• Biomolecules & Therapeutics
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• v.23 no.6
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• pp.597-603
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• 2015

Synthetic cannabinoids JWH-018 and JWH-250 in 'herbal incense' also called 'spice' were first introduced in many countries. Numerous synthetic cannabinoids with similar chemical structures emerged simultaneously and suddenly. Currently there are not sufficient data on their adverse effects including neurotoxicity. There are only anecdotal reports that suggest their toxicity. In the present study, we evaluated the neurotoxicity of two synthetic cannabinoids (JWH-081 and JWH-210) through observation of various behavioral changes and analysis of histopathological changes using experimental mice with various doses (0.1, 1, 5 mg/kg). In functional observation battery (FOB) test, animals treated with 5 mg/kg of JWH-081 or JWH-210 showed traction and tremor. Their locomotor activities and rotarod retention time were significantly (p<0.05) decreased. However, no significant change was observed in learning or memory function. In histopathological analysis, neural cells of the animals treated with the high dose (5 mg/kg) of JWH-081 or JWH-210 showed distorted nuclei and nucleus membranes in the core shell of nucleus accumbens, suggesting neurotoxicity. Our results suggest that JWH-081 and JWH-210 may be neurotoxic substances through changing neuronal cell damages, especially in the core shell part of nucleus accumbens. To confirm our findings, further studies are needed in the future.

• Molecules and Cells
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• v.41 no.5
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• pp.454-464
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• 2018

Crosstalk between G-protein signaling and glutamatergic transmission within the brain reward circuits is critical for long-term emotional effects (depression and anxiety), cravings, and negative withdrawal symptoms associated with opioid addiction. A previous study showed that Regulator of G-protein signaling 4 (RGS4) may be implicated in opiate action in the nucleus accumbens (NAc). However, the mechanism of the NAc-specific RGS4 actions that induce the behavioral responses to opiates remains largely unknown. The present study used a short hairpin RNA (shRNA)-mediated knock-down of RGS4 in the NAc of the mouse brain to investigate the relationship between the activation of ionotropic glutamate receptors and RGS4 in the NAc during morphine reward. Additionally, the shRNA-mediated RGS4 knock-down was implemented in NAc/striatal primary-cultured neurons to investigate the role that striatal neurons have in the morphine-induced activation of ionotropic glutamate receptors. The results of this study show that the NAc-specific knock-down of RGS4 significantly increased the behaviors associated with morphine and did so by phosphorylation of the GluR1 (Ser831) and NR2A (Tyr1325) glutamate receptors in the NAc. Furthermore, the knock-down of RGS4 enhanced the phosphorylation of the GluR1 and NR2A glutamate receptors in the primary NAc/striatal neurons during spontaneous morphine withdrawal. These findings show a novel molecular mechanism of RGS4 in glutamatergic transmission that underlies the negative symptoms associated with morphine administration.

• Animal cells and systems
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• v.7 no.3
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• pp.237-248
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• 2003

Recent evidence on behaviors in macaque monkeys indicate that the medial temporal cortical areas such as the entorhinal cortex (EC), perirhinal cortex, and parahippocampal cortex (PHC) are importantly involved in limbic and sensory memory function. Neuroanatomical studies also have demonstrated that the medial temporal cortical areas are connected with the ventral striatum, although comparatively little is known about the precise topography of these connections. We investigated the topographic organization of connections between the medial temporal cortical areas and the ventral striatum by placing retrograde tracers into five different regions of the ventral striatum: the ventromedial caudate nucleus, ventral shell, central shell, dorsal core of the nucleus accumbens (NA), and ventrolateral putamen. We found that the shell of the NA was the main projection site from the medial temporal cortical areas. Within the shell of the NA, there were also differential connections: EC diffusely innervates shell of the NA, while the projections from the perirhinal cortex and PHC concentrate on the ventral shell of the NA. Taken together, it is possible that the ventral shell of the NA is the main integration site of the limbic and sensory memory coming from the EC, perirhinal cortex, and PHC.

• Investigative Magnetic Resonance Imaging
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• v.26 no.2
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• pp.96-103
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• 2022

Purpose: The survival of organisms critically depends on avoidance responses to life-threatening stimuli. Information about dangerous situations needs to be remembered to produce defensive behavior. To investigate underlying brain regions to process information of danger, manganese-enhanced MRI (MEMRI) was used in olfactory fear-conditioned rats. Materials and Methods: Fear conditioning was conducted in male Sprague-Dawley rats. The animals received nasal injections of manganese chloride solution to monitor brain activation for olfactory information processing. Twenty-four hours after manganese injection, rats were exposed to electric foot shocks with odor cue for one hour. Control rats were exposed to the same odor cue without foot shocks. Forty-eight hours after the conditioning, rats were anesthetized and their brains were scanned with 9.4T MRI. Acquired images were processed and statistical analyses were performed using AFNI. Results: Manganese injection enhanced brain areas involved in olfactory information pathways in T1 weighted images. Rats that received foot shocks showed higher brain activation in the central nucleus of the amygdala, septum, primary motor cortex, and preoptic area. In contrast, control rats displayed greater signals in the orbital cortex and nucleus accumbens. Conclusion: Nasal delivery of manganese solution enhanced olfactory signal pathways in rats. Odor cue paired with foot shocks activated amygdala, the central brain region in fear, and related brain circuits. Use of MEMRI in fear conditioning provides a reliable monitoring technique of brain activation for fear learning.

