For other uses, see Drug (disambiguation).
A drug is any substance (other than food that provides nutritional support) that, when inhaled, injected, smoked, consumed, absorbed via a patch on the skin, or dissolved under the tongue causes a temporary physiological (and often psychological) change in the body.
In pharmacology, a pharmaceutical drug, also called a medication or medicine, is a chemical substance used to treat, cure, prevent, or diagnose a disease or to promote well-being. Traditionally drugs were obtained through extraction from medicinal plants, but more recently also by organic synthesis. Pharmaceutical drugs may be used for a limited duration, or on a regular basis for chronic disorders.
Pharmaceutical drugs are often classified into drug classes—groups of related drugs that have similar chemical structures, the same mechanism of action (binding to the same biological target), a related mode of action, and that are used to treat the same disease.[verification needed] The Anatomical Therapeutic Chemical Classification System (ATC), the most widely used drug classification system, assigns drugs a unique ATC code, which is an alphanumeric code that assigns it to specific drug classes within the ATC system. Another major classification system is the Biopharmaceutics Classification System. This classifies drugs according to their solubility and permeability or absorption properties.
Psychoactive drugs are chemical substances that affect the function of the central nervous system, altering perception, mood or consciousness. They include alcohol, a depressant (and a stimulant in small quantities), and the stimulantsnicotine and caffeine. These three are the most widely consumed psychoactive drugs worldwide and are also considered recreational drugs since they are used for pleasure rather than medicinal purposes. Other recreational drugs include hallucinogens, opiates and amphetamines and some of these are also used in spiritual or religious settings. Some drugs can cause addiction and all drugs can have side effects. Excessive use of stimulants can promote stimulant psychosis. Many recreational drugs are illicit and international treaties such as the Single Convention on Narcotic Drugs exist for the purpose of their prohibition.
In English, the noun "drug" is thought to originate from Old French "drogue", possibly deriving later into "droge-vate" from Middle Dutch meaning "dry barrels", referring to medicinal plants preserved in them. The transitive verb "to drug" (meaning intentionally administer a substance to someone, often without their knowledge) arose later and invokes the psychoactive rather than medicinal properties of a substance.
Main articles: Pharmaceutical drug and Drug class
A medication or medicine is a drug taken to cure or ameliorate any symptoms of an illness or medical condition. The use may also be as preventive medicine that has future benefits but does not treat any existing or pre-existing diseases or symptoms. Dispensing of medication is often regulated by governments into three categories—over-the-counter medications, which are available in pharmacies and supermarkets without special restrictions; behind-the-counter medicines, which are dispensed by a pharmacist without needing a doctor's prescription, and prescription only medicines, which must be prescribed by a licensed medical professional, usually a physician.
In the United Kingdom, behind-the-counter medicines are called pharmacy medicines which can only be sold in registered pharmacies, by or under the supervision of a pharmacist. These medications are designated by the letter P on the label. The range of medicines available without a prescription varies from country to country. Medications are typically produced by pharmaceutical companies and are often patented to give the developer exclusive rights to produce them. Those that are not patented (or with expired patents) are called generic drugs since they can be produced by other companies without restrictions or licenses from the patent holder.
Pharmaceutical drugs are usually categorised into drug classes. A group of drugs will share a similar chemical structure, or have the same mechanism of action, the same related mode of action or target the same illness or related illnesses. The Anatomical Therapeutic Chemical Classification System (ATC), the most widely used drug classification system, assigns drugs a unique ATC code, which is an alphanumeric code that assigns it to specific drug classes within the ATC system. Another major classification system is the Biopharmaceutics Classification System. This groups drugs according to their solubility and permeability or absorption properties.
Spiritual and religious use
Main article: Entheogen
Some religions, particularly ethnic religions are based completely on the use of certain drugs, known as entheogens, which are mostly hallucinogens,—psychedelics, dissociatives, or deliriants. Some drugs used as entheogens include kava which can act as a stimulant, a sedative, a euphoriant and an anesthetic. The roots of the kava plant are used to produce a drink which is consumed throughout the cultures of the Pacific Ocean.
Some shamans from different cultures use entheogens, defined as "generating the divine within" to achieve religious ecstasy. Amazonian shamans use ayahuasca (yagé) a hallucinogenic brew for this purpose. Mazatec shamans have a long and continuous tradition of religious use of Salvia divinorum a psychoactive plant. Its use is to facilitate visionary states of consciousness during spiritual healing sessions.
Silene undulata is regarded by the Xhosa people as a sacred plant and used as an entheogen. Its root is traditionally used to induce vivid (and according to the Xhosa, prophetic) lucid dreams during the initiation process of shamans, classifying it a naturally occurring oneirogen similar to the more well-known dream herb Calea ternifolia.
Peyote a small spineless cactus has been a major source of psychedelic mescaline and has probably been used by Native Americans for at least five thousand years. Most mescaline is now obtained from a few species of columnar cacti in particular from San Pedro and not from the vulnerable peyote.
The entheogenic use of cannabis has also been widely practised  for centuries.Rastafari use marijuana (ganja) as a sacrament in their religious ceremonies.
Psychedelic mushrooms (psilocybin mushrooms), commonly called magic mushrooms or shrooms have also long been used as entheogens.
Smart drugs and designer drugs
Main articles: Nootropic and Designer drug
Nootropics, also commonly referred to as "smart drugs", are drugs that are claimed to improve human cognitive abilities. Nootropics are used to improve memory, concentration, thought, mood, learning, and many other things. Some nootropics are now beginning to be used to treat certain diseases such as attention-deficit hyperactivity disorder, Parkinson's disease, and Alzheimer's disease. They are also commonly used to regain brain function lost during aging.
