INTRODUCTION

Drug addiction or substance use disorder has been defined as a chronic disease of the brain which is cha racterised by uncontrollable and compulsive drug seeking and use; and which is associated with the development of a negative emotional state in the absence of drug access[1,2]. There have been suggestions that drug ad diction is both a social and a medical problem dating as far back as recorded human history[3] and which co ntinues to be a cause for global health concern[4]. Reports suggest that an estimated total of 246 million people, or approximately 1 in 20 people aged between 15 and 64 years were exposed to illicit drug in 2013; with surveys showing that approximately 1 in 10 of these have a drug addiction problem[5]. Substance use disorder is ar guably a serious public health issue, with a significant economic and health burden on affected individuals and their families[5]. There is also a significant societal burden measured in lost productivity, lawlessness, crime and increased health care costs. Substance use disorders have also been associated with worsening of co morbid psychiatric and/or medical illness, risky behaviours and increasing mortality. While the global and economic bur den of addiction continues to increase worldwide, current psychopharmacological therapies are falling short of the desired goals of therapy[6,7].

Over the past few centuries, several theories (social,biological or psychological) have been proposed to aid in understanding the aetiology of drug addiction[8]. Also,while the distinct aetiological bases for drug addiction are yet unclear, advances in neuroscience have continued to aid our understanding of the possible mechanisms that underlie the alterations in emotional balance and decision making ability that occur with drug addiction[9].Genetic, environmental, neurodevelopmental and socio cultural factors have been listed as important contributors to the development of drug addiction[10]. These factors have also been shown to increase the susceptibility of an individual to initiation or sustenance of drug use; and potentiate the development of structural brain changes that perpetuate drug use and are characteristic of drug addiction[9,11,12].

Presently, there is a growing body of evidence ass ociating disruptions in circadian rhythms and circadian genes with the development and progression of drug addiction[13,14]. Studies in human subjects have dem onstrated circadian rhythm disruptions in individuals with addiction, with suggestions that environmental and/or genetic alteration of the normal sleep wake cyc le increases vulnerability to drug use[13,15]. Studies in rodents have also demonstrated that diurnal variations in the behavioural responses to different addiction par adigms exist[16 18]. In rodents, an increase in cocaine self administration, and the intake of drugs of abuse have been observed at night[16,17,19,20]. There have also been suggestions that the continued craving for drugs of abuse is potentiated through the entrainment of the circadian clock[16,21,22].

万：那么“科学文化”呢？前任刘钝所长在这方面写过不少文章，力陈“科学”与“人文”两种文化历经分道扬镳后还需重归整合的重要；并创办了《科学文化评论》杂志，外界评价也很好.你对科学文化的看法似乎与他们并不一样.

Melatonin is a neurohormone that is important in the entrainment of circadian rhythms, as well as in the modulation of behaviour and physiological functioning in all mammals[23]. Some studies have observed a red uction in melatonin levels, and a delay in attaining its nocturnal peak concentration in alcohol dependent hu mans and rodents[23]. Studies have also demonstrated melatonin’s ability to modulate the reinforcing effects of a number of drugs of abuse with suggestions that it may play a crucial role in drug addiction[24]. In this review,we examine the roles of melatonin and its receptors in drug addiction, by discussing how our understanding of melatonin’s modulatory effects on the brain reward system and crucial neurotransmitters such as dopamine has evolved over the years. Possible indications(s) for melatonergic agents in addiction management, and how manipulations of the endogenous melatonin syst em may be of benefit are also discussed. Finally, the potential impediments to application of melatonergic agents in the management of addictive behaviours are considered.

Neurobiological and neurochemical basis of drug addiction

Substance dependence can be described as a disorder which involves the motivational systems of the brain[25].Repeated exposure to drugs of abuse has been linked to the development of long lasting alterations in brain structure and neuronal circuitry. In the last decade or more, studies have demonstrated that repeated use of addictive drugs can alter the neural circuitries that are involved in reward/ motivation, learning/memory,affect, stress response and decision making[26]. These regions which include the ventral tegmental area (VTA),nucleus accumbens (NAc) and amygdala form a part of the mesolimbic dopaminergic system and are important in reward related processes[27]. Adaptations in cortical regions, including the prefrontal cortex, orbitofrontal cortex and the anterior cingulate gyrus, which form the mesocortical pathway, have also been implicated in addiction[28]. Increase in dopamine release in the mesolimbic or mesocortical brain regions have been sug gested to occur in parallel, appearing to mediate different phases or aspects of drug addiction. The mesolimbic regions (amygdala and hippocampus) have been linked to mediating conditioned learning in addiction; while the prefrontal cortex, orbitofrontal cortex and the anterior cingulate gyrus mediate executive control and emotional response to drugs[26].

