Hee Young Kim

Involvement of reactive oxygen species in cocaine-taking behaviors in rats

Reactive oxygen species (ROS) have been implicated in the development of behavioral sensitization following repeated cocaine exposure. We hypothesized that increased ROS following cocaine exposure would act as signaling molecules in the mesolimbic dopamine (DA) system, which might play an important role in mediating the reinforcing effects of cocaine. The aim of this study was to evaluate cocaine enhancement of brain metabolic activity and the effects of ROS scavengers on cocaine self‐administration behavior, cocaine‐induced ROS production in the nucleus accumbens (NAc) and cocaine enhancement of DA release in the NAc. Metabolic neural activity monitored by temperature and oxidative stress were increased in NAc following cocaine exposure. Systemic administration of the ROS scavenger N‐tert‐butyl‐α‐phenylnitrone (PBN) or 4‐hydroxy‐2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPOL), either pre‐ or post‐treatment, significantly decreased cocaine self‐administration without affecting food intake. Infusion of TEMPOL into the NAc inhibited cocaine self‐administration. Increased oxidative stress was found mainly on neurons, but not astrocytes, microglia or oligodendrocytes, in NAc of rats self‐administering cocaine. TEMPOL significantly attenuated cocaine‐induced enhancement of DA release in the NAc, compared to saline controls. TEMPOL had no effect on the enhancement of DA release produced by the DA transporter inhibitor GBR12909. Taken together, these findings suggest that enhancement of ROS production in NAc neurons contributes to the reinforcing effect of cocaine.

Effect of acupuncture on naloxone-precipitated withdrawal syndrome in morphine-experienced rats: The mediation of GABA receptors

Repeated morphine administration increases extracellular dopamine levels in the nucleus accumbens, which results in behavioral sensitization that can be suppressed by acupuncture at Shenmen (HT7) points. The present study was conducted to investigate the effects of acupuncture at HT7 on morphine withdrawal syndrome as well as to explore the role of GABA receptors in mediating the effects of HT7 acupuncture. We induced morphine withdrawal by injecting naloxone to rats that self-administer morphine and evaluated the effects of acupuncture and/or GABA receptor antagonists on their withdrawal symptoms. Acupuncture at HT7, but not at the control point LI5, significantly decreased symptoms of morphine withdrawal. HT7 inhibition of the withdrawal syndrome was blocked by pretreatment with either the GABA(A) receptor antagonist bicuculline or the GABA(B) antagonist SCH 50911. These findings suggest that the effects of acupuncture on suppression of morphine withdrawal syndrome are mediated, at least in part, through GABA receptors.

Acupuncture at SI5 attenuates morphine seeking behavior after extinction.

Our previous studies have shown that acupuncture attenuates morphine self-administration and sensitization behavior as well as withdrawal signs. The present study was designed to investigate the role of acupuncture in the reinstatement of morphine seeking. Male Sprague-Dawley rats weighing 270-300 g were subjected to intravenous catheterization after food training. The animals were trained to self-administer morphine (1.0mg/kg, 3 weeks), followed by extinction (1 week). Extinction conditions were introduced by substituting saline for morphine. The rats were then tested for reinstatement of morphine self-administration by a priming injection of morphine (0.25mg/kg). To see whether acupuncture can reduce morphine reinstatement, acupuncture was performed at SI5 or LI5 for 1 min immediately before a morphine injection. To further test the involvement of gamma aminobutyric acid (GABA) receptors in acupuncture effects, GABA receptor antagonists were injected before acupuncture. In the present results, acupuncture at SI5, but not at control acupoint LI5 attenuated the reinstatement of morphine seeking behavior, which was blocked by the GABA receptor antagonists. It suggests that acupuncture can reduce the reinstatement of morphine seeking, possibly due to the mediation of GABA receptor system.

