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Psychoactive substances are those which, when administered into one’s system, affect the mental processes. They are ‘mind alerting’ since they alter the perceptions and behaviours of the individual using them. This group of substances comprises both legal and illegal drugs that are categorised into stimulants, narcotics, cannabis, hallucinogens, inhalants and club drugs. Because a majority of these substances are useful as medicine or entertainment agents, they have been extensively studied and their mechanisms of action in the human body as well as in the bodies of model organisms such as rats elucidated. The drugs affect numerous signaling cascades, growth factors and physiological processes, but mainly through the dopamine system. They cause addiction through induced neuroadaptations in the dopamine reward system which elicits all the symptoms observed in the users.
Psychoactive Drugs, the Central nervous System and Addiction
Stimulants include nicotine, cocaine and amphetamines and are used basically to allay tiredness and increase alertness. Depressant (sedative-hypnotic) drugs depress or slow the functioning of the central nervous system (CNS) e.g. alcohol. The narcotics consist of opium, morphine, heroin and codeine. They dull the senses, encourage sleep and become addictive with long time use. Club drugs (Ecstasy, GHB, and ketamine) possess the effects of both hallucinogens and stimulants. Cannabis, a tropical and subtropical plant is the main source of marijuana and hashish. O’Brien (2006) noted that the active agent in cannabis, “∆-9-tetrahydrocannabinol accounts for most unique pharmacological effects of the smoked drug – changes in mood, perception, motivation and the ‘mellowing out’” (p. 1345) Hallucinogens are drugs of natural or man-made origin. They alter the sensitivity of reality and shape the thought processes. The members of this group are lysergic acid dimethylamide (LSD), phenycyclidine (PCP), and organic drugs –mescaline and psilocybin. Lastly, the inhalants are drugs that form sprays or solvents and enter the body via inhalation into the lungs from where they access the bloodstream. They elicit feelings of euphoria, excitation and light-headedness.
Drug addiction is a factor that continues to exact huge human and fiscal costs to the society. That is because the available treatments are yet to be effective for most people. Drug addiction is “a psychiatric disorder that presents as a compulsive drug seeking and taking despite harmful consequences, resulting in health and socioeconomic impacts worldwide” (Neasta et al., 2014, p. 172). Because progress in treating other medical abnormalities has resulted directly from the research on the molecular and cellular pathophysiology of the disease process, better grasp of the basic neurobiology of addiction is expected to translate into more efficacious treatments. The psychoactive drugs have a variety of effects on the circuits in the brain that mediate addiction. Some act as agonists, indirect agonists, partial agonists or antagonists of the receptors of various neurotransmitters. For example, cocaine and amphetamine are agonists at the dopamine receptors that act by promoting the release of dopamine and engage the Gi and Gs signaling mechanisms (Clapp, Sanjiv, and Hoffman, 2008). Other abused drugs act on other receptors eliciting different responses in the neurons and also employ other signaling pathways. This diversity of effects accounts for the various mental signs presented by drug addicts.
Many psychoactive drugs act on the CNS’ reward system. The dopaminergic neurons, according to Longstaff (2005), arise from “the Ventral tegmental area (VTA) to join the nucleus accumbens (NAc) to form the mesolimbic system and to the frontal cortex forming the mesocortical system” (p. 292). The mesolimbic system and its forebrain targets constitute the brain’s motivational system that regulates responses to natural rewards like food, sex, drink, and social interaction. It is also involved in “memory, acute reinforcing effects of drugs, and conditioned responses connected to craving” (Seger, 2010, p. 696). The mesocortical pathway is involved in the conscious experience of drugs, drug expectation and craving.
Longstaff (2005) notes that VTA neurons transmit impulse in reaction to “a natural reward and the dopamine release facilitates learned associations with the reward” (p. 293). The learning process takes place via the nucleus accumbens and the affective ganglia circuit. The NAc is the main focus of the mesolimbic system. It has the GABAergic medium spiny neurons (MSNs) that are roused by the periodical release of dopamine from the presynaptic ends of the VTA cells. The activity of the MSNs inhibits the GABAergic ventral pallidum cells, hence activating the affective basal ganglia circuit (Capasso and De Feo, 2002).