Other drugs known as designer drugs are produced. An early example of what today would be labelled a 'designer drug' was LSD, which was synthesised from ergot. Other examples include analogs of performance-enhancing drugs such as designer steroids taken to improve physical capabilities and these are sometimes used (legally or not) for this purpose, often by professional athletes. Other designer drugs mimic the effects of psychoactive drugs. Since the late 1990s there has been the identification of many of these synthesised drugs. In Japan and the United Kingdom this has spurred the addition of many designer drugs into a newer class of controlled substances known as a temporary class drug.
Synthetic cannabinoids have been produced for a longer period of time and are used in the designer drug synthetic cannabis.
Recreational drug use
Main article: Recreational drug use
Further information: Prohibition of drugs
Recreational drug use is the use of a drug (legal, controlled, or illegal) with the primary intention of altering the state of consciousness through alteration of the central nervous system in order to create positive emotions and feelings. The hallucinogen LSD is a psychoactive drug commonly used as a recreational drug.
Some national laws prohibit the use of different recreational drugs; and medicinal drugs that have the potential for recreational use are often heavily regulated. However, there are many recreational drugs that are legal in many jurisdictions and widely culturally accepted. Cannabis is the most commonly consumed controlled recreational drug in the world (as of 2012). Its use in many countries is illegal but is legally used in several countries usually with the proviso that it can only be used for personal use. It can be used in the leaf form of marijuana(grass), or in the resin form of hashish. Marijuana is a more mild form of cannabis than hashish.
There may be an age restriction on the consumption and purchase of legal recreational drugs. Some recreational drugs that are legal and accepted in many places include alcohol, tobacco, betel nut, and caffeine products, and in some areas of the world the legal use of drugs such as khat is common.
There are a number of legal intoxicants commonly called legal highs that are used recreationally. The most widely used of these is alcohol.
Administration of drugs
All drugs, can be administered via a number of routes, and many can be administered by more than one.
- Bolus is the administration of a medication, drug or other compound that is given to raise its concentration in blood to an effective level. The administration can be given intravenously, by intramuscular, intrathecal or subcutaneous injection.
- Inhaled, (breathed into the lungs), as an aerosol or dry powder. (This includes smoking a substance)
- Injection as a solution, suspension or emulsion either: intramuscular, intravenous, intraperitoneal, intraosseous.
- Insufflation, or snorted into the nose.
- Orally, as a liquid or solid, that is absorbed through the intestines.
- Rectally as a suppository, that is absorbed by the rectum or colon.
- Sublingually, diffusing into the blood through tissues under the tongue.
- Topically, usually as a cream or ointment. A drug administered in this manner may be given to act locally or systemically.
- Vaginally as a pessary, primarily to treat vaginal infections.
Control of drugs
There are numerous governmental offices in many countries that deal with the control and oversee of drug manufacture and use, and the implementation of various drug laws. The Single Convention on Narcotic Drugs is an international treaty brought about in 1961 to prohibit the use of narcotics save for those used in medical research and treatment. In 1971, a second treaty the Convention on Psychotropic Substances had to be introduced to deal with newer recreational psychoactive and psychedelic drugs.
The legal status of Salvia divinorum varies in many countries and even in states within the United States. Where it is legislated against the degree of prohibition also varies.
The Food and Drug Administration (FDA) in the United States is a federal agency responsible for protecting and promoting public health through the regulation and supervision of food safety, tobacco products, dietary supplements, prescription and over-the-countermedications, vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices, cosmetics, animal foods and veterinary drugs.
- Richard J. Miller (2014). Drugged: the science and culture behind psychotropic drugs. Oxford University Press. ISBN 978-0-19-995797-2.
- DrugBank, a database of 4800 drugs and 2500 protein drug targets
- "Drugs", BBC Radio 4 discussion with Richard Davenport-Hines, Sadie Plant and Mike Jay (In Our Time, May 23, 2002)
|Wikimedia Commons has media related to Drugs.|
- ^Richard Lovett (24 September 2005). "Coffee: The demon drink?". Retrieved 2014-05-01.
- ^ ab"Drug". Dictionary.com Unabridged. v 1.1. Random House. 20 September 2007 – via Dictionary.com.
- ^"Drug Definition". Stedman's Medical Dictionary. Retrieved 2014-05-01 – via Drugs.com.
- ^Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, Linder T, Wawrosch C, Uhrin P, Temml V, Wang L, Schwaiger S, Heiss EH, Rollinger JM, Schuster D, Breuss JM, Bochkov V, Mihovilovic MD, Kopp B, Bauer R, Dirsch VM, Stuppner H (December 2015). "Discovery and resupply of pharmacologically active plant-derived natural products: A review". Biotechnol Adv. 33 (8): 1582–614. doi:10.1016/j.biotechadv.2015.08.001. PMC 4748402. PMID 26281720.
- ^"Drug". The American Heritage Science Dictionary. Houghton Mifflin Company. Retrieved 20 September 2007 – via dictionary.com.
- ^ abMahoney A, Evans J (6 November 2008). "Comparing drug classification systems". AMIA Annual Symposium Proceedings: 1039. PMID 18999016.
- ^ abWorld Health Organization (2003). Introduction to drug utilization research(PDF). Geneva: World Health Organization. p. 33. ISBN 924156234X.
- ^ abBergström, CA; Andersson, SB; Fagerberg, JH; Ragnarsson, G; Lindahl, A (16 June 2014). "Is the full potential of the biopharmaceutics classification system reached?". European Journal of Pharmaceutical Sciences. 57: 224–31. doi:10.1016/j.ejps.2013.09.010. PMID 24075971.
- ^"Archived copy". Archived from the original on 2015-03-28. Retrieved 2015-03-16.