The effects of exogenous melatonin in modulating behavioural responses to specific drugs of abuse have also been studied. Vengeliene et al[23] demonstrated that administration of melatonin modulates alcohol seeking or wanting and/or relapse like drinking behaviours[23].Results of in vitro electrophysiological studies have also shown that in cerebellar neurons, nicotine stimulated currents decreased with application of increasing con centrations of melatonin[72]. Markus et al[73] also reported nocturnal elevations of melatonin mediated nicotine induced glutamate release by cerebellar neurons[73].Finally, studies have demonstrated that melatonin is able to modulate the reinforcing or relapsing effects of certain drugs of abuse[23,24].

There are reports that chronic use of substances may alter sleep quality and quantity in ways that are similar across different substances[53]. Extended sleep onset latency (SOL), a reduction in total sleep time (TST),increased frequency of night time awakenings, reduced slow wave sleep (SWS) and rapid eye movement (REM)sleep have all been described[47]. However, withdrawal from alcohol or stimulants may be associated with di stinct time related changes in pattern of TST and REM sleep[51,54]. Acute withdrawal from substance use may also be associated with sleep disturbances such as extended SOL, reduced TST, and reduced SWS[51]. Also,sleep disturbances such as REM sleep disturbances may continue weeks into abstinence; and polysomnographic evidences in cocaine dependent participants still show increased SOL, and decreased TST, SWS, and REM sleep[55]. In heavy marijuana users, polysomnography had shown that over two weeks of abstinence, incr eases in wake time after sleep onset (WASO) and decr eases in TST, sleep efficiency and REM sleep had been observed[56]. A persistence of sleep disturbances is believed to be a risk factor for relapse[55,56]. Overall, the relationship between circadian rhythm abnormalities/sleep disorders and addiction/substance abuse appears to be a complex one; with one pair increasing the pred isposition to the other pair, and vice versa.

Brain neurotransmitter/neuromodulator changes also occupy a central role in the establishment, mana gement and extinction (or otherwise) of addictive beh aviours. In the brain, the neurochemical targets for a number of drugs of addiction have been identified[33].Also, while the pharmacological profiles of the drugs of addiction are diverse, drug receptor interactions can largely explain the wide range of physiological and behavioural changes that occur with drug use[26]. Also,there have been reports that suggest that despite the diversity of behavioural responses, drugs of addiction may share a common reward neural circuitry. Studies have shown that most of the addictive drugs appear to activate the reward system, directly or indirectly stimulating dopamine release[34,35].

Research has shown that dopaminergic (DA) neurons that project from the VTA to the NAc play a crucial role in the processing of stimuli associated with substance related reward[36]. As a part of their pharmacological effects, substances with abuse potentials stimulate the brain reward system by increasing DA release from the NAc[37]. Also, there are reports that drugs of abuse induce their initial reinforcing effect by stimulating su praphysiologic levels of DA in the NAc. These DA surges(acting via D1 receptors) activate the striatal pathway(direct), while inhibiting the striato cortical pathway(indirect) through D2 receptors[10]. Repeated drug use has also been associated with triggering neuroplastic changes that involve the glutamatergic inputs to the striatum and midbrain DA neurons, these alterations enhance the ways the brain reacts to drug cues, wea kening self regulation, reducing sensitivity to non drug rewards and increasing sensitivity to stress[10].

There is also ample scientific evidence to suggest that there are DA independent reinforcement pathways in the acute rewarding or pleasurable effects of ad dictive drugs. A number of studies in animals have sh own that alcohol, opioids, nicotine and amphetamines may produce reinforcing effects via DA independent mechanisms[38 40].