Peripheral Afferent Mechanisms Underlying Acupuncture Inhibition of Cocaine Behavioral Effects in Rats

Administration of cocaine increases locomotor activity by enhancing dopamine transmission. To explore the peripheral mechanisms underlying acupuncture treatment for drug addiction, we developed a novel mechanical acupuncture instrument (MAI) for objective mechanical stimulation. The aim of this study was to evaluate whether acupuncture inhibition of cocaine-induced locomotor activity is mediated through specific peripheral nerves, the afferents from superficial or deep tissues, or specific groups of nerve fibers. Mechanical stimulation of acupuncture point HT7 with MAI suppressed cocaine-induced locomotor activity in a stimulus time-dependent manner, which was blocked by severing the ulnar nerve or by local anesthesia. Suppression of cocaine-induced locomotor activity was elicited after HT7 stimulation at frequencies of either 50 (for Meissner corpuscles) or 200 (for Pacinian corpuscles) Hz and was not affected by block of C/Aδ-fibers in the ulnar nerve with resiniferatoxin, nor generated by direct stimulation of C/Aδ-fiber afferents with capsaicin. These findings suggest that HT7 inhibition of cocaine-induced locomotor activity is mediated by A-fiber activation of ulnar nerve that originates in superficial and deep tissue.

Acupuncture suppresses reinstatement of morphine-seeking behavior induced by a complex cue in rats.

Morphine causes physical and psychological dependence for individuals after repeated-use. Above all, our previous study showed that acupuncture attenuated reinstatement of morphine-seeking behavior induced by pharmacological cue. In this study, we investigated whether acupuncture could suppress the reinstatement of morphine-seeking behavior induced by the combination of environmental and pharmacological cues and the possible neuronal involvement. Male Sprague-Dawley rats were trained to self-administer morphine (1.0 mg/kg) for 3 weeks. Following the withdrawal phase (7 days), the effects of acupuncture on reinstatement of morphine-seeking behavior were investigated. For the investigation of neuronal involvement, the GABAA receptor antagonist bicuculline and the GABAB receptor antagonist SCH 50911 were pre-treated. Morphine-seeking behavior induced by combination of re-exposure to the operant chamber and morphine injection was suppressed perfectly by acupuncture at SI5, but not at the control acupoint LI5 and this effect was blocked by pre-treatment with the GABA receptor antagonists. This study suggests that acupuncture at SI5 can be considered as a predominant therapy for the reinstatement of morphine-seeking behavior in humans.

The Effect of Temperature and Seed Soaking on Germination in Cynanchum wilfordii (Maxim.) Hemsl.

This study is part of research to develop the technology for managing major medicinal crops after harvest. We studied the optimal germination conditions of Cynanchum wilfordii (Maxim.) Hemsl. The mean germination time (MGT) of C. wilfordii seeds was higher after soaking for 4 days after storage at 5℃ for 8 weeks, than with germination at 25 ℃ (3 days). However, the germinative energy (GE) decreased as the number of days soaking increased. The greatest germi- nation rate (83.3 ± 8.8%) was at 25℃ with no soaking of seeds stored at �20℃ for 8 weeks. Based on these results, we char- acterized the germination conditions of a major medicinal crop.

The role of reactive oxygen species in methamphetamine self-administration and dopamine release in the nucleus accumbens

Methamphetamine (METH) markedly increases dopamine (DA) release in the mesolimbic DA system, which plays an important role in mediating the reinforcing effects of METH. METH‐induced DA release results in the formation of reactive oxygen species (ROS), leading to oxidative damage. We have recently reported that ROS are implicated in behavior changes and DA release in the nucleus accumbens (NAc) following cocaine administration. The aim of this study was to evaluate the involvement of ROS in METH‐induced locomotor activity, self‐administration and enhancement of DA release in the NAc. Systemic administration of a non‐specific ROS scavenger, N‐tert‐butyl‐α‐phenylnitrone (PBN; 0, 50 and 75 mg/kg, IP) or a superoxide‐selective scavenger, 4‐hydroxy‐2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPOL; 0, 50 and 100 mg/kg, IP), attenuated METH‐induced locomotor activity without affecting generalized behavior in METH‐naïve rats. PBN and TEMPOL significantly attenuated METH self‐administration without affecting food intake. Increased oxidative stress was found in neurons, but not astrocytes, microglia or oligodendrocytes, in the NAc of METH self‐administering rats. In addition, TEMPOL significantly decreased METH enhancement of DA release in the NAc. Taken together, these results suggest that enhancement of ROS in the NAc contributes to the reinforcing effect of METH.