- ^Crocq MA (June 2003). "Alcohol, nicotine, caffeine, and mental disorders". Dialogues Clin Neurosci. 5 (2): 175–185. PMC 3181622. PMID 22033899.
- ^"Recreational Drug". The Free Dictionary. Retrieved 16 March 2015.
- ^Fox, Thomas Peter; Oliver, Govind; Ellis, Sophie Marie (2013). "The Destructive Capacity of Drug Abuse: An Overview Exploring the Harmful Potential of Drug Abuse Both to the Individual and to Society". ISRN Addiction. 2013: 1–6. doi:10.1155/2013/450348. Retrieved 15 April 2015.
- ^Harper, Douglas. "drug". Online Etymology Dictionary.
- ^Tupper KW (2012). "Psychoactive substances and the English language: "Drugs," discourses, and public policy". Contemporary Drug Problems. 39 (3): 461–492. doi:10.1177/009145091203900306.
- ^"About Registration: Medicines and Prescribing". Health and Care Professions Council. Retrieved 22 January 2016.
- ^"Glossary of MHRA terms – P". U.K. Medicines and Healthcare products Regulatory Agency. Retrieved 2008-11-05.
- ^""Generic Drugs", Center for Drug Evaluation and Research, U.S. Food and Drug Administration"(PDF). Fda.gov. Retrieved 11 October 2017.
- ^Entheogen, [dictionary.com], retrieved 2012-03-13
- ^Valdés, Díaz & Paul 1983, p. 287.
- ^Sobiecki, Jean-Francois (July 2012). "Psychoactive Spiritual Medicines and Healing Dynamics in the Initiation Process of Southern Bantu Diviners". Journal of Psychoactive Drugs. 44 (3): 216–223. doi:10.1080/02791072.2012.703101. PMID 23061321.
- ^El-Seedi HR, De Smet PA, Beck O, Possnert G, Bruhn JG (October 2005). "Prehistoric peyote use: alkaloid analysis and radiocarbon dating of archaeological specimens of Lophophora from Texas". J Ethnopharmacol. 101 (1–3): 238–42. doi:10.1016/j.jep.2005.04.022. PMID 15990261.
- ^"A Brief History of the San Pedro Cactus". Mescaline.com. Retrieved 11 October 2017.
- ^Terry M (2013). "Lophophora williamsii". IUCN Red list of threatened species. doi:10.2305/IUCN.UK.2013-1.RLTS.T151962A581420.en.
- ^"Brazilian Archives of Biology and Technology – Jurema-Preta (Mimosa tenuiflora [Willd.] Poir.): a review of its traditional use, phytochemistry and pharmacology". scielo.br. Retrieved 2009-01-14.
- ^Bloomquist, Edward (1971). Marijuana: The Second Trip. California: Glencoe.
- ^"Discovery And Synthesis Of LSD: What You Probably Did Not Know About It - Chemistry Hall". 2017-06-13. Archived from the original on 2017-06-13. Retrieved 2017-06-13.
- ^Teale P, Scarth J, Hudson S (2012). "Impact of the emergence of designer drugs upon sports doping testing". Bioanalysis. 4 (1): 71–88. doi:10.4155/bio.11.291. PMID 22191595.
- ^Lingeman. Drugs from A-Z: A Dictionary. Penguin. ISBN 0-7139-0136-5.
- ^"DrugFacts: Hallucinogens - LSD, Peyote, Psilocybin, and PCP". National Institute on Drug Abuse. December 2014. Retrieved February 17, 2015.
- ^"World Drug Report 2012"(pdf). UNODC. 2012. p. 69. Retrieved 9 December 2016.
- ^Al-Mugahed, Leen (2008). "Khat Chewing in Yemen: Turning over a New Leaf: Khat Chewing Is on the Rise in Yemen, Raising Concerns about the Health and Social Consequences". Bulletin of the World Health Organization. 86 (10): 741–2. doi:10.2471/BLT.08.011008. PMC 2649518. PMID 18949206. Retrieved 22 January 2016.
- ^"The administration of medicines". Nursing Times. EMAP Publishing Limited. 19 November 2007. Retrieved 11 January 2016.
- ^"Animal Food & Feeds". Fda.gov. Retrieved 14 March 2015.
Citation: Lüscher C, Ungless MA (2006) The Mechanistic Classification of Addictive Drugs. PLoS Med 3(11): e437. https://doi.org/10.1371/journal.pmed.0030437
Published: November 14, 2006
Copyright: © 2006 Lüscher and Ungless. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors' salaries are funded by a Royal Society University Research Fellowship and the University of Geneva. In addition, CL is supported by grants from the Swiss National Science Foundation, the United States National Institute on Drug Abuse, the European Community, and the Leenaards Foundation. MU is supported by grants from the United Kingdom Medical Research Council, the Royal Society, and the Gatsby Charitable Foundation. The funders played no role in the submission or preparation of this article.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: CB1R, type 1 cannabinoid receptor; DA, dopamine; DAT, dopamine transporter; GABA, γ -aminobutyric acid; GHB, γ -hydroxy butyrate; GIRK, G protein–coupled inwardly rectifying K+; GPCR, G protein–coupled receptor; MDMA, methylenedioxymetamphetamine; MOR, μ-opioid receptor; NAc, nucleus accumbens; nAChR, nicotinic acetylcholine receptor; NMDA, N-methyl-D-aspartate; PCP, phencyclidine; PFC, prefrontal cortex; SERT, serotonin transporter; THC, delta-9-tetrahydrocannabinol; VTA, ventral tegmental area
The consumption of a variety of natural and synthetic substances can lead to addiction, which is commonly defined by the loss of control and compulsive consumption despite negative consequences. Although addictive drugs have diverse molecular targets in the brain, they share the common initial effect of increasing the concentration of dopamine released from mesocorticolimbic projections.
