5-HT3 길항제인 MDL 72222가 Methamphetamine 에 의해 유도 되는 Behavioral Sensitization을 저해 하는 효과

소개

인간에서MAP에 의해 유도되는 정신병의 시작과 재발에 중요한 요인으로 생각 되어 지는 MA에 의해 유도되는 행동 민감화 현상에서 5-HT3의 역할은 알려지지 않았다. 현재 연구에서 우리는 MAP의해 유도되는 행동 민감화 의 발생 과 표현에 5-HT3 수용체들의 역할을 시험 하였다. 더 나아가서, 우리들은 생쥐들에 5-HT3A 채널 활성도 와 5-HT3 수용체 표현에 MAP의 영향력을 측정하였다. 이러한 발견은 5-HT3 길항제인 MDL72222가 5-HT3 수용체의 상호작용을 통하여 MAP에 정신운동 민감화의 발생과 표현을 억제하는 역할을 가지고 있는 것을 제안한다

목차

1. INTRODUCTION
2. MATERIALS AND METHODS
3. RESULTS
4. DISCUSSION

본문내용

Psychostimulants are widely abused throughout the world, causing severe medical and social problems. Methamphetamine (MAP) is one of the most popular drugs of abuse in Asia resulting in serious health and social issues. Acute treatment with psychostimulants increases locomotor activity. Repeated administration of low doses of psychostimulants results in progressive increases in the locomotor activities produced by subsequent dose of the drug; the phenomenon is referred to as behavioral sensitization or reverse tolerance (Kitanaka et al., 2003a) . Animals repeatedly treated with amphetamines showed an increased behavioral sensitization. The increased sensitivity to the locomotor stimulating effect of these drugs (behavioral sensitization) is believed to be relevant to the psychopathology, neurotoxicity, and drug addiction that develops in humans abusing psychostimulants (Robinson and Berridge, 1993) .
It has been proposed that locomotor stimulation of psychostimulants is associated with the activation of the mesolimbic dopaminergic mechanism (Wise and Bozarth, 1987) . The behavioral effects of the psychostimulants, such as MAP, amphetamine and cocaine, increase synaptic levels of the neurotransmitter dopamine (DA). MAP is a potent locomotor stimulant and this stimulant effect tends to increase with repeated exposure to the drug (Itzhak, 1997) . Besides cocaine`s neurochemical effects on the dopaminergic mesoaccumbens circuit (Chen and Reith, 1994) , the psychomotor stimulant also interacts with the serotoninergic neurotransmitter system (Cunningham et al., 1996) , which may contribute to its overall behavioral profile. Indeed, an increasing number of behavioral studies suggest a modulatory role of 5-hydroxytryptamine (5-HT) on cocaine-induced locomotor activity in rodents. For example, pretreatment with the 5-HT biosynthesis inhibitor p-chlorophenylalanine enhanced the locomotor stimulatory properties of cocaine in rats, indicating an inhibitory role of 5-HT (Herges and Taylor, 1999; Herges and Taylor, 2000) . Central serotonin (5-HT) receptors can be divided into multiple families ranging from the 5-HT1 through 5-HT7 receptor families (King et al., 1998) . 5-HT3 receptors are ligand-gated ion channels (van Hooft and Vijverberg, 2000) . The principal distinction is that the 5-HT3 receptor is the only known 5-HT receptor functionally linked to an ion channel. This channel conducts primarily Na+ and K+, resulting in rapid depolarization followed by a rapid desensitization (Yakel and Jackson, 1988; Peters and Lambert, 1989; Grant, 1995) . The immediate consequence of neuronal depolarization resulting from 5-HT3 receptor activation is the release of stored neurotransmitter, an event which requires the influx of extracellular calcium through voltage sensitive calcium channels (Grant, 1995) . 5-HT3 antagonists MDL72222 and ICS205-930 is attenuate the increased locomotor activity associated with cocaine and amphetamine. Direct evidence that 5-HT3 receptors influence dopaminergic activity in the CNS was first available in the late 1980s when it was reported that the 5-HT3 agonist 2-methyl serotonin increased dopamine release in striatal slices; an effect that was blocked by tropisetron (Blandina et al., 1988) . In regarding to drug addiction, pretreatment with a 5-HT3 receptor antagonist MDL 72222 attenuated the amphetamine-induced elevation of extracellular DA concentration in the nucleus accumbens and in the dorsal striatum (Kankaanpaa et al., 1996) .
Therefore, in the present study, we investigated the effects of 5-HT3 antagonist MDL72222 on MAP-induced behavioral sensitization and MAP on the 5-HT3 receptor channel activity. For this purpose, we injected neuronal human 5-HT3A receptor cRNAs into Xenopus Oocytes (Maricq et al., 1991; Choi et al., 2003) and examined the effect of MAP on the 5-HT-elicited inward peak currents(I5-HT). Furthermore, we examined the expression of 5-HT3 receptors after acute, development and expression phases of MAP-induced behavioral sensitization study in mice.
2. MATERIALS AND METHODS

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