• International Journal of Oral Biology
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• v.34 no.3
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• pp.123-129
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• 2009

Taste is associated with hedonic evaluation as well as recognition of quality and intensity. Taste information is sent to the cortical gustatory area in a chemotopical manner to be processed for discrimination of taste quality. It is also conveyed to the reward system and feeding center via the prefrontal cortices. The amygdala, which receives taste inputs, also influences reward and feeding. In terms of neuroactive substances, palatability is closely related to benzodiazepine derivatives and $\beta$-endorphin, both of which facilitate consumption of food and fluid. The reward system contains the ventral tegmental area, nucleus accumbens and ventral pallidum and finally sends information to the lateral hypothalamic area, the feeding center. The dopaminergic system originating from the ventral tegmental area mediates the motivation to consume palatable food. The actual ingestive behavior is promoted by the orexigenic neuropeptides from the hypothalamus. Even palatable food can become aversive and avoided as a consequence of postingestional unpleasant experience such as malaise. The brain mechanism of these aspects of taste is elucidated.

• Korean Journal of Biological Psychiatry
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• v.3 no.1
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• pp.3-13
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• 1996

Many studies have been conducted to search for the anatomical abnormalities in the brain which ore etiologically related with schizophrenia. Generally schizophrenia in known to be related with decreased brain tissue, hypofrontality and abnormalities in the temporal lobe including the hippocamypus, the agmygdala and the entorhinal cortex. Other areas related with the disorder ore basal ganglia, thalamus, brain stem, pons and nucleus accumbens. Abnormality in brain asymmetry is one of the new areas of interest which needs further study. The results so for ore inconsistent and it is unlikely that the abnormality in one structure is the only cause of the disorder. Rather, schizophrenia develops from the impairment of the parallel processing of integrated and reciprocal information which is distributed to the multiple structures. Histopathologic studies in the postmortem brain suggest that schizophrenia is related with neurodevelopmental abnormality rather than neurodegenerative abnormality.

• Journal of Oriental Neuropsychiatry
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• v.16 no.2
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• pp.13-24
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• 2005

Background and Objectives : Acupuncture as a therapeutic intervention is widely used for the treatment of many functional disorders such as substance abuse and mental dysfunction. Clinical trials are currently underway to determine the effectiveness of acupuncture in the treatment of drug addiction. Yet, there are still many unanswered questions about the basic mechanism of acupuncture. Studies have shown that both the psychomotor stimulant effects and rewarding properties of addictive drugs, including morphine, are sensitized by repeated drug administration and raised the possibility that both of these effects may be linked to the same or closely overlapping the mesolimbic dopamine systems. Neiguan (PC6) point on the pericardium channel which is associated with the brain and its mental function, has been used to treat mental, psychosomatic disorders and gastroenterological disorders. The present study was designed to investigate the effect of acupuncture on repeated morphine-induced changes in extracellular dopamine levels using in vivo microdialysis and to measure the effect of acupuncture on Fos-like immunoreactivity. Methods : Male Sprague-Dawley rats were treated twice a day for three days with increasing doses of morphine (10, 20 and 40 mg/kg, s.c.) or with saline. After 15 days of withdrawal, rats were challenged with morphine hydrochloride (5 mg/kg, s.c.). Acupuncture was applied at bilateral Neiguan (PC6) points for 1 min after the morphine challenge. Results showed that acupuncture at the specific acupoint PC6, but not at control points (tail and HE8) significantly decreased Fos-like immunoreactivity induced by a systemic morphine challenge or a single s.c. morphine injection in the morphine-repeated animals. Results and Conclusions : These results suggest that reduction in sensitization may be one mechanism whereby acupuncture alleviates morphine craving in addicts. Moreover, in a more general sense these results suggest that acupuncture can be used as a therapeutic intervention for correcting reversible malfunction of the body by direction of brain pathway and thus acupuncture can contribute to the biochemical balance in the central nervous system by regulating neurotransmitters.

• Journal of Acupuncture Research
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• v.20 no.4
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• pp.170-179
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• 2003

