Mounting evidence places the dopaminergic-mesolimbic system as the leading system in the development of addiction, due to its role in encoding motivation and reward (21).

Apart from the motivation-reward-reinforcement cycle, the dopaminergic system plays numerous other roles such as executive functioning and motor planning, sleep and regulation of food intake, neuroendocrine secretion, arousal and sexual gratification. An imbalance in any function may lead to significant disorders. Several neuropsychiatric disorders (Parkinson's disease, Huntington disease, Alzheimer's disease, schizophrenia, bipolar disorder, attention-deficit disorders, Tourette's syndrome) have been associated with a variation in dopamine (22).

Studies have described five types of dopamine receptors: D1, D2, D3, D5, D4 (ordered by density) of the G-protein coupled receptor type. By studying the functioning of these five receptors two subclasses have been characterized: D-1 like receptors (D1, D5) and D-2 like receptors (D2, D3, D4). D1-like receptors activate adenylate cyclase, converting ATP to cAMP, in order to disinhibit protein kinase A, which phosphorylates cAMP regulatory element binding protein (CREB). Thus D1-like receptors have a vital role in the regulation of the reward system, learning, and memory. Furthermore, D1 receptors have been linked to various neuropsychiatric disorders, by activating the phospholipase C and inducing intracellular calcium release. In contrast, binding dopamine to D-2 like receptors inhibits adenylate cyclase which decreases the production of cAMP (23).

From a neurophysiological point of view, addiction can be translated as a hypo-dopaminergic dysfunctional state within the reward circuitry, and therefore is characterized by a decreased in dopamine D2 receptors. Moreover, a greater risk of addiction is associated with the polymorphism of Taq1A (rs1800497), responsible for the number of D2 receptors, the A1 allele having a lower density of D2 receptors (21,24).

Rebalancing dopamine is a difficult objective to reach in order to treat addiction. Using antipsychotics has shown some beneficial results for isolated alcoholism, while in the subpopulation of stimulant users it may aggravate the condition (25).

Available data demonstrate the complex roles of serotonin such as regulating neuroplasticity, cognition and memory, behavior and mood, social behavior and sexual desire, impulse control, as well as appetite, sleep, circadian rhythmicity and neuroendocrine functions (26). Analyzing this assemblage of functions, a simple conclusion can be drawn: Comorbid mood and addictive disorders are expected due to dysregulation of serotonin. When discussing serotonin, 5-HT2CR (serotonin receptor) cannot be overlooked, as it is recognized as an important nominator in depression, suicide, sexual dysfunction, addiction and obesity (27,28).

5-HT has been linked to addiction by several studies (26,29). Additionally, the serotonergic response is believed to differ from the initial exposure to chronic use, from development of dependence to withdrawal, from abstinence to relapse. For example, during substance intake, 5-HT levels increase which is correlated with a boost in mood while in withdrawal syndrome there is hypoactivity of the serotonin system which may contribute to dysphoria (26-29).

Recent research has examined the role of 5-HT in impulse control, as high levels of impulsivity may be considered a risk factor for the vulnerability to addiction and relapse (29).

Whether to treat the underlying depression, ameliorate withdrawal symptoms, or reduce craving, the efficiency of using antidepressants in addiction disorders is still being debated by physicians. Certain antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), can be used for mood elevation during detox, while bupropion is used to reduce nicotine cravings and ease withdrawal symptoms (29,30).

Endogenous opioids are natural pain killers, much like exogenous opioids. Additionally, they control motor activity, intestinal tract motility and peristalsis, the hypothalamic neuroendocrine axis and limbic system regulation of emotional behavioral, modulating euphoric responses and opposing stress (31-33). These effects glorify opioids in substance users. The euphoria together with their highly addictive properties are a recipe for disaster. Endorphins impact addiction via two routes, either by stimulating the mesolimbic dopamine system also independently, by an increase in endorphins in the extracellular space in the nucleus accumbens (34).

Naltrexone, a subtype-nonspecific opioid receptor antagonist, is currently used to treat opioid addiction and alcoholism. Some studies propose naltrexone as a pan-addiction treatment, yet more research is needed (34,35).

The cholinergic system plays a supporting role in encoding motivation alongside dopamine, but it is also involved in sensory and motor processing, sleep, nociception, mood, stress response, attention, arousal and memory (36).

In regards to addiction, ACH is involved by processing reward, acquisitioning conditional associations and conditioned learning, satiation and aversion, drug procurement through arousal and attention. Learning and memory are essential to repeated behaviors (37,38).

