Three factors are generally involved in drug dependence: tolerance, physical dependence and psychological dependence.
Tolerance often occurs, whereby an increasing amount of the drug must be administered to obtain the required pharmacological effect; tolerance may occur as a result of the drug being more rapidly metabolized, so-called metabolic tolerance, or through a drug-induced insensitivity of the receptors or target sites upon which it acts within the brain, termed tissue tolerance. Thus tolerance should be considered a general phenomenon that is not restricted to drugs of abuse. For example, tolerance is known to develop to anticholinergic agents.
Regarding drugs of abuse, tissue tolerance commonly occurs to the opioids, ethanol, and the sedatives of the benzodiazepine type. Tolerance does not develop to all drugs of abuse, however. Thus cocaine and the amphetamines maintain their stimulant and euphoriant effects for a prolonged period of administration without any need to increase the dose appreciably.
Psychological tolerance is the term used to describe the reduction in the desired psychological effects of the drug; this may not be paralleled by an increase in the metabolic tolerance.
This term is used to describe the phenomenon in which abnormal behavioural and autonomic symptoms occur when the drug is abruptly withdrawn or its effects are terminated by the administration of a specific antagonist. Most drugs of abuse (e.g. the opioids, sedatives, alcohol) produce some physical dependence, although withdrawal symptoms are relatively mild following the abrupt withdrawal of cannabis, the stimulants, and cocaine.
The nature of the withdrawal symptoms depends upon the neurotrans-mitter systems which are the target of the drug. Thus cocaine and the amphetamines alleviate fatigue, cause anorexia and elevate mood; withdrawal therefore results in feelings of fatigue, hyperphagia and depression. Abrupt withdrawal from the sedatives, such as barbiturates or following high doses of benzodiazepines, can be associated with anxiety, insomnia and spontaneous seizures.
It must be emphasized that the relationship between tolerance, physical dependence and compulsive drug use is complex and depends both on the category of drug and the personality of the abuser. For example, it appears that the majority of patients prescribed benzodiazepines for periods of many months experience relatively minor withdrawal symptoms when the drugs are abruptly stopped. Others, however, experience severe anxiety states and have extreme difficulty in stopping the drug.
Psychological dependence occurs with most drugs of abuse. Such drugs produce an immediate pleasurable effect and, following their continuous administration, the individual experiences dysphoria and intense craving should the drug be abruptly stopped. Many drugs of abuse cause both physical and psychological dependence.
Cross-dependence arises when a drug can suppress the symptoms of withdrawal due to another drug. For example, the effects of alcohol withdrawal can be suppressed by the administration of a benzodiazepine. As both drugs enhance gamma-aminobutyric acid-ergic (GABAergic) transmission, albeit by different mechanisms, a benzodiazepine can prevent the withdrawal symptoms that arise following the abrupt cessation of alcohol. However, cross-tolerance and cross-dependence can only occur between drugs with a similar mechanism of action at the cellular level. For example, benzodiazepines cannot directly suppress the effects of morphine withdrawal.
The occurrence of the withdrawal syndrome following the abrupt termination of administration of the drug is the only objective evidence of physical dependence. The symptoms of withdrawal have at least two origins: (a) the abrupt removal of the drug of dependence and (b) the hyperarousal of the brain due to re-adaptation following the absence of the drug. The pharmacokinetic properties of the drug are of major importance in determining the amplitude and duration of the withdrawal syndrome. The symptoms of drug withdrawal are characteristic for the specific category of the drug and are usually the opposite of those produced when the drug is first administered. For example, an opioid agonist such as morphine produces constricted pupils and bradycardia but on abrupt withdrawal dilated pupils and tachycardia occur.
Tolerance, physical dependence and withdrawal are a natural consequence of the properties of drugs of dependence. They can be produced in experimental animals as readily as they can in man but the symptoms do not always imply that the individual is dependent on a drug of abuse. For example, a patient with hypertension who is receiving a beta-adrenoceptor antagonist such as propranolol will probably exhibit a withdrawal syndrome consisting of a rebound hypertension when the drug is abruptly withdrawn.
Are there some basic neuronal mechanisms which are affected by all drugs of abuse?
In recent years, many of the molecular targets for drugs of abuse have been identified and cloned. In addition, it has been possible to integrate this information into a system that extends from the neuron to the behavioural consequences that follow prolonged drug abuse.
