies. Comparative studies on constitution between Koreans and Japanese mental patients and prisoners were also unique. However, no Korean psychiatrists participated in such comparative studies. In studies on morphine addiction in Koreans, Japanese researchers argued that such studies were necessary to prevent introduction of morphine-related criminal phenomena to Japan. Meanwhile, Dr. Kubo had left a notion on adaptation problems of Japanese living in the foreign country, Korea. Nevertheless he reported nothing about psychosocial aspects of mental illness in relation to political, cultural, and economic difficulties Koreans were experiencing under the colonial rule of Japan. These general trends of studies based on German biological and descriptive psychiatry and policies of colonial government to isolate "dangerous" mental patients in hospital appeared to reflect colonial or ethnopsychiatry of those days. These policy and research trends seem to have worsened stigma attached to mental disorders. Japanese tradition of psychiatric research was discontinued by return home of Japanese scholars with the end of WWII and colonial rule.
Asian Continental Ancestry Group* ; Biological Psychiatry ; Bipolar Disorder ; Constitution and Bylaws ; Criminals ; Delusions ; Diagnosis ; Epilepsy ; Ethnopsychology ; Hallucinations ; Hospitals, Psychiatric ; Humans ; Hygiene ; Inpatients ; Japan ; Korea ; Malaria ; Marriage ; Mental Disorders ; Mentally Ill Persons ; Morphine Dependence ; Narcolepsy ; Neurasthenia ; Neuropsychiatry ; Neurosyphilis ; Poverty ; Prevalence ; Prisoners ; Prisons ; Psychiatry* ; Psychotic Disorders ; Schizophrenia ; Shamanism ; Violence

OBJECTIVETo investigate the changes of telemetry electrical activity in the infralimbic cortex (IL) of morphine-dependent rats with extinguished drug-seeking behavior.

METHODSSD rats were randomly divided into model group and control group and received operations of brain stereotaxic electrode embedding in the IL. The rats in the model group were induced to acquire morphine dependence and then received subsequent extinction training, and the changes of electrical activity in the IL were recorded with a physical wireless telemetry system.

RESULTSIn rats with morphine dependence, the time staying in the white box was significantly longer on days 1 and 2 after withdrawal than that before morphine injection and that of the control rats, but was obviously reduced on days 1 and 2 after extinction training to the control level. Compared with the control group, the morphine-dependent rats on day 2 following withdrawal showed significantly increased β wave and decreased δ wave when they stayed in the white box but significantly increased δ wave and decreased α wave and β wave when they shuttled from the black to the white box. On day 2 of extinction, the model rats, when staying in the white box, showed significantly decreased θ wave compared with that of the control rats group but decreased β wave and θ wave and increased δ wave compared with those in the withdrawal period. When they shuttled from black to white box, the model rats showed decreased δ wave and increased α wave and β wave compared with those in the withdrawal period.

CONCLUSIONMorphine-dependent rats have abnormal changes of electrical activity in the IL in drug-seeking extinction to affect their drug-seeking motive and inhibit the expression and maintenance of drug-seeking behaviors.

Animals ; Cerebral Cortex ; drug effects ; physiology ; Drug-Seeking Behavior ; physiology ; Electrophysiological Phenomena ; Extinction, Psychological ; Morphine ; pharmacology ; Morphine Dependence ; physiopathology ; Rats ; Rats, Sprague-Dawley ; Telemetry

BACKGROUNDOpiate addiction remains intractable in a large percentage of patients, and relapse is the biggest hurdle to recovery. Many studies have identified a central role of the nucleus accumbens (NAc) in addiction. Deep brain stimulation (DBS) has the advantages of being reversible, adjustable, and minimally invasive, and it has become a potential neurobiological intervention for addiction. The purpose of our study was to investigate whether high-frequency DBS in the NAc effectively attenuates the reinstatement of morphine seeking in morphine-primed rats.

METHODSA morphine-dependent group of rats was given increasing doses of morphine during conditioned place preference training. A control group of rats was given equal volumes of saline. After the establishment of this model, withdrawal syndromes were precipitated in these two groups by administering naloxone, and the differences in withdrawal symptoms between the groups were analyzed. Electrodes for DBS were implanted in the bilateral shell of the NAc in the experimental group. The rats were stimulated daily in the NAc for 5 hours per day over 30 days. Changes in the conditioned place preference test and withdrawal symptoms in the rats were investigated and place navigation studies were performed using the Morris water maze. The data were assessed statistically with one-way analysis of variance (ANOVA) followed by Tukey's tests for multiple post hoc comparisons.