The involvement of some other neurochemicals and neuromodulators such as opioids, gamma aminobutyric acid, glutamate, noradrenaline, cannabinoids and ser otonin in drug addiction have also been suggested[41].Reports from brain imaging studies have demonstrated an increase in opioid receptors density in persons ex periencing withdrawal from alcohol[42], opioids[43] and cocaine[44]. Studies have also shown that the cortico striatal glutamate pathway may be important in the initiation and/or expression of a number of addictive behaviours; examples include conditioned place pref erence, drug seeking behaviour and locomotor sensi tisation[45]. The overall conclusion is that although a number of neurotransmitters and neuromodulators are involved in the short term reinforcing effects of addictive drugs; the dopaminergic reward pathway is central to the reinforcing properties of drugs and the initiation of the cycle of addiction. However, other mediators are believed to exert their influence via dopamine mo dulation[26,41].

在物流作业这一环节中，针对作业时间以及货物遗失等来说，订单处理、分拣与验货等都是其关键控制点。要控制关键点，必须明确安全和不安全产品之间的界限，要保证产品安全性，必须严格管理关键控制点，使其处于特定临界范围。可以将临界范围分为三种类型，分别为化学范围、微生物范围以及物力范围。

Drug addiction and circadian rhythm/gene abnormalities

There is ample scientific evidence to suggest the im portance of chronological events like the biological rhythms in determining response to drugs of abuse.Earlier studies have argued that chronobiological varia bles including time of day, sleep wake patterns and light dark cycles may modulate the development and maintenance of drug addiction[46]. More recent evi dences derived from animal models suggest and sup port the existence of strong links between appetitive processes and various circadian genes[47]. Also, while det ails of the exact mechanisms are still being studied; it is becoming more obvious that a strong relationship exists between disturbance of circadian rhythms (as a result of factors like alteration of normal light dark cycle) and the development of addiction[48].

关于代表性传承人，以《黑龙江省非物质文化遗产条例》为例，该条例规定代表性传承人应当符合下列条件：（一）熟练掌握其传承的代表性项目；（二）在特定领域内具有代表性，并在一定区域内具有较大影响；（三）积极开展传承活动，培养传承人才。仅从事非物质文化遗产资料收集、整理、研究的人员以及不直接从事代表性项目传承活动的其他人员，不得被认定为代表性传承人。该条例还规定了代表性传承人的权利和义务。

It also appears that circadian phase shifting activities such as repeated travels across time zones may influence the pattern of consumption of certain substances with addictive potentials; and this has also been demonstrated in experimental animals[49]. Using male Sprague Dawley rats, Doyle et al[49] studied the effects of experimentally induced chronic jet lag on methamphetamine consum ption; and concluded that pre exposure to metham phetamine (via 2 wk of forced consumption through drinking water) was associated with a significantly higher consumption of methamphetamine in phase shifted rats(four consecutive 6 h advancing phase shifts of the light dark cycle) during the second week following abstinence,when compared to those with undisturbed rhythms[49].

Melatonin exerts its effects on behaviours and ph ysiological functions largely via the melatonin (MT) re ceptors 1 and 2[74,75]. Also, while research has continued to demonstrate the possible roles that melatonin may play in drug addiction, including modulation of the development of dopaminergic behaviours, like drug seeking behaviours or psychostimulant induced diurnal locomotor sensitisation; the contributions of melatonin receptors, especially as it relates to specific drugs, are still being evaluated[23]. Research has demonstrated the presence of the MT1 receptor subtype in a number of brain regions, including areas like the prefrontal cortex,hippocampus, nucleus accumbens and amygdala wh ich have been associated with regulating the effects of addictive drugs or behaviours[76,77]. Uz et al[76] stu died the expression pattern of MT1 receptors in the dopaminergic system of the human and rodent brain,and observed the presence of MT1 receptor in these regions of the post mortem human brain; while in the mouse brain, they observed a diurnal variation (high protein levels and low mRNA at night) in the expression of the mouse MT1 receptor in the dopaminergic sy stem[76]. A few studies have also observed an incr ease in melatonin receptor related cyclic AMP in the mesolimbic dopaminergic system[62]. In another stu dy, prolonged treatment with antidepressants and cocaine was associated with alteration in the content of melatonin receptor mRNA, with the effects of these drugs on MT1/MT2 mRNAs being brain region spe cific[78]; however, prolonged cocaine use did not alter MT2 receptor expression[78,79]. There have been reports suggesting that genetic deletion of MT1 and MT2 rece ptors abolished the development and expression of methamphetamine induced locomotor sensitisation[79],and methamphetamine induced reward[80] in melatonin expressing C3H/HeN mice. Uz et al[68] however reported that MT1, and not MT2 receptor was required for cocaine induced locomotor sensitisation in rodents.In another study by Hutchinson et al[81], this time co mparing the differences in locomotor sensitisation obs erved following a single dose of methamphetamine in low melatonin expressing C57BL/6 wild type and MT1 knockout mice, to melatonin proficient C3H/HeN mice;it was reported that methamphetamine pre treatment induced locomotor sensitisation during the light per iod in C3H and C57 wild type mice. A diminution in magnitude of sensitisation in C57 mice in the dark per iod, and a complete abrogation in the MT1 receptor knockout (MT1KO) mice was observed; buttressing the role of MT1 receptors in the possible management of drug addiction[81]. On the other hand, MT2 receptors have been linked to the modulation of hippocampal dependent long term potentiation; with a few studies demonstrating loss of long term potentiation in tra nsgenic mice deficient of MT2 receptors[82]. There were also reports of loss of experience–dependent short term latency to enter the closed arm on the second day of elevated plus maze exposure; a feature which suggests that MT2 receptors may play an important role in modulating memory processes and hippocampal synaptic plasticity[82]. These properties may prove useful in the management of addiction related neuroplasticity.

