Nam Jun Kim

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.

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 acupuncture on the anxiety-like behavior induced by withdrawal from chronic morphine use

OBJECTIVES In the previous studies, it has been demonstrated that acupuncture treatment was effective on the suppression of withdrawal signs as well as self-administration behavior induced by morphine. Based on, the present study has investigated whether acupuncture could attenuate the anxiety-like behavior induced by withdrawal from chronic morphine treatment. MATERIALS & METHODS Male Sprague-Dawley rats weighing 270-300g were treated saline or morphine hydrochloride (10mg/kg, s.c.) for 2 weeks. Following abstinence of 5days in home cage, rats were subjected to the measurement of anxiety-like behavior in the elevated plus maze. Bicuculline (1mg/kg, i.p.) and SCH 50911 (2mg/kg, i.p.) were used to investigate the possible mechanism of acupuncture effects focusing on the GABA receptors system. RESULTS Acupuncture at HT7 increased the time spent in open arms significantly. Also, these effects of acupuncture at HT7 were blocked by GABAA receptor antagonist. CONCLUSION Results of the present study suggest that acupuncture at HT7 can attenuate anxiety-like behavior induced by withdrawal from chronic morphine treatment through the mediation of GABAA receptor system.

Acupuncture suppresses intravenous methamphetamine self-administration through GABA receptor’s mediation

OBJECTIVES Methamphetamine is one of the widely abused drugs. In spite of a number of studies, there is still little successful therapy to suppress the methamphetamine abuse. Acupuncture has shown to attenuate the reinforcing effects of psychostimulant. Based on, the present study investigated if acupuncture could suppress intravenous methamphetamine self-administration behavior. In addition, a possible neuronal mechanism was investigated. MATERIALS & METHODS Male Sprague-Dawley rats weighing 270-300g were trained to intake food pellet. After catheter implantation, animal was trained to self-administer methamphetamine (0.05mg/kg) intravenously using fixed ratio 1 schedule in daily 2h session during 3 weeks. After training, rats who established baseline (infusion variation less than 20% of the mean for 3 consecutive days) received acupuncture treatment on the next day. Acupuncture was performed at each acupoint manually. In the second experiment, the selective antagonists of GABAA or GABAB receptor were given before acupuncture to investigate the possible neuronal involvement of GABA receptor pathway in the acupuncture effects. C-Fos expression was examined in the nucleus accumbens to support behavioral data. RESULTS Acupuncture at HT7, but not at control acupoint LI5, reduced the self-administration behavior significantly. Also, the effects of acupuncture were blocked by the GABA receptor antagonists. C-Fos expression was shown to be parallel with the behavioral data. CONCLUSIONS Results of this study have shown that acupuncture at HT7 suppressed methamphetamine self-administration through GABA receptor system, suggesting that acupuncture at HT7 can be a useful therapy for the treatment of methamphetamine abuse.

Acupuncture inhibition of methamphetamine-induced behaviors, dopamine release and hyperthermia in the nucleus accumbens: mediation of group II mGluR: Acupuncture on METH addiction

Methamphetamine (METH) increases metabolic neuronal activity in the mesolimbic dopamine (DA) system and mediates the reinforcing effect. To explore the underlying mechanism of acupuncture intervention in reducing METH‐induced behaviors, we investigated the effect of acupuncture on locomotor activity, ultrasonic vocalizations, extracellular DA release in the nucleus accumbens (NAcs) using fast‐scan cyclic voltammetry and alterations of brain temperature (an indicator of local brain metabolic activity) produced by METH administration. When acupuncture was applied to HT7, but not TE4, both locomotor activity and 50‐kHz ultrasonic vocalizations were suppressed in METH‐treated rats. Acupuncture at HT7 attenuated the enhancement of electrically stimulated DA release in the NAc of METH‐treated rats. Systemic injection of METH produced a sustained increase in NAc temperature, which was reversed by the DA D1 receptor antagonist SCH 23390 or acupuncture at HT7. Acupuncture inhibition of METH‐induced NAc temperature was prevented by pre‐treatment with a group II metabotropic glutamate receptors (mGluR2/3) antagonist EGLU into the NAc or mimicked by injection of an mGluR2/3 agonist DCG‐IV into the NAc. These results suggest that acupuncture reduces extracellular DA release and metabolic neuronal activity in the NAc through activation of mGluR2/3 and suppresses METH‐induced affective states and locomotor behavior.

Spinal pathways involved in somatosensory inhibition of the psychomotor actions of cocaine

Previous studies have demonstrated that somatosensory stimuli influence dopamine transmission in the mesolimbic reward system and can reduce drug-induced motor behaviors, craving and dependence. Until now, the central links between somatosensory and brain reward systems are not known. Here, we show that the dorsal column (DC) somatosensory pathway contains projections that convey an inhibitory input from the periphery to mesolimbic reward circuits. Stimulation of the ulnar nerve under HT7 acupoint suppressed psychomotor response to cocaine, which was abolished by disruption of the DC pathway, but not the spinothalamic tract (STT). Low-threshold or wide-dynamic range neurons in the cuneate nucleus (CN) were excited by peripheral stimulation. Lesions of dorsal column or lateral habenula (LHb) prevented the inhibitory effects of peripheral stimulation on cocaine-induced neuronal activation in the nucleus accumbens (NAc). LHb neurons projecting to the ventral tegmental area (VTA)/rostromedial tegmental nucleus (RMTg) regions were activated by peripheral stimulation and LHb lesions reversed the inhibitory effects on cocaine locomotion produced by peripheral stimulation. These findings suggest that there exists a pathway in spinal cord that ascends from periphery to mesolimbic reward circuits (spino-mesolimbic pathway) and the activation of somatosensory input transmitted via the DC pathway can inhibit the psychomotor response to cocaine.