薬物依存・行動薬理
Drug Addiction and Behavioral Pharmacology
O3-7-3-1
11C-doxepinを用いたPETによる抗ヒスタミン薬levocetirizineの脳内ヒスタミンH1受容体占拠率の測定
Brain histamine H1 receptor occupancy measured by PET in humans after oral administration of levocetirizine, a new second-generation antihistamine

○平岡宏太良1, 田代学1, 石渡喜一2, 石井賢二2, 谷内一彦3
○Kotaro Hiraoka1, Manabu Tashiro1, Kiichi Ishiwata2, Kenji Ishii2, Kazuhiko Yanai3
東北大学サイクロトロン・RIセンター1, 東京都健康長寿医療センター研究所 神経画像研究チーム2, 東北大学医学部 機能薬理学分野3
Div. of Cyclotron Nuclear Medicine, Cyclotron and Radioisotope Center, Tohoku Univ., Sendai1, Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo2, Dep. of Pharmacology, Tohoku University Graduate School of Medicine, Sendai3

Histamine H1-receptor (H1R) antagonists, or antihistamines, often induce sedative side-effects. The unfavorable side effects of antihistamines are caused by blocking neural transmission of the histaminergic neuron system. Levocetirizine is a new second-generation antihistamine and nowadays it is widely used in the world. The sedative profile of levocetirizine has been evaluated in clinical trials in subjective and objective studies (driving tests, reaction and memory tests, etc.). The cerebral H1R occupancies (H1RO) of antihistamines can be evaluated using positron emission tomography (PET) and 11C-doxepin, a tracer that specifically binds to H1Rs. We examined brain H1RO and subjective sleepiness induced by levocetirizine in comparison to another second-generation antihistamine, fexofenadine. The mean H1RO of all the regions in levocetirizine (9.7%) was significantly higher than that in fexofenadine (-9.2%). Difference in subjective sleepiness was not significant between levocetirizine and placebo, which could be explained by its low H1RO. According to our standard, levocetirizine can be classified as a non-sedative antihistamine.
O3-7-3-2
Blockade of orexin receptor 1 attenuates the development of morphine tolerance and physical dependence in rats
○Elaheh Erami1,3, Azhdari Zarmehri Hassan2, Rahmani Abolfazl2, Haghparast Abbas4
Torbateheydariyeh Univ of Medical Sciences, Torbateheydariyeh, Iran1, Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran2, Physiology- Pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran3, Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran4

The goals of this study were to evaluate the effects of pretreatment by orexin receptor-1 antagonist on the development of morphine tolerance and physical dependence in rat. Animals were rendered dependent on morphine by subcutaneous (SC) injection of morphine sulfate (10 mg/kg) at set intervals of 12 h for 10 days. Just before the morphine administration, the animals received SB-334867, a selective orexin receptor 1 (OXR1) antagonist. To assess morphine tolerance, the antinociceptive responses of morphine were measured using the warm-water tail immersion test before and after its administration. On day 11, naloxone was injected 2 h after morphine administration and the physical dependence evaluated by quantifying/scoring naloxone-precipitated withdrawal signs for 30 min. The effect of chronic SB-334867 on locomotion was carried out by calculating the number of grid crossings as a measure of locomotor activity. Our findings demonstrated that although morphine-tolerance tended to develop in response to repeated injections of morphine, pre-treatment of OXR1 antagonist prevented this effect, causing a delay in the development of morphine-tolerance. Moreover, co-administration of orexin receptor 1 antagonist with morphine significantly decreased the somatic signs of withdrawal including diarrhea, teeth chattering, jumping, and defecation. Administration of SB-334867 alone or in a chronic co-administration with morphine failed to change locomotor activity. These results suggest that the activation of OXR1 might be involved in the development of morphine tolerance and dependence.
O3-7-3-3
Operant behavior disrupted by SKF 83959 is related to decreased expression of CaM-KII in dorsal striatum
○Pei-Pei Liu1, Ruey-Ming Liao1,2,3, Chih-Chang Chao2
Department of Psychology, National Cheng-Chi University, Taipei, Taiwan1, Institute of Neuroscience, National Cheng-Chi University, Taipei, Taiwan2