4.6 设立减压场所，积极引导合理减压 护理工作是充满高压力的工作，护士是工作倦怠的高发群体，容易产生心理问题，导致护理质量的下降［7］。管理者要提供一个恰当的场所，能使护士发泄各种不满情绪，保持良好的心态。护士工作压力大，应对方式的不同将直接影响事物发展结果，进而影响人的健康。护理管理者和教育者应充分认识压力对护士身心健康的影响，应充分认识压力对护理质量的影响，要采取各种方式减轻护士的职业压力。

2.1.4 护肝剂缺白芍的阴性对照溶液的制备 按护肝剂的制备方法制得除白芍的护肝剂，取1 mL置于PE管中，水浴蒸干，其余操作同“2.1.1”项。

The roles played by neuropeptides in addiction rela ted behaviours have also been examined; and for the most part, neuropeptides including signalling molecules like substance P, endogenous opioids, and neuropeptide Y have been studied extensively as possible therapeutic targets for addiction management[26].

MELATONIN

Melatonin is an endogenously produced indolamine th at is predominantly secreted by the pineal gland, and widely recognised as a regulator of several physiolo gical functions. Melatonin production is controlled by the photoperiod through the suprachiasmatic nucleus(SCN), with production peaking at night and being at its lowest in daytime. In mammals, melatonin is a mas ter synchroniser of biological rhythms, a regulator of physiological processes such as cardiac function; and an important modulator of behaviours, body posture and balance[57 59]. Fluctuations in melatonin levels (in a 24 h period) tune the body’s cellular activities to the actual time of day; and while high levels of melatonin potentiate behaviours and physiological functions ass ociated with darkness, low levels attenuate such be haviours and functions[23].

In biological systems, melatonin’s effects are exerted via interactions with melatonin receptors (MT1 and MT2),orphan nuclear receptors, and intracellular proteins like calmodulin[60 62]. As an ampiphillic molecule, melatonin is capable of autocrine, paracrine and endocrine signalling;and it permeates several body compartments to exert effects on a variety of functions such as diurnal/seasonal rhythms, reproduction, neurobehaviour, antioxidant de fense and general immunity.

由图3可知，以综合滋味得分3分(y值)为接受临界点，确定铝箔袋脆口萝卜产品各储存温度的货架期(保质期)： 35 ℃产品货架期=Qs(35)=(5.046-3)/0.0146=140.14天；45 ℃产品货架期=Qs(45)=(5.02-3)/0.0333=60.66天；Q10value=Qs(35)/Qs(45)=115.61/58.38=2.31；推算产品流通中货架期为Qs(25)=Q10value×Qs(35)=2.31×140.14=323.76天，即铝箔袋脆口萝卜产品货架期(保质期)为324天。

Over the years, exogenous melatonin and melatonin analogues have been known to have an established role in the management of a range of sleep disorders.However, melatonin’s therapeutic application is not limited to the central nervous system; and research has continued to shed light on the potential use of mela tonergic drugs for the management of an increasing number of disorders/diseases including respiratory ail ments such as asthma, pneumonias, chronic obstructive airway diseases, pleural cavity diseases, vascular pu lmonary disease, and even lung cancer[63] Melatonin adm inistration had also been shown to be protective against intestinal ischaemic reperfusion injury in young male Sprague Dawley rats[64] and Wistar albino rats[65].