In this article, we review recent research that has advanced our understanding of the molecular mechanisms underlying this increase of dopamine. Based on this research, we propose a new classification for addictive drugs that we believe may help in directing research towards more effective treatment of addiction (see Table 1 and Figure 1).
Figure 1. The Dominant Targets Involved in Increasing Dopamine for the Major Types of Addictive Drugs
G, Gi/o-coupled receptors; i, ionotropic receptors/ion channels; T, monoamine transporters
Induction of Addiction
The mesocorticolimbic dopamine system originates in the ventral tegmental area (VTA), which projects most notably to the nucleus accumbens (NAc) and the prefrontal cortex (PFC). It is a defining commonality of all addictive drugs that they increase dopamine concentrations in target structures of the mesocorticolimbic projections [1,2]. The release of dopamine from these projections is thought to play a crucial role in the induction of compulsive addictive behaviour. The precise role of dopamine in reinforcement and the modulation of reward-related behaviour remains controversial . Most experts in the field agree that some aspects of reward (e.g., euphoria/ pleasure) are dopamine-independent . In rats, for example, blockade of mesolimbic DA (dopamine) signalling with either systemic or intra-NAc neuroleptic pre-treatment potentiated the sensitivity to nicotine's rewarding properties . Also, dopamine-deficient mice display conditioned place preference for morphine .
Moreover, it is important to realize that, once compulsive use has been established, addiction is thought to be largely dopamine-independent. Nonetheless, it is widely accepted that the induction of addiction crucially involves mesocorticolimbic dopamine.
Taken together, these findings suggest that it may be possible to dissociate the hedonic value of a drug from its addictive properties using modern molecular tools. Such experiments, which may have important clinical ramifications, obviously depend on further mechanistic insight regarding drug action. We believe that our classification, based on the molecular and cellular mechanisms through which addictive drugs increase mesocorticolimbic dopamine, will provide the conceptual framework required to facilitate research to resolve these and related issues.
Some of the Key Papers on the Cellular Effects of Addictive Drugs
Johnson and North, 1992 : A classic paper demonstrating the disinhibitory effect of opioids on dopamine neurons.
Cruz et al., 2004 : A current model explaining how the popular club drug GHB activates VTA neurons via its action on the GABAB receptor.
Maskos et al., 2005 : An elegant study showing that in knockout mice lacking the β2 subunit of the acetylcholine receptor, the rewarding properties of nicotine can be restored by selective re-expression in VTA neurons.
Chen et al., 2006 : A recent paper demonstrating that the rewarding properties of cocaine are absent in mice that express a cocaine-insensitive dopamine transporter.
Ungless et al., 2001 : The first in a series of papers to observe a form of long-term synaptic plasticity of glutamatergic synapses in the VTA in response to addictive drugs. This and other adaptive changes common to several addictive drugs downstream of the dopamine increase are the focus of much current research.
Saal et al., 2003 : In this paper the authors observe a form of long-term synaptic plasticity of glutamatergic synapses in the VTA in response to several addictive drugs. This and other adaptive changes downstream of the dopamine increase are the focus of much current research.
Addictive drugs are a chemically heterogeneous group with very distinct molecular targets. Moreover, an individual drug may have more than one molecular target. Here we will focus on those mechanisms that are directly responsible for the increase in dopamine concentration. We distinguish three groups of addictive drugs: (1) drugs that bind to G protein–coupled receptors (GPCRs)—this group includes the opioids, cannabinoids, and γ -hydroxy butyrate (GHB); (2) drugs that interact with ionotropic receptors or ion channels—this group includes nicotine, alcohol, and benzodiazepines; and (3) drugs that target monoamine transporters—this group comprises cocaine, amphetamine, and methylenedioxymetamphetamine (MDMA, ecstasy) (see Table 1 and Figure 1).
GPCRs that are of the Gi/o family inhibit neurons through post-synaptic hyperpolarisation and pre-synaptic regulation of the transmitter release. In the VTA, the action of these drugs is preferentially on the γ -aminobutyric acid (GABA) neurons that act as local inhibitory interneurons. They also inhibit glutamate release , but in the VTA their dominant mechanism of action is inhibition of GABA neurons leading to a net disinhibition of dopamine neurons and increased dopamine release. Addictive drugs that bind to ionotropic receptors and ion channels can have combined effects on dopamine neurons and GABA neurons, eventually leading to enhanced release of dopamine. Finally, addictive drugs interfering with monoamine transporters block the re-uptake of dopamine, or stimulate non-vesicular release of dopamine, causing an accumulation of extracellular dopamine in target structures. We will now discuss examples for each type of mechanism in detail.
Class I: Drugs That Activate Gi/o-Coupled Receptors
Morphine and other opioids.
These strongly increase the release of mesolimbic dopamine by their action on μ-opioid receptors (MORs), which are expressed on inhibitory GABAergic interneurons of the VTA . MORs have a dual action: they hyperpolarise GABA neurons and decrease GABA release. The post-synaptic hyperpolarisation is mediated by Kir3/ G protein–coupled inwardly rectifying K+ (GIRK) channels coupled to MORs on the soma and the dendrites, in analogy to other parts of the brain , while MORs expressed on the pre-synaptic terminals decrease release by inhibiting Ca2+ channels or activating voltage-gated K+ channels . MORs in the two cellular compartments therefore rely on distinct effectors, which together lead to strong inhibition of GABA neurons and disinhibition of dopamine neurons .
Delta-9-tetrahydrocannabinol (THC) binds to type 1 cannabinoid receptors (CB1Rs) in the brain. In the VTA, these receptors are expressed on GABA neurons and on terminals of glutamatergic synapses on dopamine neurons . Pharmacological application of THC causes a net disinhibition by decreasing the release of the neurotransmitter GABA in acute midbrain slices . To date, no evidence is available to suggest that CB1Rs also activate Kir3/GIRK channels in these neurons.