Considering its implication, cholinergic medications may represent a potential treatment for addiction but further research is needed. However, AChE inhibitors (donepezil, rivastigmine) can be considered for cognitive impairment associated with long-term substance use (37).

GABA is the prime inhibitory neurotransmitter; in normal conditions it regulates fear and anxiety. A decrease in cerebral GABA has been linked to schizophrenia, depression, anxiety, addiction and sleep disorders (39).

A decreased activation in the GABAA receptor induces tolerance when exposed to chronic doses of alcohol, while the GABAB receptor is involved in adjunct treatments to aid in the initiation of abstinence, maintenance of abstinence, and prevention of cue-related relapse in some addictions (40).

Baclofen, a GABA derivative and GABAB agonist, has been proposed as treatment for alcohol disorders, yet additional research is warranted (41).

Glutamate is the most substantial excitatory neurotransmitter and is known for the following roles: Synaptic plasticity, cognition, learning and memory, and emotions. Glutamatergic dysfunction has been associated with a series of neuropsychiatric disorders including depression, anxiety, bipolar disorder, schizophrenia and addiction disorder.

Chronic substance use is responsible for plastic changes in glutamatergic response in striatum and midbrain dopamine neurons, intensifying the brain's reactivity to drugs (42).

Ketamine and esketamine are antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor. Preliminary data suggest that ketamine can prolong abstinence from alcohol and heroin as well as reduce the craving for cocaine, but ketamine itself may lead to addiction if used ill-advisedly exceeding the therapeutical dose (43).

Alcohol addiction is a global burden; therefore, it has been immensely studied throughout the decades. Repeated administration of ethanol is the cause of neurological alteration within the circuits that control motivational processes. This leads to affecting how arousal, reward, and stress are encoded in the brain, creating a vicious cycle. Additionally, chronic use of alcohol induces a change in the aforementioned neurotransmitters leading to sensitization and tolerance.

One neurotransmitter that undergoes change is dopamine. Once acquainted with alcohol, the nucleus accumbens will increase dopamine activity in the anticipation of the substance reinforcing repeated consumption. In reverse, withdrawal produces a decrease in dopamine function, which may contribute to withdrawal symptoms and alcohol relapse (34).

Secondarily, alcoholism affects the expression of GABAA genes resulting in substance tolerance (27,32). Other genes identified that are involved in the metabolism of alcohol are ADH1B and ALDH2, including GABRA2, CHRM2, KCNJ6 and AUTS2. These genes increase the risk of alcoholism or related traits (49).

Thirdly, a difference in the behavioral responses to stress has been described; alcohol use produces a dysregulation in the hypothalamic-pituitary-adrenal axis (34).

Moreover, alcoholism causes neuroimmune gene induction which alters the limbic system and frontocerebellar neuronal nodes contributing to persistent drinking (50).

Multiple imaging techniques have been utilized to observe the dynamic metabolic changes and imbalance of neurotransmitter accelerating neurodegenerative alteration that occur after chronic exposure to ethanol. Examining the data presented by Sullivan and Pfefferbaum, it was found that both frontal lobe and connective circuitry suffered modifications due to the chronic intake of alcohol (51).

Future research must attempt to fully understand the genetic impact behind alcohol dependency in order to discover genetically tailored treatment for alcoholism.

Nicotine is at the root of tobacco addiction, one of the most abused substances in the world due to its legal status and easy access. Few genetic components have been described in nicotine addiction, especially in adolescent smokers (52). Nicotine binds to nicotinic cholinergic receptors (nAChRs), mediating the complex actions of nicotine in tobacco users. CYP2A6 is responsible for metabolizing nicotine and variability in the metabolic rate contributes to the susceptibility of tobacco dependence, withdrawal symptoms and the risk of lung cancer (53,54). Much like other substances, repeated nicotine exposure alters sensitivity to dopamine within the reward network and circuits involved in learning, stress, and self-control. One particularity of nicotine is that levels peak after 10 sec of inhalation reaching a quicker and faster ‘endorphin high’ in comparisons to other drugs which translates to frequent cravings and relapses (55).

Electrochemical signaling modifications in the anterior frontal lobe as well as atrophy and neurodegenerative disease have been linked to chronic smoking. In regards to smoking tobacco, a close look to the vascular changes is called for, because the associated decreased cerebral blood perfusion can be a determinant factor in cognitive dysfunction. Moreover, in addition to nicotine, cigarettes contain a multitude of potentially cytotoxic compounds hence singling out a sole cause of atrophy would be challenging (55).