From the foregoing, it is obvious that due to its unique chemical characteristics and diverse effects,melatonin may be useful in the management of several human diseases/disorders including those of the central nervous system such as drug addiction. Therefore, a better understanding of melatonin’s role in addiction might open a new door in addiction management.

Melatonin and drug addiction

The ability of melatonin to mitigate different as pects of addiction neurobiology has been examined extensively. Studies have reported the efficacy of mela tonin supplementation in the control of drug seeking behaviour, opiate withdrawal/ relapse[24], behavioural sensitisation[84,85], regulation of the sleep and or circadian rhythm disorders[86], neuroplasticity, and prevention of:Mitochondrial induced autophagy, apoptosis, oxidative stress and neurotoxic injury[84] in brain areas linked to reward and emotionality.

Studies by Uz et al[68], and Kurtuncu et al[69] dem onstrated loss of diurnal variation in cocaine induced locomotor sensitisation and cocaine induced place preference respectively, in melatonin deficient pine alectomised mice, suggesting that the cocaine induced diurnal variations were mediated by melatonin[68,69].There have also been reports suggesting that (drug induced) hypothermic responses to injections of mor phine, nicotine or ethanol varied with the light dark cycle[70]. There have been suggestions that disturbances in sleep observed after months of abstinence in humans with alcohol dependence could be linked to delayed peak of melatonin’s nocturnal rise and lower melatonin levels[68,71]. Studies in rodents have also demonstrated similar alterations[67], further buttressing the role of the melatonergic system in drug addiction.

Chronic drug use has also been associated with alt erations in the “anti reward” pathway which include the hypothalamic pituitary adrenal axis[29,30]. Adaptations in stress response, involving levels of corticosterone cortisol releasing factor and the adrenocorticotrophic hormone have also been reported to occur with drug addiction[31,32].

2.2.1 不同处理下基于DM的草地载畜量 不同处理下基于DM的草地载畜量变化与DM产量的变化相似(图1)。除6月施肥对杂类草DM载畜量(4.38羊单位/hm2)有显著促进作用外，其余各月施肥和补播处理对杂类草DM载畜量无促进效果。6月补播对禾本科(13.55羊单位/hm2)、豆科(7.68羊单位/hm2)和莎草科(5.68羊单位/hm2)DM载畜量的促进作用最明显。7月施肥处理下禾本科的DM载畜量(21.34羊单位/hm2)与CK差异显著(P<0.05)；补播处理下禾本科(22.88羊单位/hm2)和豆科(11.48羊单位/hm2)DM载畜量显著高于施肥和CK(P<0.05)。

Melatonin receptors and drug addiction

Earlier studies in humans had observed that drug seeking behaviours are probably linked to mutations in certain key genes that are related to circadian rhythm maintenance; suggesting a link between abnormalities of circadian rhythm maintenance and addiction[47]. How ever, the associations between these genetic alterations and addiction have also been demonstrated in animals by using specific experimental paradigms. In male Wistar rats, a month of constant light exposure exe rts a significant effect on voluntary consumption of morphine, exhibition of withdrawal symptoms, plasma concentration of melatonin [evaluated by enzyme linked immunosorbent assay (ELISA)] and the mRNA expression of period homolog genes (Per1, Per2) and dopamine (D1) receptors in the striatum and prefrontal cortex[48]. One month exposure to constant light caused a significant decrease in melatonin concentration, an upregulation of mRNA levels of Per2 and D1 receptor in the striatum and prefrontal cortex, up regulation of Per1 gene in the striatum of rats under constant light(in comparison to those under standard light cycle),increased morphine consumption and preference ratio,and also a significant increase in severity of naloxone induced withdrawal syndrome[48]. In humans, more studies are beginning to demonstrate that core genes that are involved in circadian rhythm maintenance are also important regulators of reward related behaviours which occur in response to common substances of abuse[50]. On the other hand, substance use has been known to cause disruptions in circadian rhythms and affect functions such as the sleep/wake cycle; hence,the relationship that exists between substance ab use/addiction and circadian rhythm abnormalities is bidirectional, such that one could lead to the other,and vice versa. Also, abnormalities of sleep and circa dian rhythms appear intimately linked to substance abuse, and they could appear as either predictors or consequences of substance abuse[47]. Documented eff ects of substance use on sleep is not only dependent on the class of agents, but also on the phase of usage,with acute sleep effects, chronic sleep effects, and sleep effects due to withdrawal or abstinence being described. Acute ingestion of drugs such as cocaine and amphetamine which have stimulant effects have been associated with a light, restless and disrupted sleep[51];while ingestion of drugs with depressant effects such as benzodiazepines, alcohol and opiates can have an initial sleep promoting effect (increased daytime sleepiness and reduced sleep latency) but sleep disruptions (incr eased night awakenings) later in the night, as a result of acute withdrawal effects[51,52].