RESULTSHigh-frequency stimulation of the bilateral NAc prevented the morphine-induced reinstatement of morphine seeking in the conditioned place preference test. The time spent in the white compartment by rats following 30 days of DBS ((268.25 ± 25.07) seconds) was not significantly different compared with the time spent in the white compartment after relapse was induced by morphine administration ((303.29 ± 34.22) seconds). High-frequency stimulation of the bilateral NAc accelerated the innate decay of drug craving in morphine-dependent rats without significantly influencing learning and memory.

CONCLUSIONBilateral high-frequency stimulation of the shell of the NAc may be useful as a novel therapeutic modality for the treatment of severe morphine addiction.

Animals ; Electric Stimulation ; Male ; Morphine ; toxicity ; Morphine Dependence ; therapy ; Nucleus Accumbens ; metabolism ; Rats ; Rats, Sprague-Dawley

OBJECTIVE: To observe the protein expression of growth associated protein-43 (GAP-43) in midbrain ventral tegmental area in morphine withdrawal rats at different time, and to evaluate the effect of GAP-43 on morphine withdrawal memory. METHODS: Rat models of morphine dependent 1 week, 2 weeks and 4 weeks were established by morphine hydrochloride intraperitoneal injection with increasing doses to establish natural withdrawal. The protein expression of GAP-43 in midbrain ventral tegmental area was observed by immunohistochemical staining and the results were analyzed by Image-Pro Plus 5.1 image analysis system. RESULTS: With prolongation of dependent time, the expression of GAP-43 was decreased then increased in midbrain ventral tegmental area. CONCLUSION GAP-43 could play a role in morphine withdrawal memory in midbrain ventral tegmental area.
Animals ; Behavior, Animal/drug effects* ; Disease Models, Animal ; Female ; GAP-43 Protein/metabolism* ; Immunohistochemistry ; Male ; Mesencephalon/metabolism* ; Morphine/adverse effects* ; Morphine Dependence/metabolism* ; Naloxone/pharmacology* ; Rats ; Rats, Sprague-Dawley ; Substance Withdrawal Syndrome/metabolism* ; Time Factors ; Ventral Tegmental Area/metabolism*

Repeated exposure to morphine leads to the addiction, which influences its clinical application seriously. The glutamatergic projection from prefrontal cortex (PFC) to the nucleus accumbens (NAc) plays an important role in rewarding effects. It is still unknown whether morphine exposure changes PFC-NAc synaptic transmission. To address this question, in vivo field excitatory postsynaptic potentials (fEPSPs) induced by electric stimulating PFC-NAc projection fibers were recorded to evaluate the effect of acute morphine exposure (10 mg/kg, s.c.) on glutamatergic synaptic transmission in NAc shell of repeated saline/morphine pretreated rats. It was showed that acute morphine exposure enhanced fEPSP amplitude and reduced paired-pulse ratio (PPR) in saline pretreated rats, which could be reversed by following naloxone injection (1 mg/kg, i.p.), an opiate receptor antagonist. However, repeated morphine pretreatment significantly inhibited both the enhancement of fEPSP amplitude and reduction of PPR induced by acute morphine exposure. Those results indicate that the initial morphine exposure enhances PFC-NAc synaptic transmission by pre-synaptic mechanisms, whereas morphine pretreatment occludes this effect.
Animals ; Excitatory Postsynaptic Potentials ; drug effects ; physiology ; Female ; Glutamate Plasma Membrane Transport Proteins ; metabolism ; Glutamates ; metabolism ; Morphine ; administration & dosage ; Morphine Dependence ; physiopathology ; Nucleus Accumbens ; physiopathology ; Prefrontal Cortex ; physiopathology ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo explore neurobiological mechanisms of the withdrawal-induced aversion. The changes of protein kinase A were measured in central amygdaloid nucleic (CeA) of conditioned place aversion (CPA) model rats.

METHODS(1) All 72 male SD rats were divided into three groups, model group (MN group), and control group (MS group and SN group). MN group was injected with morphine,6.5 days, 10 mg/kg, intraperitoneally (ip), twice per day, naloxone injection, 0.3 mg/kg, ip, along with conditioned place aversion training, to develop the CPA model. The MS group was administrated equivalent volume of morphine and saline. Also the SN group was injected with equivalent volume of saline and naloxone. (2) During the process of morphine-induced CPA, the expression of protein kinase A was assayed with immunohistochemistry in the CeA.