SKF 83959 is a dopamine D1 receptor partial agonist whose effects have been previously tested on animals' motor behaviors to examine its therapeutic potentials for Parkinson's disease. However, the neurobehavioral mechanisms for SKF 83959 are still unclear. The present study examined the effects of SKF 83959 on rats' operant behaviors and levels of protein expression in specific brain regions to draw inferences between the dopamine signalling pathways and the animals' motivated behavior performance. Male Wistar rats deprived of water were divided into two groups and trained for one month to lever-press for water on either a differential reinforcement of low-rate (DRL-10 sec) or a fixed-interval (FI-30) schedule respectively. After training to stable performance levels, the rats were injected with SKF 83959 (dosing given in the order of 0.0, 0.1, 0.01, and 1.0 mg/kg) on four consecutive days 30 minutes before being placed into the operant chambers for a 30-minutes test session. The results showed that the highest dose of SKF 83959 significantly disrupted both types of operant behavior by reducing the total number of lever presses. The rats trained on the DRL-10 behavioral task were then divided into two groups receiving the vehicle and SKF 83959 (1.0 mg/kg) treatments respectively. On the test day, after the behavioral session, brain tissues located in the dorsal hippocampus and the dorsal striatum were collected for Western blot assays on PKA and CaM-KII. The behavioral data replicated the above findings of disrupted DRL behavior in SKF 83959-treated rats, while the immunoblotting data showed a decrease in CaM-KII levels in the dorsal striatum but not in the dorsal hippocampus of drug-treated rats. In contrast to CaM-KII, PKA in either site was not affected. Together, these data indicate that the level of CaM-KII in the dorsal striatum is involved in the drug-behavior interaction of SKF 83959 on operant responding.
O3-7-3-4
OX1R-initiated endocannabinoid retrograde disinhibition of dopamine neurons in the ventral tegmental area -A novel mechanism for stress-induced cocaine seeking
○Lih-Chu Chiou1, Li-Wei Tung1, Kuan-Ling Lu1, Yu-Cheng Ho1, Ming-Shiu Hung2, Andreas Zimmer3
Grad Inst Pharmacol, Natl Taiwan Univ, Taipei, Taiwan.1, Inst Biotech Pharmaceut Res Natl Health Res Inst, Miaoli, Zhunan,Taiwan.2

The orexin system, consisting of orexin A and B and their receptors, OX1R and OX2R, is implicated in reward regulation. Orexin neurons project widely throughout the brain, including the ventral tegmental area (VTA), a crucial region involved in reward processing where dopaminergic activity can be increased by addictive substances. Orexin neuron activation has been reported in stress-induced drug seeking while its mechanism remains unclear. We recently revealed a novel analgesic mechanism of orexins in the periaqueductal gray: Activation of postsynaptic OX1R, a Gq-protein coupled receptor, results in synthesis of 2-arachydonoylglycerol (2-AG) via phospholipase C (PLC)-diacylglycerol lipase (DAGL) enzymatic pathway. 2-AG, an endocannabinoid, produces retrograde inhibition of GABA release (disinhibition) by activating presynaptic CB1 receptors (CB1Rs). Here, we validated if this OX1R-PLC-DAGL-2-AG retrograde disinhibition cascade also exists in VTA dopamine neurons, leading to dopamine release and hence stress-induced drug seeking, by examining effects of orexin A on GABAergic inhibitory postsynaptic currents (IPSCs) in dopamine neurons of rat VTA slices. Orexin A (100 nM) depressed IPSCs in VTA dopamine neurons presynapticall. This effect of orexin A was reversed by SB334867 (3 μM, an OX1R antagonist), AM251 (3 μM, a CB1R antagonist) and tetrahydrolipstatin (10 μM, a DAGL inhibitor). In the conditioned place preference test, the reinstatement of cocaine (20 mg/kg) seeking induced by restraint stress, which led to orexin neuron activation, was prevented by SB 334867 (15 mg/kg, i.p.) and abolished in CB1R knockout mice. These results suggest that orexin A inhibits GABAergic transmission (disinhibition) in VTA dopamine neurons via a retrograde signaling mediated by 2-AG. This endocannabinoid-mediated retrograde disinhibiton mechanism in VTA dopamine neurons may contribute to restraint stress-induced reinstatement of cocaine seeking.
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