The CNS synapse is where neurons communicate with one another by means of chemical neurotransmitters. These are synthesised in the neuron, moved into vesicles and released into the synaptic cleft. The amount of neurotransmitter secreted is determined by the “synaptic and vesicular concentration of the neurotransmitter and the level of stimulation of the autoreceptor on the presynaptic nerve cell membrane” (Mereu et al., 2013, p. 414). The neurotransmitter diffuses through the synaptic cleft and associates with its specific receptor on the postsynaptic nerve cell membrane.
Neurotransmitters are terminated by their reabsorption into the presynaptic nerve via a plasma membrane reuptake transporter. The abused drugs produce addiction by acting on and activating the mesolimbic dopamine system, which involves increased dopaminergic transmission from the VTA of the midbrain to the NAc (ventral striatum) and other regions of the forebrain. Cocaine and metamfetamine, for example, increase the CNS synaptic dopamine by inducing its secretion into the synapse and binding to the dopamine reuptake transporter, which inhibits reuptake of dopamine back into the nerve cell. Narcotics produce their effects by mimicking β-endorphin, and enkephalins.
The drugs excite transmembrane G coupled receptors, the µ-subunit being closely linked to the dopamine system. Cannabinoids and phenycyclidine act on NAc via other mechanisms. The net effect of all these reactions is the general inhibition of the medium spiny neurons MSNs) of the NAc, because of the localization of the opioid, cannabinoid and certain dopamine receptors, all of which are Gi-coupled on to the same NAc neurons. There is evidence to suggest that the various mechanisms play a fundamental role in mediating the acute rewarding properties shared by the all the drugs of abuse (Nestler and Chao, 2006). Other neurotransmitters that have been shown to associate with the limbic system include glutamate and the corticotropin-releasing factor (CRF).
Constant stimulation triggers cells to make physiological adjustments or anatomical changes in order to maintain homeostasis. Compensatory modifications in the CNS that are caused by drugs of abuse constitute the neuroadaptations and they oppose the reinforcing effects of the drug (Xiao et al., 2016, p. 3). If the drug use stops, these changes may reverse after some time. However, continued drug use restructures neural circuits and synapses, making these adaptive changes become permanent. Each neuron is terminally programmed to react to a certain level of input from each neurotransmitter. If a neuron receives too many impulses from the continued presence of synaptic neurotransmitter – induced by drugs of abuse- the neuron responds by decreasing the number of receptors for this neurotransmitter (down regulation).
Receptor up-regulation occurs in the event of diminishing stimuli from the neurotransmitter. Up or down regulation of receptors affects receptor sensitivity to the drug. It is achieved by the “trafficking and internalization of the receptors, resulting in receptor desensitization, hence contributing to receptor tolerance” (Thomas, Kalivas, and Shaham, 2008, p. 388). Other receptor neuroadaptations entail variations in the receptor function or post-receptor mechanisms that oppose the effect of the drug. An example of this mechanism is the drug-induced adaptations or alterations in G proteins, or proteins that regulate G proteins (regulators of G protein signaling proteins). At the gene expression levels, neurons may respond to continuous impulse by up or down regulating some pathways by control of the protein synthesis through modulation of transcription factors. For instance, evidence shows that upregulation of the cAMP pathway and cAMP response element binding protein (CREB) in the NAc as a result of chronic administration reduces the rewarding effects of drugs of abuse and thereby serves as a mechanism of tolerance (Parrot, 2015).
Generally, drugs of abuse cause dysfunction of CNS intracytoplasmic and plasma membrane transporters that move neurotransmitters in and out of intracellular vesicles, neurons, and synapses. An abnormal concentration of synaptic neurotransmitters is one outcome and neuroadaptations occur to maintain the balance. The length of time or the quantity of drug required to elicit these changes is unknown. The neuroadaptations help to account for the subsequent responses to acute and chronic drug use and addiction.
