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 suggested 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].

Chronic drug use has also been associated with alterations 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].

Brain neurotransmitter/neuromodulator changes also occupy a central role in the establishment, management and extinction (or otherwise) of addictive behaviours. 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 supraphysiologic 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, weakening 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 addictive drugs. A number of studies in animals have shown 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 serotonin in drug addiction have also been suggested[41]. Reports from brain imaging studies have demonstrated an increase in opioid receptors density in persons experiencing 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 preference, drug seeking behaviour and locomotor sensitisation[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 modulation[26,41].

The roles played by neuropeptides in addiction-related 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].

There is ample scientific evidence to suggest the importance of chronological events like the biological rhythms in determining response to drugs of abuse. Earlier studies have argued that chronobiological variables including time of day, sleep-wake patterns and light-dark cycles may modulate the development and maintenance of drug addiction[46]. More recent evidences derived from animal models suggest and support the existence of strong links between appetitive processes and various circadian genes[47]. Also, while details 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].

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 consumption; and concluded that pre-exposure to methamphetamine (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].

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]. However, 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 exerts 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 abuse/addiction and circadian rhythm abnormalities is bidirectional, such that one could lead to the other, and vice versa. Also, abnormalities of sleep and circadian rhythms appear intimately linked to substance abuse, and they could appear as either predictors or consequences of substance abuse[47]. Documented effects 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 (increased night awakenings) later in the night, as a result of acute withdrawal effects[51,52].

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 distinct 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, increases in wake time after sleep onset (WASO) and decreases 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 predisposition to the other pair, and vice-versa.

The roles played by circadian rhythm/gene abnormalities in the development or entrainment of addiction–related behaviours, or in potentiating changes in neurohormone, 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. Observations 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].

Studies by Uz et al[68], and Kurtuncu et al[69] demonstrated loss of diurnal variation in cocaine-induced locomotor sensitisation and cocaine-induced place-preference respectively, in melatonin-deficient pinealectomised 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 morphine, 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.

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 concentrations 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].

Melatonin exerts its effects on behaviours and physiological functions largely via the melatonin (MT) receptors 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 which have been associated with regulating the effects of addictive drugs or behaviours[76,77]. Uz et al[76] studied 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 system[76]. A few studies have also observed an increase in melatonin receptor-related cyclic AMP in the mesolimbic dopaminergic system[62]. In another study, 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-specific[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 receptors 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 comparing the differences in locomotor sensitisation observed 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 period in C3H and C57 wild-type mice. A diminution in magnitude of sensitisation in C57 mice in the dark period, 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 transgenic 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.

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 hormone, 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 demonstrated 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 groups of rats that had been exposed to repeated cocaine 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 weekly 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 provided increase the complexity of assessing melatonin’s efficacy with regards to the measured outcome, there is insufficient evidence to demonstrate melatonin’s benefits 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 elements (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 treatment 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 done 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-administered 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 Sprague-Dawley rats (which had been exposed to long-term cocaine self-administration training). Behavioural parameters measured included the motivation for cocaine 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].

Chronic intermittent use of cocaine and a number of other psychostimulants have been associated with the development of a progressive, long-lasting enhancement of psychomotor effects which have been referred to as cocaine or psychostimulant sensitisation. Studies have demonstrated that behavioural sensitisation to psychostimulants is associated with an increase 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 behavioural sensitisation, while a single injection of melatonin did not halt behavioural sensitisation in rats already sensitised to cocaine. Sircar[85] concluded that while melatonin supplementation increased cocaine’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 development 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 sensitisation 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 protracted opiate withdrawal in rats was associated with the disruption of the circadian rhythm of hormones (adrenocorticotropin, 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 addiction and reported that melatonin was able to reverse 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 that melatonin also counteracted morphine–induced autophagic effects and decrease in mitochondrial DNA copy number in the hippocampus[84].

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], benzodiazepines[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 associated 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 agomelatine (a melatonergic agonist at MT1 and MT2 receptors, 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].