This is an increasingly popular club drug that is readily self-administered and induces conditioned place preference (see Glossary) in animal models, and leads to addiction in humans . GHB has two binding sites in the brain, but its pharmacological effects are absent in knockout mice lacking functional GABAB receptors [15,16], suggesting that they are entirely mediated by these receptors. Although GABAB receptors are expressed on both GABA and dopamine neurons of the VTA, GHB affects almost exclusively GABA neurons at concentrations typically obtained with recreational use. This happens because the coupling efficiency of Kir3/GIRK channels in dopamine neurons is very low (the EC50 differs by an order of magnitude between GABA and dopamine neurons), which in turn is due to the cell type–specific subunit expression of Kir3/GIRK channels . Dopamine neurons lack GIRK1, but express GIRK2 and GIRK3, which when co-assembled have a lower affinity for the βγ-dimer of the Gi/o protein compared to channels that contain GIRK1 As a consequence, only GABA neurons are hyperpolarised at concentrations below 1 mM, causing a disinhibition of dopamine neurons.
Class II: Drugs That Mediate Their Effects Via Ionotropic Receptors
This drug targets nicotinic acetylcholine receptors (nAChRs) in the brain. When nicotine binds nAChRs they become cation-permeable and depolarise the cell. Nicotine increases dopamine through a complex interplay of actions at these ionotropic receptors on GABA and dopamine neurons, and glutamatergic inputs to dopamine neurons . Brief applications of nicotine to these neurons in rat brain slices causes a depolarisation and increased firing, although prolonged exposure leads to rapid receptor desensitisation . In addition, following desensitisation of β2-containing nAChRs on GABA neurons, GABA release is decreased (i.e., the excitatory effect of endogenous acetylcholine is reduced), leading to a more prolonged disinhibition of dopamine neurons . It is evident that β2-containing nAChRs are responsible for the rewarding effects of nicotine because β2 knockout mice do not self-administer nicotine and do not show nicotine-evoked dopamine release . These deficits can be restored through in vivo transfection of the β2 subunit in the VTA .
This view is further complicated by two more actions of nicotine. Homomeric a7-containing nAChRs, which are mainly expressed on synaptic terminals of excitatory glutamatergic afferents onto dopamine neurons in the VTA, facilitate glutamate release . This effect may also contribute to nicotine-evoked dopamine release and/or the long-term changes induced by the drugs related to addiction (e.g., long-term synaptic potentiation of excitatory inputs). Furthermore, recent evidence suggests that nicotine directly modulates dopamine release in the NAc [23,24].
Benzodiazepines (BZD) increase mesocorticolimbic dopamine and can lead to addiction. BZD are positive modulators of the GABAA receptor. When injected into the VTA, the GABAA receptor agonist muscimol seems to inhibit interneurons more efficiently compared to dopamine neurons, which may lead to a net disinhibition of the dopamine neurons . This selectivity may relate to cell-type specific subunit expression. For example, when dopamine neurons were isolated from the VTA of transgenic mice that express green fluorescent protein under the control of the tyrosine hydroxylase gene promoter, reverse transcriptase–PCR analysis revealed the presence of a2, a3, and a4 subunits. Conversely, a1 was the major subunit expressed in GABA neurons .
This drug has a complex pharmacology. No single receptor mediates all of the effects of alcohol . On the contrary, alcohol alters the function of a number of receptors and cellular functions, including GABAA receptors , Kir3/GIRK [29,30] and other K channels , Ih , N-methyl-D-aspartate (NMDA) receptors , nAChRs , and 5-HT3 receptors . In addition, ethanol also interferes with adenosine re-uptake by inhibiting the equilibrative nucleoside transporter ENT1, although it is not clear if this plays a role in ethanol-induced dopamine release . How ethanol causes the increase in dopamine remains unclear. Possibilities include a net disinhibition similar to that proposed for benzodiazepines or direct depolarisation, for example by inhibition of a K channel .
Class III: Drugs That Bind to Transporters of Biogenic Amines
In the central nervous system, cocaine blocks dopamine, noradrenaline, and serotonin uptake through inhibition of their respective transporters. Blocking of the dopamine transporter (DAT) leads to an increase of dopamine concentrations in the nucleus accumbens. (The firing rate of DA neurons of the VTA actually decreases with cocaine application, which is due to the effects of dopamine on D2 autoreceptors on DA neurons .) In mice lacking DAT, dopamine still increases in response to cocaine , which could be the result of inhibition of dopamine uptake by other monoamine transporters. Consistent with this suggestion, DAT knockout mice still self-administer cocaine, and this behaviour is abolished in combined DAT– serotonin transporter (SERT) knockout mice . SERT-mediated re-uptake of dopamine only occurs in situations where dopamine levels are already high, as in DAT knockout mice. This is confirmed by a study that used a knock-in mouse line carrying a functional DAT that was insensitive to cocaine. In these mice, cocaine did not elevate extracellular dopamine in the nucleus accumbens, and did not produce reward, as measured by conditioned place preference . Finally, it is important to point out that selective SERT inhibition in humans (e.g., fluoxetine to treat depression) does not carry any addiction liability.
Amphetamine, methamphetamine, and their many derivates.