Serotonergic hallucinogens or psychedelics are highly psychoactive substances that are associated with perceptual disorders such as hallucinations, complex cognitive symptoms and mood disturbances. The most common representatives from this class are LSD (d-lysergic acid diethylamide), psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine), peyote (mescaline), DMT (dimethyltryptamine), and ayahuasca. The method by which psychedelics function is through binding to serotonin 5-HT2A receptors which is associated with increased cortical glutamate levels. Correspondingly, neuroimaging has demonstrated an increase in prefrontal cortical metabolism. Recreational use of psychedelics is more frequent than addiction although with repeated exposure tolerance sets in rapidly due to downregulation of 5-HT2A receptors (56).

Early studies have sought to use hallucinogens as agonists or partial agonists of 5-HT to alleviate severe forms of depression (57).

Inhalants define a class of substances based on the route of administration (inhalatory or breathing in volatile chemical vapors). Individually, the representatives of this class have different pharmacokinetics. These substances include solvents, aerosol, sprays, gases and nitrites.

Intoxication from acute volatile substances can vary from alcohol-like effects with stimulation or loss of inhibition to intense euphoria and hallucinations, depending on the substance and the dose. Accurate evidence on the effects of chronic inhalant administration is scarce and the results are usually influenced by polydrug use (58).

Dependence on inhalants is often explained by the nature of the substance, the easy availability, the cheap price and the faster onset of effects, yet the neurophysiological and neurochemical aspects need more documentation (59).

Δ9-tetrahydrocannabinol (THC) is the principal psychoactive component in cannabis; the one responsible for the addictive potential. Available data suggest that THC is a partial agonist of the CB1R (endocannabinoid receptor). Direct effects on the endocannabinoid system and indirect impact on the GABA-ergic, glutamatergic and dopaminergic systems, result in THC producing effects on emotional, executive, memory and reward processing (60).

Cannabidiol (CBD) is also synthesized by the cannabis plant and, in comparison to THC, lacks intoxicating effects, and can offset some of the acute effects of THC. Recent studies suggest it has a positive role in the treatment of epilepsy, addictions, anxiety disorders and psychosis (61,62).

Cannabis plants have become more and more selected to produce THC only in order to maintain consumption.

CB1R is a G protein-coupled receptor that exists in high concentrations in the amygdala, hippocampus, thalamus, cerebellum, basal ganglia and neocortex (especially in the limbic and frontal areas), areas associated with emotional, cognitive and reward processing. Activation of these receptors situated within the central brain reward circuits plays an important role in the pleasurable and anxiolytic effects of the drug. Researchers suggest that THC acts upon reward substrates in a seemingly way as do other abused drugs (60).

There are endogenous lipid-based retrograde neurotransmitters that form the endocannabinoid system which influences the motivation for natural rewards (social interaction, food, sexual activity) and modulates the rewarding effects of addictive drugs. Endocannabinoids bind to the CB1Rs and this leads to suppression in glutamatergic nerve terminals and suppression of inhibition in GABA-ergic nerve terminals. This signaling pathway is disrupted by THC (60).

After THC exposure, impaired salience processing has been observed, a fact that has been explained by the dysregulation of the dopaminergic and endocannabinoid systems that are involved in salience attribution (63).

Research has shown that chronic exposure to THC downregulates CB1Rs, a fact that explains the tolerance to the rewarding effects of the drug (64). Moreover, there is evidence that CB1R density is restored after one month of abstinence (except the hippocampus), so not all neurobiological changes are permanent in chronic cannabis users (65,66).

An interest in discovering a link between genetic factors and lifelong cannabis use has increased over time. There is interesting data available on this subject, but further research is needed. An association between rs1800497 Taq1A of the ANKK1 gene, the gene locus HES7/PER1 on chromosome 17 and cannabis consumption has been found (67), and parental care has also been shown to play an important role (68). More so, depression and self-harm appear to be genetically and phenotypically linked to cannabis use, but the direction of the causality requires further study (69). HTR2B is a major locus associated with cannabis-induced aggression, as it is known that cannabis increases impulsivity and decreases behavioral inhibition (70). The largest genome-wide association study pointed out the significant single nucleotide polymorphism and gene associations in 16 regions. It was shown that the CHRNA2 gene has a decreased expression in the cerebellum of cannabis-dependent people (71). Other genes associated with lifetime cannabis use are NCAM1 (implicated in alcohol use, smoking, schizophrenia, mood disorders), SCOC, CADM2 (a synaptic cell adhesion molecule from the immunoglobulin family, linked to risk-taking behavior, alcohol consumption, processing speed) and KCNT2 (72,73).