목적 : 침(鍼)은 정신이상 및 약물중독과 같은 많은 기능상의 장애질환을 치료, 조정하는데 널리 쓰이고 있으며, 중추신경계에서 생화학적인 균형을 유지하는데 기여한다고 밝혀져 있다. 동물 연구에서 코카인의 강화 및 민감화 특성과 중추의 도파민 활성과의 관련 가능성이 높아지고 있다. 본 연구에서는 약물중독 치료에 이용할 수 있는 침의 효과를 규명하기 위하여 침자극 후 급성 코카인 투여에 의한 도파민 유리 및 자발적 코카인 섭취량에 미치는 침자극의 효과를 측정하였다. 방법 : 웅성 SD 쥐에 코카인 (1mg/kg, i.v.)의 주사 직전 양측의 신문혈(HT7)을 1분간 침자극 한 후, 측핵내 세포외액의 도파민 및 대사산물의 함량변화를 미세투석법을 이용하여 HPLC로 분석하였다. 침자극 후 two-bottle, free choice protocol을 이용하여 자발적 코카인 섭취량의 변화를 관찰하였다. 별도의 쥐를 이용하여 1회 동량의 코카인 정맥주사하고 2주간의 철회를 거친 다음 two-bottle, free choice protocol을 실시하여 자발적 코카인 섭취량과 급성 코카인 투여 후 측핵 중 도파민유리증가율 사이의 상관관계를 조사하였다. 결과 : 신문혈(HT7) 자침이 코카인 1회 주사 후에 유도된 도파민 증가를 대조혈(내관혈(PC6), 또는 꼬리)에 비해 유의하게 억제하였으며 two-bottle choice protocol에 의한 동물의 자발적 코카인 섭취량을 억제하였다. 아울러 자발적 코카인 섭취량과 급성 코카인 투여 후 측핵 중 도파민유리증가율 사이에는 상관관계가 있었다. 결론 : 본 실험결과 침자극에 의해 자발적 코카인 섭취량이 억제되는 것은 측핵에서의 도파민 유리억제에 의해 중개되는 것으로 보여지므로 침자극은 코카인중독과 같은 약물의 중독치료에 이용될 수 있을 것으로 사료된다.

• Journal of Physiology & Pathology in Korean Medicine
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• v.19 no.4
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• pp.982-992
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• 2005

Acupuncture as a therapeutic intervention is widely used for the treatment of many functional disorders such as substance abuse and mental dysfunction. Clinical trials are currently underway to determine the effectiveness of acupuncture in the treatment of drug addiction. Yet, there are still many unanswered questions about the basic mechanism of acupuncture. Studies have shown that both the psychomotor stimulant effects and rewarding properties of addictive drugs, including morphine, are sensitized by repeated drug administration and raised the possibility that both of these effects may De linked to the same or closely overlapping the mesolimbic dopamine systems. Neiguan (PC6) point on the pericardium channel which is associated with the brain and its mental function, has been used to treat mental, psychosomatic disorders and gastroenterological disorders. The present study was designed to investigate the effect of acupuncture on repeated morphine-induced changes in extracellular dopamine levels using in vivo microdialysis and to measure the effect of acupuncture on repeated morphine-induced behavioral changes. Male Sprague-Dawley rats were treated twice a day for three days with increasing doses of morphine (10, 20 and 40 mg/kg, s.c.) or with saline. After 15 days of withdrawal, rats were challenged with morphine hydrochloride (5 mg/kg, s.c.). Acupuncture was applied at bilateral Neiguan (PC6) points for 1min after the morphine challenge. Results showed that acupuncture at the specific acupoint PC6, but not at control points (tail and HE8) significantly decreased both dopamine release, behavior induced by a systemic morphine challenge or a single s.c. morphine injection in the morphine-repeated animals. These results suggest that reduction in sensitization may be one mechanism whereby acupuncture alleviates morphine craving in addicts. Moreover, in a more general sense these results suggest that acupuncture can be used as a therapeutic intervention for correcting reversible malfunction of the body by direction of brain pathway and thus acupuncture can contribute to the biochemical balance in the central nervous system by regulating neurotransmitters.

• Journal of Pharmacopuncture
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• v.7 no.1 s.12
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• pp.53-61
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• 2004

Substantial evidence suggests that behavioral and reinforcing effects of cocaine can be mediated by the mesolimbic dopaminergic system. It has been shown that repeated injections of cocaine produce increase in locomotor activity, expression of the immediate-early gene, c-fos in the nucleus accumbens (NAc), which was one of the main dopaminergic terminal areas. Herbal-acupuncture as a therapeutic intervention has been widely used for the treatment of many functional disorders such as drug abuse. Coptidis Rhizoma (CR) and its main component, berberine (BER) were selected as herbal medicine of herbal-acupuncture. Both medicines have been known to have the therapeutic effect on the central nervous system. In order to investigate the effects of CR and BER herbalacupuncture at shenmen (HT7) point (CR/H and BER/H) on the cocaine-induced behavioral sensitization, the influence of CR/H and BER/H on repeated cocaine-induced locomotor activity, the change of c-Fos expression in the brain by immunohistochemistry were examined. Male SD rats were given CR/H (0.4mg/kg) and BER/H (0.1mg/kg) 30 min before daily injections of cocaine hydrochloride (15mg/kg. i.p.) 10 days. After 3 days withdrawal, rats received a challenge injection of cocaine (15mg/kg, i.p.). Systemic challenge with cocaine produced much larger increased locomotor activity, accumbal Fos-like immunoreactivity in the NAc. Pretreatment with CR/H and BER/H significantly inhibited cocaine-induced locomotor activity, the change of c-Fos expression in the rats. Our data demonstrated that the inhibitory effects of cocaine-induced behavioral sensitization by CR/H and BER/H were closely associated with the reduction of presynaptic dopamine release in the NAc. These results suggest that CR/H and BER/H can be effectively applied to cocaine addiction.