MELATONIN AND THE PHARMACOLOGIC MANAGEMENT OF DRUG ADDICTION

Information garnered from years of research into the aetiopathogenesis of addiction point to the conclusion that drug dependence is a multifactorial behavioural and biological disorder, which is amenable to medical treatment. The current treatment protocol for drug use disorders involves the use of psychosocial and pharmacological interventions[5]. The main goals of management include: (1) reduction of drug use and drug craving; (2) improvement of general wellbeing and functioning of the individual; and (3) decreasing the risk of the development of complications and/or recurrence[5]. However, currently available treatment options remain inadequate, with varying addiction relapse rates, depending on the drugs involved[83,84].Thankfully, advances in science and research are ope ning new vistas for possible therapeutic interventions,and as such, current research interests are directed at developing or discovering new treatments options like the use of melatonin (a regulator of the circadian rhythm and potent antioxidant) that could be beneficial in reducing craving/withdrawal period and preventing relapse.

早在中本聪提出比特币之前，BFT算法已经存在，1999年LISKOU B等提出了实用拜占庭容错算法。该算法达成共识需要“请求、预准备、准备、确认、回应”5个步骤。其中“预准备、准备、确认”3个步骤用于保障一致性。该算法虽然拥有1/3的容错性，但并不能防范女巫攻击，因此不能用于公有链类型货币中。实用拜占庭容错算法（PBFT）是传统一致性算法的改进，算法十分高效，在不需要货币体系的许可链或者私有链中较为常用。目前，IBM创建的超级账本就是使用了该算法作为共识机制。

The roles played by circadian rhythm/gene abnorm alities in the development or entrainment of addiction–related behaviours, or in potentiating changes in neu rohormone, neuromodulator or neurotransmitter levels which result in the development of addiction are well documented[24]. Melatonin’s role in the entrainment of circadian rhythms is also well documented. Obse rvations that alcohol consumption altered the circadian profile of melatonin production in alcohol dependent humans and alcohol drinking rodents[66,67] have also increased interests in the importance of melatonin in addiction[23].

Melatonin, withdrawal syndrome and relapse

Prolonged use or abuse of drugs (such as opioids) by humans have been linked to the development of physical dependence and/or addiction, which is usually associated with alterations in brain biochemistry and hormone levels;and disruption of the sleep/wake cycle[87 89]. Also, sudden clearance or reduction in the plasma concentration of opioids of abuse results in withdrawal symptoms,including circadian rhythm disturbances like insomnia,jitteriness and restlessness[90,91]. Studies in animals have reported that chronic morphine administration resulted in a reduction in total activity within a 24 h period, and a dampening of the circadian amplitude in locomotor activity rhythm[92,93]. Abrupt withdrawal of morphine administration in rats has also been associated with sustained disruption of the circadian rhythms in locomotor activity, and alterations in plasma melatonin,β endorphin, corticosterone, adenocorticothrophic hor mone, and orexin concentrations[93 95]. Studies have also reported evidence of anxiety related behaviour following cocaine withdrawal[96].