Combined approaches for the relief of spinal cord injury-induced neuropathic pain

The adequate treatment of spinal cord injury (SCI)-induced neuropathic pain still remains an unresolved problem. The current medications predominantly used in the SCI-induced neuropathic pain therapy are morphine, anticonvulsants, antidepressants, and antiepileptics, which suggests that psychiatric aspects might be important factors in the treatment of neuropathic pain. It is well documented that the modulation of the sensory events is not a unique way for achieving pain relief. In addition, pain patients still express dissatisfaction and complain of unwanted effects of the medications, suggesting that alternative approaches for the treatment of neuropathic pain are essential. In psychiatry, pain relief represents relaxation and a feeling of comfort and satisfaction, which suggests that cognitive and emotional motivations are important factors in the treatment of neuropathic pain. The comorbidity of chronic pain and psychiatric disorders, which is well recognized, suggests that the effective therapeutic relief for neuropathic pain induced by SCI can be achieved in conjunction with the management of the sensory and psychiatric aspects of patient. In this review, we address the feasibility of a combined acupuncture and pharmacotherapy treatment for the relief of neuropathic pain behavior following SCI.

Acupuncture at HT7 suppresses morphine self-administration at high dose through GABA system

In the previous study, acupuncture at HT7 has shown to attenuate the self-administration of morphine at a low dose (0.1mg/kg). In this study, it was further investigated whether acupuncture at HT7 could attenuate the morphine self-administration at a high dose (0.5mg/kg). Male Sprague-Dawley rats weighing 270-300g were used. After surgery of catheterization, animals were trained to self-administer morphine solution (0.5mg/kg) using daily 1h session under fixed ratio 1 schedule for 3 weeks. Animals that had shown stable morphine-taking (establish baseline: variation less than 20% of the mean of three consecutive days) were subjected to the acupuncture treatment. Bicuculline and SCH 50911 were used to investigate the possible relation between the effect of acupuncture and the GABA receptor system. Acupuncture at HT7, but not at control acupoint, LI5, suppressed spontaneous morphine-taking behavior significantly. In addition, the effect of acupuncture was blocked by both GABA receptor antagonists. The results of this study suggest that acupuncture at HT7 suppresses morphine-taking behavior through the mediation of GABA receptor system.

Effects of saikosaponin A on cocaine self-administration in rats.

We have previously demonstrated that saikosaponin A (SSA) attenuated morphine self-administration behavior. In the present study, we evaluated the effects of SSA on cocaine-maintained responding using self-administration procedure. Rats self-administered cocaine (0.25mg/kg per infusion) under a fixed ratio 1 schedule of reinforcement during daily 3-h session. Once stable basal responses were obtained, rats were pretreated with each doses of SSA (1.0, 2.5, 5.0mg/kg) or its vehicle (5% Tween-80) by an intraperitoneal injection 30min before the start of self-administration testing. Additionally, different groups of rats received either the selective GABAB antagonist SCH 50911 or the GABAA antagonist bicuculline before systemic administration of SSA at dose of 2.5mg/kg. Results showed that SSA significantly reduced cocaine self-administration without affecting food consumption. SSA inhibition of cocaine reinforced-responding was blocked by SCH 50911, but not bicuculline. Results suggest that SSA may attenuate cocaine-reinforced behavior through activation of GABAB receptors.