These exert their effects by reversing the action of biogenic amine transporters at the plasma membrane . Amphetamines are substrates of these transporters and are taken up into the cell. Every molecule that is taken up generates a current causing a depolarisation of the dopamine neurons, which could contribute to enhanced dopamine release . In addition, once in the cell, amphetamines interfere with the vesicular monoamine transporter, depleting synaptic vesicles. As a consequence, dopamine increases in the cytoplasm from where it is released by plasma membrane transporters working in reverse. In other words, normal vesicular release of dopamine decreases (i.e., synaptic vesicles contains less transmitter, the quantal content becomes smaller), while non-vesicular release increases. Similar mechanisms apply for other biogenic amines such as serotonin and norepinephrine.
As for the amphetamines, MDMA causes the release of biogenic amines by reversing the action of their respective transporters. Although MDMA has a preferential affinity for SERTs and therefore increases the extracellular concentration of serotonin, it also strongly increases dopamine .
Drugs of Abuse Yet to Be Classified
There are a number of abused drugs about which there is no clear consensus concerning their addictive properties (e.g., hallucinogens and dissociative anaesthetics). For example, LSD, which is widely abused, does not appear to be addictive. Animals will not self-administer hallucinogens, suggesting that they are not rewarding . Importantly, these drugs fail to evoke dopamine release, further supporting the idea that only drugs that activate the mesolimbic dopamine system are addictive. Instead, the critical action of hallucinogens may be increased glutamate release in the cortex, presumably through a pre-synaptic effect on 5-HT2A receptors expressed on excitatory afferents from the thalamus .
The main effect of the NMDA receptor antagonists phencyclidine (PCP) and ketamine are feelings of separation of mind and body and, at higher doses, stupor and coma, which is why they are called dissociative anaesthetics. Based on early assessments, NMDA receptor antagonists have been classified as non-addictive drugs of abuse . This classification has recently been questioned for PCP. For example, PCP has some reinforcing properties in rodents when applied directly to the NAc and the PFC . Moreover, increased dopamine levels were measured in vivo with micro-dialysis after systemic or PFC injection of PCP in freely moving rats. Similar results were also obtained with local injections of MK-801, a more selective and potent NMDA receptor antagonist than PCP, which supports the conclusion that PCP's effect on dopamine is mediated via the inhibition of NMDA receptors . In this case, PCP would be a Class II drug according to our classification.
Inhalant abuse is defined by the recreational exposure to chemical vapours, such as nitrates, ketones, and aliphatic and aromatic hydrocarbons. In some countries it is particularly common among children, and some chemicals do induce addiction . The mechanism of action remains unknown for most volatile substances. A very limited literature provides evidence that some inhalants alter the function of ionotropic receptors and ion channels throughout the central nervous system . Nitrous oxide, for example, binds to NMDA receptors [51,52] and fuel additives enhance the GABAA receptor function . Toluene increases firing in VTA neurons  and causes conditioned place preference . Others, such as amyl nitrite (“poppers”), primarily produce smooth muscle dilatation, and enhance erection, but are not addictive. While this literature suggests that some inhalants may be Class II addictive drugs, clearly more research will be needed to confirm this choice.
Conditioned place preference: A behavioural test for examining the rewarding properties of drugs. The preference of a particular environment associated with drug exposure is measured by comparing the time an animal spends in the compartment where the drug was previously administered compared to a control compartment.
Coupling efficiency: The efficiency with which a given G protein–coupled receptor can activate an effector.
DARP32: Dopamine and cAMP-regulated phosphoprotein. A key target protein for increased dopamine that plays a role in signalling the effects of many addictive drugs.
DeltaFosB: A transcription factor that is induced in areas such as the NAc in response to many addictive drugs, and thought to be involved in the long-term maintenance of addictive behaviour.
EC50: 50% effective concentration, i.e., the concentration of an agonist that produces 50% of the maximal effect.
Equilibrative nucleoside transporter ENT1: Transporter responsible for the re-uptake of adenosine.
Homomeric α7-containing nAChRs: Nicotinic acetylcholine receptors formed by five subunits of the α7 type.
Kir3/GIRK channels: One class of inwardly rectifying potassium channels; Kir3 are also termed G protein–coupled inwardly rectifying K+ channels.
Quantal content: The amount of neurotransmitter released by a single vesicle.
Implications for Research
We have presented a new mechanistic classification system for addictive drugs. There are a number of key features of this system. First, there are three types of mechanism. Second, each addictive drug only activates the dopamine system through a single mechanism (with the possible exception of ethanol, which has multiple molecular targets whose relative contributions to addiction remain elusive). Third, within each type of mechanism the effect on the dopamine system is similar (e.g., Class I drugs all activate dopamine neurons via disinhibition).
Although substantial progress into unravelling the neurobiological bases of addiction has been made, many open questions remain and few effective treatments are currently available. Much current research is therefore aimed at understanding the neuroadaptive changes induced by addictive drugs, such as increased expression of deltaFosB and DARP32  or the effects on excitatory glutamate transmission [56–58]. The present classification represents a framework that will facilitate research aiming at understanding how each drug induces the adaptive changes listed above and predicts that drugs of the same group are likely to share similar mechanisms.
Implications for Developing Better Treatments for Addiction
Understanding the early phases of the induction of adaptive processes will also be important for the discovery of novel pharmacological treatment strategies. If activation of the dopamine system is indeed crucial for the development of addiction, then an interesting strategy may be to inhibit the mesocorticolimbic DA system (either pharmacologically or through direct stimulation). This idea is further supported by the observation that increases in dopamine play an important role in relapse, particularly drug-induced relapse [59,60]. In this context, the present classification would also serve to identify and organise treatments at the level of the VTA. For example, naloxone will block the effect of opioids, while the high affinity GABAB receptor agonist baclofen would inhibit GABA and dopamine neurons, thus efficiently blocking DA release.
