||This article is incomplete. (December 2011)|
|• addiction – a state characterized by compulsive engagement in rewarding stimuli, despite adverse consequences|
|• reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them|
|• rewarding stimuli – stimuli that the brain interprets as intrinsically positive or as something to be approached|
|• addictive drug – a drug that is both rewarding and reinforcing|
|• addictive behavior – a behavior that is both rewarding and reinforcing|
|• sensitization – an amplified response to a stimulus resulting from repeated exposure to it|
|• drug tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose|
|• drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose|
|• drug dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated drug intake|
|• physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue, delirium tremens, and/or persistent insomnia depending on substance)|
|• psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)|
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Physiological tolerance or drug tolerance is commonly encountered in pharmacology, when a subject's reaction to a specific drug and concentration of the drug is progressively reduced, requiring an increase in concentration to achieve the desired effect. Drug tolerance can involve both psychological drug tolerance and physiological factors. The following are characteristics of drug tolerance: it is reversible, the rate depends on the particular drug, dosage and frequency of use, differential development occurs for different effects of the same drug. Physiological tolerance also occurs when an organism builds up a resistance to the effects of a substance after repeated exposure. This can occur with environmental substances, such as salt or pesticides. A rapid drug tolerance is termed tachyphylaxis.
Tachyphylaxis is a sudden onset drug tolerance which is not dose dependent.
The response to a given dose of a drug can vary dramatically across individuals, a phenomenon called tolerance. There are several types of tolerance listed below.
Tolerance due to genetic factors. Some people may be born with more drug-metabolizing enzymes in the liver, or have more of a certain type of receptor in the brain, compared to other people. Previous drug exposure is not required for this type of tolerance.
For example men generally have greater dispositional tolerance to alcohol than women do, because men are born with higher levels of alcohol-metabolizing enzymes in their liver than women.
Tolerance due to learning. A widely accepted mechanism of behavioral tolerance is when people learn how to actively overcome drug-induced impairments through practice. This type of tolerance can only develop when there is active practice of a particular skill when under the influence of the drug. An example of displayed behavioral tolerance can be seen in driving simulator studies that reveal experienced marijuana smokers usually perform better than novice smokers at the same level of intoxication.
Pharmacokinetics refers to the absorption, distribution, metabolism, and excretion of drugs. All psychoactive drugs are first absorbed into the bloodstream, carried in the blood to various parts of the body including the site of action (distribution), broken down in some fashion (metabolism), and ultimately removed from the body (excretion). All of these factors are very important determinants of crucial pharmacological properties of a drug, including its potency, side effects, and duration of action.
Pharmacokinetic tolerance (dispositional tolerance) occurs because of a decreased quantity of the substance reaching the site it affects. This may be caused by an increase in induction of the enzymes required for degradation of the drug e.g. CYP450 enzymes. This is most commonly seen with substances such as ethanol.
This type of tolerance is most evident with oral ingestion, because other routes of drug administration bypass first-pass metabolism. Enzyme induction is partly responsible for the phenomenon of tolerance, in which repeated use of a drug leads to a reduction of the drug’s effect. However, it is only one of several mechanisms of tolerance
Tolerance is a reduced response to repeated administration of the same dose or increase in the dose are required to produce the same magnitude of response. Liver damage can lead to dramatic loss of drug tolerance. For example chronic alcoholics at a late stage of alcoholism can get drunk on just a few drinks due to death of liver cells
Pharmacodynamic tolerance (reduced responsiveness) is when the response to the substance is decreased by cellular mechanisms. This may be caused by a reduced receptor response to receptor agonists (receptor desensitization), a reduction in receptor density (usually associated with receptor agonists), or other mechanisms leading to changes in action potential firing rate. Pharmacodynamic tolerance to a receptor antagonist involves the reverse, i.e., increased receptor firing rate, an increase in receptor density, or other mechanisms.
Tolerance is mediated by neural changes at the synaptic level that are induced by frequent drug use. These may include changes in number of postsynaptic receptors, receptor desensitization, or depletion of neurotransmitters. For example chronic ingestion of alcohol (a GABA agonist) eventually leads to down-regulation of inhibitory GABA receptors, as postsynaptic cells compensate for too much GABA-receptor-mediated inhibition. This process is called neural adaptation and it is also the basis of the withdrawal symptoms that can occur in chronic alcoholics and heroin addicts.
One example of pharmacodynamic tolerance occurs with cocaine. Heavy use of cocaine temporarily depletes axon terminals of neurotransmitters such as dopamine and serotonin, thus cocaine has much less of a mood-elevating effect after several successive doses than it did initially.
Morphine as an example
Tolerance to the analgesic effects of morphine is fairly rapid. There are several hypotheses about how tolerance develops, including opioid receptor phosphorylation (which would change the receptor conformation), functional decoupling of receptors from G-proteins (leading to receptor desensitization), mu-opioid receptor internalization and/or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of the cAMP pathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt.) CCK might mediate some counter-regulatory pathways responsible for opioid tolerance. CCK-antagonist drugs, specifically proglumide, have been shown to slow the development of tolerance to morphine or any other kind of drug, including alcohol.
Significant involvement of the intracellular beta-arrestin-2 protein expression in the agonist-mediated desensitization of G protein-coupled receptors, such as the μ-opioid receptor (MOR), has been elucidated.
It was reported that VTA dopamine neurons in rats remain increased for at least 3 days after a single morphine exposure. Within this limited window of time, the VTA dopamine neurons failed to respond to additional morphine challenge. Indicating a transient morphine tolerance in VTA DA neuron activity in rats was developed with a single dose of morphine treatment. It further demonstrated that this acute morphine tolerance was associated with impairment of opiate receptor-G protein coupling, indicating that down regulation of G-protein activation may contribute to acute morphine tolerance.
- Rebound effect
- Drug intolerance
- Physical dependence
- Reverse tolerance
- Drug resistance
- Multidrug resistance
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- Drug Tolerance at the US National Library of Medicine Medical Subject Headings (MeSH)
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