RESULTSIn the MN group, protein kinase A expressions in the CeA occurred adaptive changes at different points of CPA (P < 0.05). Protein kinase A expressions after establishment(Day7,134.43 +/- 4.481, P < 0.05), and after extinction (Day 13, 141.01 +/- 3.360, P < 0.01), and after reinstatement (Day 14,137.18 +/- 40.330, P < 0.05) were also lower than those before the establishment of the CPA (Day 5, 124.48 +/- 6.722). However, PKA expressions were not significantly different both in MS group (P > 0.05)and SN group (P > 0.05).

CONCLUSION(1) Protein kinase A expression, in turn regulating the aversion expression, in the CeA probably is a key pathway contributing to the development of CPA. (2) The neuroadaptation mediated by protein kinase A may be one of the important molecular underpinnings of CPA.

Amygdala ; enzymology ; Animals ; Conditioning, Operant ; Cyclic AMP-Dependent Protein Kinases ; metabolism ; Disease Models, Animal ; Extinction, Psychological ; Male ; Morphine Dependence ; psychology ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo explore the effects of intrathecal injection of neuronal nitric oxide synthase (nNOS) inhibitors 7-Nitroindazole (7-Ni) and inducible nitric oxide synthase(iNOS) inhibitors aminoguanidine (AG) on the behavioral changes of morphine-induced dependent and withdrawal rats; the expression of Fos, nNOS and iNOS in spinal cord.

METHODSTo set up morphine dependence model, rats were subcutaneously injected with morphine (twice a day, for 5 d). The dose of morphine was 10 mg/kg in the first day and was increased by 10 mg/ kg every 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 ip). 7-Ni, an nNOS inhibitor or iNOS inhibitors AG were intrathecally injected 30 min before the administration of naloxone respectively. The scores of morphine withdrawal symptom and morphine withdrawal-induced allodynia were observed. One hour after naloxone-precipitated withdrawal, Fos protein expression was assessed by immunohistochemical analysis and Western blot was used to detect the expression of nNOS and iNOS in the rat spinal cord.

RESULTSIntrathecal administration of nNOS inhibitor 7-Ni and iNOS inhibitors AG decreased the scores of morphine withdrawal, attenuated morphine withdrawal-induced allodynia and also inhibited the increase of Fos protein expression in the spinal cord of morphine withdrawal rats. nNOS and iNOS positive neurons in dorsal horn in nNOS group and iNOS group were significantly lower than that in withdrawal group. Compared with withdrawal group, level of nNOS and iNOS protein in spinal cord in nNOS group and iNOS group were significantly lower.

CONCLUSIONIt is suggested that nNOS and iNOS in the spinal cord may contribute to naloxone-precipitated withdrawal in rats and may play different roles in the above-mentioned effect.

Animals ; Guanidines ; pharmacology ; Indazoles ; pharmacology ; Male ; Morphine Dependence ; metabolism ; Naloxone ; pharmacology ; Nitric Oxide Synthase Type I ; antagonists & inhibitors ; metabolism ; Nitric Oxide Synthase Type II ; antagonists & inhibitors ; metabolism ; Rats ; Rats, Sprague-Dawley ; Spinal Cord ; drug effects ; metabolism ; Substance Withdrawal Syndrome ; metabolism

OBJECTIVETo explore if induced nitric oxide in the spinal cord mediates withdrawal syndrome in morphine-dependent rats.

METHODSMale SD rats weighing 200-250 g were employed in the present study. To set up morphine dependence model, rats were subcutaneously injected with morphine (twice a day, for 5 d). The dose of morphine was 10 mg/kg in 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, ip). Inducible nitric oxide synthase (iNOS) inhibitors aminoguanidine (AG) was intrathecally injected 30 min before the administration of naloxone. All the rats were divided into four groups: control group, dependence group, withdrawal group, AG group. Morphine withdrawal score, touch evoked agitation scores (TEA scores), immunohistochemical and Western blot technique were used to evaluate morphine withdrawal response and the expression of iNOS in the spinal cord.

RESULTSIntrathecal injection of iNOS inhibitors AG could alleviate morphine withdrawal symptoms. Morphine withdrawal scores and touch evoked agitation scores in AG group were significantly lower than that of withdrawal group (P < 0.05). iNOS positive neurons in dorsal horn of AG group were significantly lower than that of withdrawal group (P < 0.05). Level of iNOS protein in spinal cord of AG group was significantly lower than that of withdrawal group (P < 0.05).

CONCLUSIONInduced nitric oxide in the spinal cord may mediate withdrawal syndrome in morphine-dependent rats.

Animals ; Male ; Morphine Dependence ; metabolism ; Naloxone ; pharmacology ; Nitric Oxide Synthase Type II ; metabolism ; Rats ; Rats, Sprague-Dawley ; Spinal Cord ; metabolism ; Substance Withdrawal Syndrome ; metabolism