Treatments in use, or at pre-clinical stages of development, are either drug-specific (e.g., vaccines or antagonists that directly block drug action, or agonists for use as drug substitutes) or target a mechanism that is common to several drugs (e.g., medications that reduce craving in multiple forms of addiction) . Many new addiction treatments (for a comprehensive list of approved and experimental medications see ) appear to operate downstream of initial targets (e.g., naltrexone or acamprosate for opiate and alcohol addiction), although their precise mechanisms of action are not entirely clear. Our classification points to a third approach of developing treatments for different classes of drugs based on the mechanisms through which they increase dopamine. For example, targeting the DAT should be useful in treating addiction to any Class III drug. The same may be true for future treatments that interfere with G protein–coupled signalling—such treatments may be useful for all Class I drugs.
Finally, we hope that our strikingly simple mechanistic classification will provide students and clinicians with a useful conceptual framework for understanding a diverse and often complex literature concerning such an important medical issue.
We thank M. Frerking for many helpful comments on an earlier draft.
- 1. Nestler EJ (2005) Is there a common molecular pathway for addiction? Nat Neurosci 8: 1445–1449.EJ Nestler2005Is there a common molecular pathway for addiction?Nat Neurosci814451449
- 2. Pierce RC, Kumaresan V (2006) The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse? Neurosci Biobehav Rev 30: 215–238.RC PierceV. Kumaresan2006The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse?Neurosci Biobehav Rev30215238
- 3. Berridge KC, Robinson TE (1998) What is the role of dopamine in reward: Hedonic impact, reward learning, or incentive salience? Brain Res Brain Res Rev 28: 309–369.KC BerridgeTE Robinson1998What is the role of dopamine in reward: Hedonic impact, reward learning, or incentive salience?Brain Res Brain Res Rev28309369
- 4. Bechara A, Nader K, van der Kooy D (1998) A two-separate-motivational-systems hypothesis of opioid addiction. Pharmacol Biochem Behav 59: 1–17.A. BecharaK. NaderD. van der Kooy1998A two-separate-motivational-systems hypothesis of opioid addiction.Pharmacol Biochem Behav59117
- 5. Laviolette SR, van der Kooy D (2003) Blockade of mesolimbic dopamine transmission dramatically increases sensitivity to the rewarding effects of nicotine in the ventral tegmental area. Mol Psychiatry 8: 50–59.SR LavioletteD. van der Kooy2003Blockade of mesolimbic dopamine transmission dramatically increases sensitivity to the rewarding effects of nicotine in the ventral tegmental area.Mol Psychiatry85059
- 6. Hnasko TS, Sotak BN, Palmiter RD (2005) Morphine reward in dopamine-deficient mice. Nature 438: 854–857.TS HnaskoBN SotakRD Palmiter2005Morphine reward in dopamine-deficient mice.Nature438854857
- 7. Meir A, Ginsburg S, Butkevich A, Kachalsky SG, Kaiserman I, et al. (1999) Ion channels in presynaptic nerve terminals and control of transmitter release. Physiol Rev 79: 1019–1088.A. MeirS. GinsburgA. ButkevichSG KachalskyI. Kaiserman1999Ion channels in presynaptic nerve terminals and control of transmitter release.Physiol Rev7910191088
- 8. Pickel VM, Garzon M, Mengual E (2002) Electron microscopic immunolabeling of transporters and receptors identifies transmitter-specific functional sites envisioned in Cajal's neuron. Prog Brain Res 136: 145–155.VM PickelM. GarzonE. Mengual2002Electron microscopic immunolabeling of transporters and receptors identifies transmitter-specific functional sites envisioned in Cajal's neuron.Prog Brain Res136145155
- 9. Lüscher C, Jan LY, Stoffel M, Malenka RC, Nicoll RA (1997) G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons. Neuron 19: 687–695.C. LüscherLY JanM. StoffelRC MalenkaRA Nicoll1997G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons.Neuron19687695
- 10. Vaughan CW, Ingram SL, Connor MA, Christie MJ (1997) How opioids inhibit GABA-mediated neurotransmission. Nature 390: 611–614.CW VaughanSL IngramMA ConnorMJ Christie1997How opioids inhibit GABA-mediated neurotransmission.Nature390611614
- 11. Johnson SW, North RA (1992) Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci 12: 483–488.SW JohnsonRA North1992Opioids excite dopamine neurons by hyperpolarization of local interneurons.J Neurosci12483488
- 12. Melis M, Pistis M, Perra S, Muntoni AL, Pillolla G, et al. (2004) Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors. J Neurosci 24: 53–62.M. MelisM. PistisS. PerraAL MuntoniG. Pillolla2004Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors.J Neurosci245362
- 13. Szabo B, Siemes S, Wallmichrath I (2002) Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids. Eur J Neurosci 15: 2057–2061.B. SzaboS. SiemesI. Wallmichrath2002Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids.Eur J Neurosci1520572061
- 14. Snead OC 3rd, Gibson KM (2005) Gamma-hydroxybutyric acid. N Engl J Med 352: 2721–2732.OC Snead 3rdKM Gibson2005Gamma-hydroxybutyric acid.N Engl J Med35227212732