Some years ago, converging evidence suggested that all drugs of abuse affected the dopaminergic system in the brain. It was suggested that although the different classes of drugs of abuse (e.g. stimulants, depressants, hallucinogens, opiates, cannabinoids) influence many different neurotransmitter systems within the brain, all drugs of abuse appear to directly or indirectly enhance dopaminergic function in the limbic system. For example, it is known that opiates act as agonists at opioid receptors but that these receptors also increase the activity of the mesolimbic dopaminergic system. This pathway projects to the prefrontal cortex and also to the striatum. The nucleus accumbens, located near the striatum, is of primary importance in mediating the rewarding effects of stimulants such as cocaine and the amphetamines; this is associated with an increase in the concentration of dopamine in this region of the brain. The relevance of such changes is suggested by results of experimental studies in which rats self-administer amphetamine to the nucleus accumbens and increase the amount of drug administered when the dopamine receptors are partially blocked by a neuroleptic. Such positive reinforcement is evidence that dopamine is the neurotransmitter involved in the behaviour of reward and is supported by the observation that lesions of the dopaminergic system completely block the self-administration of amphetamine. Other experimental studies have shown that other types of abused drugs, such as nicotine, the opiates and alcohol, also induce positive behavioural reinforcement by enhancing dopamine release in the mesolimbic pathway while abrupt withdrawal of such drugs leads to a dramatic reduction in the concentration of dopamine in the nucleus accumbens. Thus it appears that the reinforcing effects of drugs of abuse partly depend on the functioning mesolimbic dopaminergic system which normally mediates the motivational properties of food and sex.
Other aspects of the dopaminergic system have also been implicated in drug dependence. For example, different allelic forms of the dopamine D2 receptor gene have been implicated in predisposing some individuals to drug abuse. In addition, the dopamine transporter is undoubtedly involved in the stimulant action of cocaine and the amphetamines. The importance of the dopaminergic system is further suggested by the use of ''knock-out'' mice which lack the D2 receptor. These mice show a reduction in the amount of cocaine which they self-administer. Interestingly, in brain imaging studies, it has been shown that the subjective responses to cocaine do not correlate with its action on the dopamine transporter. Thus the simplistic view that enhanced mesolimbic dopaminergic function explains all aspects of drug dependence must be treated with caution.
Of the other transmitters believed to be involved in drug abuse, serotonin has achieved some prominence. There is physiological evidence to suggest that serotonergic and dopaminergic systems are mutually inhibitory. Cocaine, like the SSRI antidepressants such as fluoxetine and citalopram, blocks the serotonin transporter. Again, it seems improbable that the serotonergic system provides the common neurochemical pathway. Thus mice lacking the 5-HT1B receptor self-administer cocaine more readily than normal mice but paradoxically 5-HT1B receptor agonists have the same effect.
Other approaches that have been used to find a common pathway which accounts for all drugs of abuse include the effects of such drugs on gene expression. Experimental intercellular second messenger systems increase the activity of adenylate cyclase and cyclic AMP dependent kinase, factors which increase gene transcriptase. Thus the cyclic AMP response element binding protein (CREB) increases the expression of the immediate early genes c-fos and c-jun. Chronic morphine administration reduces CREB while fos-like proteins are induced by stimulants, morphine and nicotine. It has been speculated that the genetic composition could affect neurodevelopment which then leads to adaptive changes to the presence of the drugs, thereby leading to an increase in the reinforcing properties of the drugs of abuse.
Attempts to develop novel drugs to treat dependence usually focus on the reward region of the brain, namely the dopamine-rich median forebrain bundle. However, it is now apparent that at least in the rat the reward region functions independently of the area concerned with craving. Experimentally it has been shown that when rats become dependent on cocaine and are then withdrawn from the drug, they will increase their electrical self-stimulation of the median forebrain bundle to a greater extent than they do when cocaine is administered. By contrast, stimulation of the ventral subiculum, a glutamate-rich region of the hippocampus, has been shown to produce behaviour associated with craving for cocaine. Thus while it would appear that stimulation of either the median forebrain bundle or ventral subiculum leads to dopamine release, it is only when the stimulus originates in the hippocampus that the stimulus triggers the memory that is integral to craving. It therefore appears that drug dependence entails two separate processes, one that involves neuroadap-tive changes that are a direct result of the drug and another that involves the establishment of memory traces that are located in the hippocampus.
It is well known that, despite the widespread availability of drugs of dependence, particularly alcohol and nicotine, the majority of individuals do not become drug abusers. The neurophysiological explanation is that inhibitory mechanisms within the brain normally hold potentially maladaptive behaviour in check. Such a mechanism is usually attributed to the neural networks involving the prefrontal cortex and striatum. In fact, some of the behavioural and cognitive characteristics of drug abuse, such as impulsivity, risk-taking and poor-decision making abilities, resemble those changes which follow damage to the ventromedial prefrontal cortex. For example, in decision-making tasks, chronic amphetamine abusers perform similarly to patients with damage to the prefrontal cortex. However, opiate abusers show only part of this deficit. These differences appear to be related to the fact that chronically administered amphetamine causes a reduction in the serotonin content of the orbitofrontal cortex; similar changes have been reported to occur in those abusing methenedioxymethamphetamine (MDMA, ''ecstasy'').
These general comments on the cellular basis of drug abuse and dependence, while emphasizing the common features that may be ascribed to all drugs of abuse, also indicate that there are differences which may be of primary importance in predisposing the individual to prolonged drug abuse.
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