The possible effects of melatonin on withdrawal symptoms have also been examined; and while there is a dearth of clinical trials, studies in rodents have dem onstrated its effectiveness. Zhdanova and Giorgetti[96]assessed the effects of melatonin supplementation on cocaine induced anxiety like behaviour and nucleus accumbens cyclic adenine monophosphate (AMP)levels in rats. In their study, melatonin (200 ng/mL)was administered in drinking water (at night) to gr oups of rats that had been exposed to repeated co caine administration (15 mg/kg i.p.), or during its withdrawal. Results showed that melatonin caused a reduction in anxiety like behaviour in a defensive withdrawal paradigm, 48 h after the last injection of cocaine[96]. Melatonin pretreatment also attenuated the augmentation of cAMP levels in the nucleus accumbens following acute administration of cocaine. These results suggest that a low dose night time melatonin treatment was effective in militating against symptoms of cocaine withdrawal in rats[96]. Bondi et al[97] conducted a single centre, randomised, double blind, placebo controlled,parallel group trial to assess the effect of melatonin(5 mg) compared to placebo as adjuvant treatment(alongside behavioural and pharmacotherapy) on we ekly self reported severity of depression, anxiety, stress,and insomnia complaints in recovering substance use disorder subjects males (aged 18 years or older) who were at a residential program. Results showed no significant differences were observed for baseline characteristics; although the frequency of reported adverse events was higher in the melatonin group[97]. The authors were of the opinion although the diversity of medication regimens and behavioural interventions pro vided increase the complexity of assessing melatonin’s efficacy with regards to the measured outcome, there is insufficient evidence to demonstrate melatonin’s be nefits as an adjuvant in addiction recovery[97].

The use of melatonin for its antioxidant effects during recovery from drug abuse has also been studied.The naloxone induced heroine withdrawal syndrome has been associated with derangement in antioxidant enzymes and bio elements which are essential for the maintenance of life[98]. Cemek et al[98] examined the effect of melatonin supplementation on the levels of antioxidant enzymes and bio elements in naloxone induced heroine withdrawal syndrome and reported a reversal in heroine withdrawal related alteration in glutathione, catalase levels, and the levels of bio ele ments (iron, manganese, magnesium, aluminium,calcium and copper). The researchers concluded that exogenous melatonin could be effective in militating bio element and antioxidant enzyme derangements in heroine withdrawal syndrome[98].

A very powerful challenge to drug addiction trea tment is the high incidence of drug use relapse during abstinence[99]. However, years of extensive clinical and preclinical research on drug use relapse[100,101] have do ne little to reduce relapse rates[83,102]. Reports from a number of studies have reported that drug use relapse is usually triggered by acute exposure to the self adm inistered drug[103], stress[102], the presence of drug related cues and contexts[104], and protracted periods of withdrawal or exposure to cure that have been previously associated with withdrawal[105]. Extensive research work has led to the identification of possible cellular, neurotransmitter, and/or receptor mediated mechanisms that increase the risk of relapse to drug use with the intent of identifying novel pharmacological treatment options[106 108]. Takahashi et al[24] assessed the effects of melatonin supplementation (administered at either 25 or 50 mg/kg body weight) on cocaine self administration and relapse like behaviours in male Sp rague Dawley rats (which had been exposed to long term cocaine self administration training). Behavioural parameters measured included the motivation for co caine self administration in the break point test, relapse like behaviour in the cue induced reinstatement test,sucrose preference and distance travelled in the open field. Results showed a reduction in the cocaine seeking behaviour and the desire to self administer cocaine. The researchers concluded that melatonin supplementation could be beneficial in reducing relapse[24].

Melatonin, addiction-related behavioural sensitisation,neuroplasticity and neurotoxicity

Chronic intermittent use of cocaine and a number of other psychostimulants have been associated with the development of a progressive, long lasting enha ncement of psychomotor effects which have been ref erred to as cocaine or psychostimulant sensitisation.Studies have demonstrated that behavioural sensi tisation to psychostimulants is associated with an inc rease in nitric oxide synthase[109]. While examining the effect of melatonin on cocaine induced behavioural sensitisation in rats, Sircar[85] reported that: (1) acute or repeated melatonin injections on its own did not affect locomotor behaviour in rats; (2) acute melatonin pre exposure augmented the acute locomotor effects of cocaine; and (3) repeated melatonin pre exposure prevented the development of cocaine induced be havioural sensitisation, while a single injection of me latonin did not halt behavioural sensitisation in rats already sensitised to cocaine. Sircar[85] concluded that while melatonin supplementation increased co caine’s acute behavioural effects and prevented the development of cocaine’s behavioural sensitisation,it had no effect in militating fully developed cocaine behavioural sensitisation[85]. Itzhak et al[110] studied the effects of melatonin supplementation on the de velopment of methamphetamine (METH) induced behavioural sensitisation and reported that pre treatment with melatonin at 10 mg/kg body weight prevented the development of METH induced depletion of dopamine and/or its metabolites and depletion of dopamine transporter binding sites. It also attenuated METH induced behaviours and diminished METH induced hyperthermia, although it did not reverse fully developed METH–induced behavioural sensitisation[110].Feng et al[84] also examined the effects of melatonin on morphine induced behavioural sensitisation and reported that pre treatment with melatonin prevented the development of morphine induced behavioural se nsitisation and analgesic tolerance; effects which were dose dependent[84].