- 15. Quéva C, Bremmer-Danielsen M, Edlund A, Ekstrand AJ, Elg S, et al. (2003) Effects of GABA agonists on body temperature regulation in GABA(B(1))-/- mice. Br J Pharmacol 140: 315–322.C. QuévaM. Bremmer-DanielsenA. EdlundAJ EkstrandS. Elg2003Effects of GABA agonists on body temperature regulation in GABA(B(1))-/- mice.Br J Pharmacol140315322
- 16. Kaupmann K, Cryan JF, Wellendroph P, Mombereau C, Sansig G, et al. (2003) Specific gamma-hydroxybutyrate-binding sites but loss of pharmacological effects of gamma-hydroxybutyrate in GABA(B)(1)-deficient mice. Eur J Neurosci 18: 2722–2730.K. KaupmannJF CryanP. WellendrophC. MombereauG. Sansig2003Specific gamma-hydroxybutyrate-binding sites but loss of pharmacological effects of gamma-hydroxybutyrate in GABA(B)(1)-deficient mice.Eur J Neurosci1827222730
- 17. Cruz HG, Ivanova T, Lunn ML, Stoffel M, Slesinger PA, et al. (2004) Bi-directional effects of GABA(B) receptor agonists on the mesolimbic dopamine system. Nat Neurosci 7: 153–159.HG CruzT. IvanovaML LunnM. StoffelPA Slesinger2004Bi-directional effects of GABA(B) receptor agonists on the mesolimbic dopamine system.Nat Neurosci7153159
- 18. Fagen ZM, Mansvelder HD, Keath JR, McGehee DS (2003) Short- and long-term modulation of synaptic inputs to brain reward areas by nicotine. Ann N Y Acad Sci 1003: 185–195.ZM FagenHD MansvelderJR KeathDS McGehee2003Short- and long-term modulation of synaptic inputs to brain reward areas by nicotine.Ann N Y Acad Sci1003185195
- 19. Pidoplichko VI, DeBiasi M, Williams JT, Dani JA (1997) Nicotine activates and desensitizes midbrain dopamine neurons. Nature 390: 401–404.VI PidoplichkoM. DeBiasiJT WilliamsJA Dani1997Nicotine activates and desensitizes midbrain dopamine neurons.Nature390401404
- 20. Mansvelder HD, Keath JR, McGehee DS (2002) Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron 33: 905–919.HD MansvelderJR KeathDS McGehee2002Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas.Neuron33905919
- 21. Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, et al. (1998) Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391: 173–177.MR PicciottoM. ZoliR. RimondiniC. LenaLM Marubio1998Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine.Nature391173177
- 22. Maskos U, Molles BE, Pons S, Besson M, Guiard BP, et al. (2005) Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 436: 103–107.U. MaskosBE MollesS. PonsM. BessonBP Guiard2005Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors.Nature436103107
- 23. Rice ME, Cragg SJ (2004) Nicotine amplifies reward-related dopamine signals in striatum. Nat Neurosci 7: 583–584.ME RiceSJ Cragg2004Nicotine amplifies reward-related dopamine signals in striatum.Nat Neurosci7583584
- 24. Zhang H, Sulzer D (2004) Frequency-dependent modulation of dopamine release by nicotine. Nat Neurosci 7: 581–582.H. ZhangD. Sulzer2004Frequency-dependent modulation of dopamine release by nicotine.Nat Neurosci7581582
- 25. Kalivas PW, Duffy P, Eberhardt H (1990) Modulation of A10 dopamine neurons by gamma-aminobutyric acid agonists. J Pharmacol Exp Ther 253: 858–866.PW KalivasP. DuffyH. Eberhardt1990Modulation of A10 dopamine neurons by gamma-aminobutyric acid agonists.J Pharmacol Exp Ther253858866
- 26. Okada H, Matsushita N, Kobayashi K, Kobayashi K (2004) Identification of GABAA receptor subunit variants in midbrain dopaminergic neurons. J Neurochem 89: 7–14.H. OkadaN. MatsushitaK. KobayashiK. Kobayashi2004Identification of GABAA receptor subunit variants in midbrain dopaminergic neurons.J Neurochem89714
- 27. Koob GF, Roberts AJ, Schulteis G, Parsons LH, Heyser CJ, et al. (1998) Neurocircuitry targets in ethanol reward and dependence. Alcohol Clin Exp Res 22: 3–9.GF KoobAJ RobertsG. SchulteisLH ParsonsCJ Heyser1998Neurocircuitry targets in ethanol reward and dependence.Alcohol Clin Exp Res2239
- 28. Morrow AL (1995) Regulation of GABAA receptor function and gene expression in the central nervous system. Int Rev Neurobiol 38: 1–41.AL Morrow1995Regulation of GABAA receptor function and gene expression in the central nervous system.Int Rev Neurobiol38141
- 29. Kobayashi T, Ikeda K, Kojima H, Niki H, Yano R, et al. (1999) Ethanol opens G-protein-activated inwardly rectifying K+ channels. Nat Neurosci 2: 1091–1097.T. KobayashiK. IkedaH. KojimaH. NikiR. Yano1999Ethanol opens G-protein-activated inwardly rectifying K+ channels.Nat Neurosci210911097
- 30. Lewohl JM, Wilson WR, Mayfield RD, Brozowski SJ, Morrisett RA, et al. (1999) G-protein-coupled inwardly rectifying potassium channels are targets of alcohol action. Nat Neurosci 2: 1084–1090.JM LewohlWR WilsonRD MayfieldSJ BrozowskiRA Morrisett1999G-protein-coupled inwardly rectifying potassium channels are targets of alcohol action.Nat Neurosci210841090
- 31. Appel SB, Liu Z, McElvain MA, Brodie MS (2003) Ethanol excitation of dopaminergic ventral tegmental area neurons is blocked by quinidine. J Pharmacol Exp Ther 306: 437–446.SB AppelZ. LiuMA McElvainMS Brodie2003Ethanol excitation of dopaminergic ventral tegmental area neurons is blocked by quinidine.J Pharmacol Exp Ther306437446
- 32. Okamoto T, Harnett MT, Morikawa H (2005) Hyperpolarization-activated cation current (Ih) is an ethanol target in midbrain dopamine neurons of mice. J Neurophysiol 95: 619–626.T. OkamotoMT HarnettH. Morikawa2005Hyperpolarization-activated cation current (Ih) is an ethanol target in midbrain dopamine neurons of mice.J Neurophysiol95 619626