Even though effective treatment is available for opioid intoxication, relapse is frequent in opioid addicts, mainly due to the opioid receptors' tolerance after repeated use of opioids. After tolerance is developed and the euphoria fades, addicts start feeling symptoms of withdrawal, such as abdominal cramps, diarrhea, sweating, agitation, bone pain, myalgia, and rhinorrhea (74). These withdrawal symptoms develop quickly and can be alleviated by correct treatment.

Opioid receptors are located in the brain, skin, spinal cord, gastrointestinal tract and after stimulation cause euphoria, analgesia, sedation and respiratory depression.

There are three discovered subtypes of opioid receptors: Mu, kappa and delta, with different effects (the common effect is analgesia) and disposition. Mu receptor stimulation produces euphoria, respiratory depression and physical dependence; kappa receptors trigger sedation and dysphoria, while delta receptors stimulate anxiolysis. Mu receptors are crucial for the activation of the reward system (75). An interesting explanation for why adolescents are more predisposed to addictive behaviors in comparison with adults lies in the fact that in this category of patients mu opioid receptors have increased positive reinforcement and less withdrawal symptoms (76).

Studies have concluded that kappa opioid receptors have anti-reward effects in opposition to mu receptors. They are involved in the relapse of addicts, because during the addiction process these receptors are stimulated, leading to dysphoria in withdrawal and abstinence phases, and finally to relapse (77,78).

In order to stave off withdrawal symptoms without consuming more heroin, patients can receive opioid agonist therapy with methadone, buprenorphine or naloxone. Methadone is a full mu opioid receptor, which also has some agonist effects on kappa and delta receptors. Its half-life is longer, causes fewer withdrawal symptoms and helps opioid addicts have a more stable life. Buprenorphine is a partial mu agonist, partial kappa agonist or functional antagonist, delta agonist and is safer than methadone. Naloxone is an opioid receptor antagonist used for acute opioid intoxications (79).

Researchers have attempted to discover genes linked to opioid addiction and a genome-wide association study discovered SNPs from multiple loci-KCNG2*rs62103177 are connected to opioid dependence (80).

Genes associated with heroin addiction have been classified into two systems: The dopaminergic one and the mu opioid receptor one. In the dopaminergic gene system, the following SNPs are listed: rs1800497, rs1079597, rs4680, rs747302, rs936462, rs1800498, rs1800955, while in the mu opioid receptor gene system, rs7997012, rs1799971 and rs540825 are included (81).

Benzodiazepines (BZDs) are the most representative class for this category of drugs. BZDs have been increasingly prescribed by doctors in the last few years, thus BZD abuse and dependence have become a serious medical issue (82).

The calming or sedating effect of BZDs occurs after binding to a specific site on the GABA type A receptors (ligand-gated ion channels), the excitatory neurons are inhibited, the VTA glutaminergic drive is reduced, as well as the nucleus accumbens' dopamine release. The GABA-ergic neurotransmission is modulated by chronic exposure to BZDs, which leads to tolerance, dependence and withdrawal. KB220 is a pro-dopamine regulator, that can be used to produce dopamine homeostasis and combat benzodiazepine use disorder, but future research is needed in this field (83,84).

There have been attempts to discover genetic factors that play a role in BZD addiction. Researchers have investigated the genetic polymorphisms of MAOA (the gene metabolizing catecholamine) and GABA A subunit alpha 2, because of their potential link with anxiety and addiction. The results have been unsatisfactory, as none of the investigated polymorphisms did determine addiction. However, studies revealed some genetic predispositions to personality features. For example, genotype 3/3 MAOA is associated with lack of anxiety and higher extraversion, while genotype 4/4 MAOA was found in individuals with higher levels of introversion and anxiety (85). Given these data, the genetic implication in BZD dependence remains a subject for further exploration.

