|Addiction and dependence glossary|
|• addiction – a medical condition characterized by compulsive engagement in rewarding stimuli despite adverse consequences|
|• addictive behavior – a behavior that is both rewarding and reinforcing|
|• addictive drug – a drug that is both rewarding and reinforcing|
|• dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)|
|• drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose|
|• drug withdrawal – symptoms that occur upon cessation of repeated drug use|
|• physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)|
|• psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)|
|• 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|
|• sensitization – an amplified response to a stimulus resulting from repeated exposure to it|
|• substance use disorder - a condition in which the use of substances leads to clinically and functionally significant impairment or distress|
|• tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose|
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Drug tolerance is a pharmacological concept describing subjects' reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug's effects, however this may accelerate tolerance, further reducing the drug's effects. Drug tolerance is a contributing factor of drug addiction.[medical citation needed]
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.[medical citation needed]
Tachyphylaxis is a sudden onset drug tolerance which is not dose dependent.
Pharmacodynamic tolerance occurs when the cellular response to a substance is reduced with repeated use. A common cause of pharmacodynamic tolerance is high concentrations of a substance constantly binding with the receptor, desensitizing it through constant interaction. Other possibilities include 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.
While most occurrences of pharmacodynamic tolerance occur after sustained exposure to a drug, instances of acute or instant tolerance can occur.
Pharmacokinetic (metabolic) tolerance
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
Behavioral tolerance occurs with the use of certain psychoactive drugs, where tolerance to a behavioral effect of a drug, such as increased motor activity by methamphetamine, occurs with repeated use; it may occur through drug-independent learning or as a form of pharmacodynamics tolerance in the brain; the latter mechanism of behavioral tolerance occurs when people learn how to actively overcome drug-induced impairments through practice. Behavioral tolerance is often context dependent, meaning tolerance depends on the environment in which the drug is administered, and not the drug itself. Behavioral sensitization describes the opposite phenomenon.
- Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274.
- Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin. Neurosci. 15 (4): 431–443. PMC . PMID 24459410.
DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
- "Glossary of Terms". Mount Sinai School of Medicine. Department of Neuroscience. Retrieved 9 February 2015.
- Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". N. Engl. J. Med. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMID 26816013.
- Drug Tolerance at the US National Library of Medicine Medical Subject Headings (MeSH)
- Bespalov, Anton; Müller, Reinhold; Relo, Ana-Lucia; Hudzik, Thomas (2016-05-01). "Drug Tolerance: A Known Unknown in Translational Neuroscience". Trends in Pharmacological Sciences. 37 (5): 364–378. doi:10.1016/j.tips.2016.01.008. ISSN 1873-3735. PMID 26935643.
- Klaassen, Curtis D. (2001-07-27). Casarett & Doull's Toxicology: The Basic Science of Poisons (6th ed.). McGraw-Hill Professional. p. 17. ISBN 0-07-134721-6.
- Swanson, James; Gupta, Suneel; Guinta, Diane; Flynn, Daniel; Agler, Dave; Lerner, Marc; Williams, Lillie; Shoulson, Ira; Wigal, Sharon (1999-10-01). "Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children*". Clinical Pharmacology & Therapeutics. 66 (3): 295–305. doi:10.1016/S0009-9236(99)70038-X. ISSN 0009-9236. PMID 10511066.
- Wolgin, D. L (2000-05-01). "Contingent tolerance to amphetamine hypophagia: new insights into the role of environmental context in the expression of stereotypy". Neuroscience & Biobehavioral Reviews. 24 (3): 279–294. doi:10.1016/S0149-7634(99)00070-6.