Addiction is a complex disease whose susceptibility is incumbent upon multiple genes and environmental factors. Because of involved of genes, addiction can be passed from parents to children. Probabilities for inheritance of addictive disorders range from 0.39 for hallucinogens to 0.72% for cocaine (Seger, 2010). Many genes suspected of involvement in addiction were identified by the aid of model organisms (mice, drosophila) because of similarities in the reward pathway and participatory molecules between these animals and people.
Dopaminergic gene polymorphism is singled out among other neurotransmitter genes involved in the brain reward cascade and its interaction with the environmental elements influence limbic reward activation of the abused drug response (Neasta et al., 2014). An association between DRD2 A1 allele and severe drug addiction, especially alcoholism has also been reported. Other genes that have been linked with differential use and metabolism of abused drugs include Mpdz gene, Cannabinoid receptor gene (Cnr1), serotonin receptor gene (Htr1), neuropeptide Y gene, per 2 gene, Cyp 2A6 gene, ALDH*2 gene and the CREB gene. These genes were pinpointed by genome-wide analysis (whole genome linkage, whole-genome association and mRNA expression analyses) that allows mapping of the disease-causing loci within the genome.
Offermanns and Rosenthal (2008) define abstinence (withdrawal) syndrome as “the withdrawal signs that occur after self or forced restraint from a drug to which one is addicted” (p. 1234). Its occurrence is an evidence of physical dependence. Neonatal abstinence syndrome (NAS) occurs in newborn babies born to mothers who abuse drugs during pregnancy. Since fetal and maternal circulations are connected via the placenta, the infant becomes addicted to drugs used by the mother. At birth, the supply of these drugs is terminated and the child begins to suffer from withdrawal symptoms. Withdrawal symptoms originate from (1) exclusion of the substance of dependence and (2) CNS hyperactivation due to readaptation to the absence of the drug of dependence (Maccarrone et al., 2014).
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The abstinence symptoms are unique for a given group of drugs and are usually opposite to the initial effects produced by the drug before tolerance developed. For example, abrupt withdrawal of a drug that produces miotic (constricted) pupils and reduced heart rate will produce withdrawal syndromes including dilated pupils and tachycardia. In adults, emotional withdrawal symptoms include anxiety, restlessness, irritability, insomnia, headaches, poor concentration, depression and social isolation. Physical withdrawal symptoms comprise sweating, racing heart, palpitations, muscle tension, tightness in the chest, difficulty in breathing, tremor, nausea, vomiting and diarrhea.
Medical approaches to treating the abstinence syndrome are drug specific and several. Management of heroin (an opioid) abstinence syndrome is used as an example. Opioids are used mainly for treatment of pain but mostly abused because of the state of euphoria the user experiences. Characteristics of opioid withdrawal include “craving for opioids whose sign is pupillary dilation, restlessness, increased sensitivity to pain, tachycardia, muscle aches, dysphoric mood, insomnia and anxiety” (Blum et al., 2012, p. 39). The first stage of treatment consists of detoxification in which withdrawal is treated with a long-acting opioid agonist, such as methadone 20-30mg/d or buprenorphine 4-16mg/d, spread over days to weeks. Clonidine 0.1 – 0.2 mg two to three times a day also decreases the severity of symptoms. Long acting benzodiazepines may be included to regulate insomnia and muscle cramps. Methadone is also recommended for the long term management of the protracted withdrawal syndrome, which occurs in patients who revert to heroin abuse immediately after treatment and discharge from hospital (Betz et al., 2000).
Abused drugs employ several mechanisms to elicit addiction, but all these mechanisms have common actions, prominent of which is the effect on mesolimbic system. The mechanisms result in increased release of neurotransmitters into the synapse and blockage of reuptake transporter proteins. The result is the prolonged potentiation of the effects of these neurotransmitters in the CNS. The body reacts to this by launching neuroadaptations intended to restore normalcy. This leads to addiction. In order to rectify this, medical intervention may be necessary.
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