The development of long lasting addiction related behavioural dysfunction and structural deficits in the brain have been linked to alterations in the methylation processes for purine metabolism/serotonin pathways[111],oxidative stress induced autophagy[84], mitochondrial mediated apoptosis[112,113], alteration in mitochondrial DNA copy number in distinct brain regions[81], and neurotoxicity[84,114]. Li et al[95] also reported that protr acted opiate withdrawal in rats was associated with the disruption of the circadian rhythm of hormones (adr enocorticotropin, orexin and corticosterone), leading to the induction of neurobiological changes which may worsen the risk of relapse[95].

Feng et al[84] examined the ability of melatonin to militate against the deleterious effects of opiate ad diction and reported that melatonin was able to reve rse morphine induced mitochondrial dysfunction and oxidative stress, in cultured cells. They also demonstrated that melatonin reversed morphine induced autophagy and changes in mitochondrial DNA copy number in cultured cells and neurons[84]. In vivo studies using a mouse model of morphine addiction demonstrated th at melatonin also counteracted morphine–induced au tophagic effects and decrease in mitochondrial DNA copy number in the hippocampus[84].

Melatonin in the management of drug-addiction related sleep and circadian rhythm disorders

Sleep and circadian rhythm disorders have been well defined in a number of substances use disorders, including those of marijuana[115], alcohol[52,116,117], nicotine[118], be nzodiazepines[86,119] and cocaine[51]. Also, results from a number of rodent studies have reported interactions between alcohol and homeostatic mechanisms[120] and/or circadian systems[121 123]. Treatment options for insomnias in drug addiction are limited, largely because traditional hypnotics that target benzodiazepine receptors are ass ociated with abuse potential, withdrawal effects, and the potential for overdose. Melatonin supplement has been found particularly valuable in the management of circadian rhythm disorders[124], in the treatment of insomnias in subjects with chronic schizophrenia[125],in the elderly[126,127], and among children with sleep onset insomnia[128]. However, its benefits in addiction related sleep and/or circadian rhythm disorders are still being evaluated. A double blind cross over control study that examined melatonin’s ability in militating sleep difficulties associated with benzodiazepine (BDZ)withdrawal reported that while melatonin did not increase the likelihood of BDZ discontinuation, it improved sleep quality, especially in subjects who continued to use BDZ[86].

Its use in alcohol addicts have been supported by studies that have reported low plasma melatonin levels in this group of substance users[66,129]. Other studies have examined the efficacy of melatonin analogs in militating addiction related sleep disorders.Brower et al[116] examined the ability of the melatonin receptor agonist ramelteon to attenuate insomnia in recovering alcoholics, and reported an improvement in sleep quality and quantity. Another study using ag omelatine (a melatonergic agonist at MT1 and MT2 rec eptors, and a 5 HT2C antagonist approved for use as an antidepressant) reported improved sleep in alcohol dependent subjects with insomnia; with participants reporting improved subjective sleep quality after 6 wk of administration[130].

（2）识别是否钻出油气层。进入E区后，气测值较D区略有降幅，甲烷相对含量及3H曲线均发生了较大变化，3H曲线变化尤为明显。进入E区后，CH曲线和BH 曲线突然交叉，CH 值增大，BH 值减小，WH 增大，形成WH＞CH＞BH 的格局；甲烷相对含量曲线也突然发生变化，其值突然减小。此时CH和BH 的交叉点及甲烷相对含量突变点恰好和电阻率变化的半幅点相吻合。

CONCLUSION

To date, melatonin and its analogs have continued to show promise in the management of drug addiction.However, the use of melatonin may be limited by its short half life and an additive sedative effect when used alongside BDZs and other drugs such as morphine;also, its safety in the younger age groups are still being debated. Despite these, evidences from both animal and human studies continue to show the potentials of melatonin and its analogs in the management of drug addiction. Therefore, research must continue to focus on the applications of melatonergic agents in drug addiction management, especially, beyond their established use for associated sleep disorders.

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