Cocaine hydrochloride is used especially intranasally, but it can also be administered subcutaneous and intravenous or by smoking crack cocaine. The path of administration is related to the severity of the dependence; therefore higher levels of addiction have been described in injection users, followed by smokers, and lower levels with intranasal users (86). Its effects include euphoria, increased sexual appetite, enhancement of intellectual and physical activity, higher self-esteem and easier social networking, which makes cocaine an attractive substance. It has been linked with high economic status and male to female ratio (87). Like in the case of other substances that cause dependence, environmental risk factors are important in cocaine addiction. Some of those factors include childhood abuse, peer drug use, drug availability, household drug use and poor social activities (86). Interestingly, parental monitoring is not important for cocaine use (88).

Regarding genetics, research indicates that there is little specific genetic variance for cocaine addiction. One genome-wide association study on cocaine addiction identified an SNP which maps to an intron of the FAM53B gene. This gene is believed to be linked with axonal extension during development and cell proliferation (89).

Some research suggests a hereditary factor in cocaine addiction. Several studies regarding the effects of paternal cocaine use on offspring behavior conclude that individuals from the next generation were more likely to consume drugs of abuse (90).

The medical community is awaiting the discovery of an effective treatment for cocaine addiction, such as a cocaine vaccine (91), cocaine hydrolase, or even deep brain stimulation of the nucleus accumbens (92).

Although METH is a highly addictive drug, its addiction mechanisms are less studied.

Available data suggest that METH exposure activates neuroinflammatory and neuroplastic processes in the brain, which may lead to parkinsonism (secondary to DA neuron damage), cognitive deficits, depression and promote addiction (93).

Researchers have found important decreases in DA levels, density of dopamine transporters, tyrosine hydroxylase levels in both the striatum and the cortex of METH addicts (94).

More so, imaging studies have shown a reactive astrogliosis inside the brain of METH abusers. The microgliosis has been shown to precede changes in striatal dopamine neurons, thus suggesting that microglial activation is implicated in the development of neurodegeneration (94). Microgliosis was found to persist two years after the beginning of abstinence and has been linked to long-term neurological damage of METH (95).

Studies have aimed to ascertain whether METH addiction can be caused by epigenetically induced alterations in gene expression known to play a role in cognitive functions and synaptic plasticity. It has been found that this drug upregulates several genes that are involved in cell-to-cell signaling and in cAMP response element-binding protein (CREB), such as GIRK2, HCRTR1, GABBR2, and KCNJ6. Activation of GIRK and GABBR2 mediate DA neuronal excitability (96).

Based on the ICD-11 criteria for gambling disorder (4), gambling disorder is characterized by a pattern of persistent or recurrent gambling behavior, which may be online (i.e., over the internet) or offline, manifested by: i) impaired control over gambling (e.g., onset, frequency, intensity, duration, termination, context); ii) increasing priority given to gambling to the extent that gambling takes precedence over other life interests and daily activities; and iii) continuation or escalation of gambling despite the occurrence of negative consequences.

The behavior pattern is of sufficient severity to result in significant impairment in personal, family, social, educational, occupational or other important areas of functioning. The pattern of gambling behavior may be continuous or episodic and recurrent. The gambling behavior and other features are normally evident over a period of at least 12 months in order for a diagnosis to be assigned, although the required duration may be shortened if all diagnostic requirements are met and symptoms are severe.

The severity of gambling can be predicted with two main personality traits found in gamblers: Harm avoidance and self-directedness. Additionally, the inability to regulate negative emotions has also been associated with a risk of non-strategic gambling (100). Approximately 96% of gambling addicts have overlapped criteria with at least one other psychiatric diagnosis, and 49% have been treated for another mental illness (101). The study of neuroimaging in gamblers shows structural and functional modifications in the reward circuits (102).

Gambling disorder presents 50-60% heritability rates (103). Furthermore, genetic findings were described in gambling disorder such as the associations of the C/C genotype of the serotonin receptor 2A T102C (rs 6313) polymorphism and the PG phenotype (103).

A nuclear medicine tomographic imaging technique (SPECT) found an interesting parallel between psychostimulant drugs such as amphetamines and a motorbike-riding computer game regarding the ventral striatum's dopamine release (104). It is known that video game addiction in adolescence is a disguised form of academic burnout syndrome. Behind the phenomenon there may be disorders of the hormonal balance, of the hypothalamic-pituitary-adrenal axis, connected with disturbances of dopamine levels (105). Moreover, greater activation of orbitofrontal, anterior cingulate, dorsolateral prefrontal and nucleus accumbens was found when World of Warcraft fans who played more than 30 h per week were exposed to game cues, in comparison to those playing less (106).

Genetic research has pointed out the importance of the CRHR1 gene in gaming addiction (107).