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The Mechanistic Classification of Addictive Drugs

The Mechanistic Classification of Addictive Drugs

  • Christian Lüscher, 
  • Mark A Ungless
PLOS
x

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).

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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

https://doi.org/10.1371/journal.pmed.0030437.g001

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 [3]. Most experts in the field agree that some aspects of reward (e.g., euphoria/ pleasure) are dopamine-independent [4]. 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 [5]. Also, dopamine-deficient mice display conditioned place preference for morphine [6].

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.

Some of the Key Papers on the Cellular Effects of Addictive Drugs

Johnson and North, 1992 [11]: A classic paper demonstrating the disinhibitory effect of opioids on dopamine neurons.

Cruz et al., 2004 [17]: A current model explaining how the popular club drug GHB activates VTA neurons via its action on the GABAB receptor.

Maskos et al., 2005 [21]: 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 [39]: 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 [56]: 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 [57]: 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.

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.

The Classification

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 [7], 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 [8]. 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 [9], while MORs expressed on the pre-synaptic terminals decrease release by inhibiting Ca2+ channels or activating voltage-gated K+ channels [10]. 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 [11].

Delta-9-tetrahydrocannabinol.

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 [12]. Pharmacological application of THC causes a net disinhibition by decreasing the release of the neurotransmitter GABA in acute midbrain slices [13]. To date, no evidence is available to suggest that CB1Rs also activate Kir3/GIRK channels in these neurons.

GHB.

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 [14]. 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 [17]. 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

Nicotine.

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 [18]. 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 [19]. 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 [20]. 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 [21]. These deficits can be restored through in vivo transfection of the β2 subunit in the VTA [22].

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 [20]. 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.

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 [25]. 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 [26].

Ethanol.

This drug has a complex pharmacology. No single receptor mediates all of the effects of alcohol [27]. On the contrary, alcohol alters the function of a number of receptors and cellular functions, including GABAA receptors [28], Kir3/GIRK [29,30] and other K channels [31], Ih [32], N-methyl-D-aspartate (NMDA) receptors [33], nAChRs [34], and 5-HT3 receptors [35]. 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 [36]. 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 [31].

Class III: Drugs That Bind to Transporters of Biogenic Amines

Cocaine.

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 [37].) In mice lacking DAT, dopamine still increases in response to cocaine [38], 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 [39]. 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 [40]. 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 [41]. 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 [42]. 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.

Methylenedioxymetamphetamine (ecstasy).

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 [43].

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 [44]. 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 [45].

Glossary

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.

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 [46]. 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 [47]. 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 [48]. 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 [49]. 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 [50]. Nitrous oxide, for example, binds to NMDA receptors [51,52] and fuel additives enhance the GABAA receptor function [53]. Toluene increases firing in VTA neurons [54] and causes conditioned place preference [55]. 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.

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 [1] 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) [57]. Many new addiction treatments (for a comprehensive list of approved and experimental medications see [61]) 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.

Acknowledgments

We thank M. Frerking for many helpful comments on an earlier draft.

References

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
  33. 33. Krystal JH, Petrakis IL, Mason G, Trevisan L, D'Souza DC (2003) N-methyl-D-aspartate glutamate receptors and alcoholism: Reward, dependence, treatment, and vulnerability. Pharmacol Ther 99: 79–94.JH KrystalIL PetrakisG. MasonL. TrevisanDC D'Souza2003N-methyl-D-aspartate glutamate receptors and alcoholism: Reward, dependence, treatment, and vulnerability.Pharmacol Ther997994
  34. 34. Soderpalm B, Ericson M, Olausson P, Blomqvist O, Engel JA (2000) Nicotinic mechanisms involved in the dopamine activating and reinforcing properties of ethanol. Behav Brain Res 113: 85–96.B. SoderpalmM. EricsonP. OlaussonO. BlomqvistJA Engel2000Nicotinic mechanisms involved in the dopamine activating and reinforcing properties of ethanol.Behav Brain Res1138596
  35. 35. Lovinger DM (1999) 5-HT3 receptors and the neural actions of alcohols: An increasingly exciting topic. Neurochem Int 35: 125–130.DM Lovinger19995-HT3 receptors and the neural actions of alcohols: An increasingly exciting topic.Neurochem Int35125130
  36. 36. Choi DS, Cascini MG, Mailliard W, Young H, Paredes P, et al. (2004) The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference. Nat Neurosci 7: 855–861.DS ChoiMG CasciniW. MailliardH. YoungP. Paredes2004The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference.Nat Neurosci7855861
  37. 37. Brodie MS, Dunwiddie TV (1990) Cocaine effects in the ventral tegmental area: Evidence for an indirect dopaminergic mechanism of action. Naunyn Schmiedebergs Arch Pharmacol 342: 660–665.MS BrodieTV Dunwiddie1990Cocaine effects in the ventral tegmental area: Evidence for an indirect dopaminergic mechanism of action.Naunyn Schmiedebergs Arch Pharmacol342660665
  38. 38. Rocha BA, Fumagalli F, Gainetdinov RR, Jones SR, Ator R, et al. (1998) Cocaine self-administration in dopamine-transporter knockout mice. Nat Neurosci 1: 132–137.BA RochaF. FumagalliRR GainetdinovSR JonesR. Ator1998Cocaine self-administration in dopamine-transporter knockout mice.Nat Neurosci1132137
  39. 39. Rocha BA (2003) Stimulant and reinforcing effects of cocaine in monoamine transporter knockout mice. Eur J Pharmacol 479: 107–115.BA Rocha2003Stimulant and reinforcing effects of cocaine in monoamine transporter knockout mice.Eur J Pharmacol479107115
  40. 40. Chen R, Tilley MR, Wei H, Zhou F, Zhou FM, et al. (2006) Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter. Proc Natl Acad Sci U S A 103: 9333–9338.R. ChenMR TilleyH. WeiF. ZhouFM Zhou2006Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter.Proc Natl Acad Sci U S A10393339338
  41. 41. Sulzer D, Sonders MS, Poulsen NW, Galli A (2005) Mechanisms of neurotransmitter release by amphetamines: A review. Prog Neurobiol 75: 406–433.D. SulzerMS SondersNW PoulsenA. Galli2005Mechanisms of neurotransmitter release by amphetamines: A review.Prog Neurobiol75406433
  42. 42. Ingram SL, Prasad BM, Amara SG (2002) Dopamine transporter-mediated conductances increase excitability of midbrain dopamine neurons. Nat Neurosci 5: 971–978.SL IngramBM PrasadSG Amara2002Dopamine transporter-mediated conductances increase excitability of midbrain dopamine neurons.Nat Neurosci5971978
  43. 43. Morton J (2005) Ecstasy: Pharmacology and neurotoxicity. Curr Opin Pharmacol 5: 79–86.J. Morton2005Ecstasy: Pharmacology and neurotoxicity.Curr Opin Pharmacol57986
  44. 44. Nichols DE (2004) Hallucinogens. Pharmacol Ther 101: 131–181.DE Nichols2004Hallucinogens.Pharmacol Ther101131181
  45. 45. Aghajanian GK, Marek GJ (1999) Serotonin and hallucinogens. Neuropsychopharmacology 21: 16S–23S.GK AghajanianGJ Marek1999Serotonin and hallucinogens.Neuropsychopharmacology2116S23S
  46. 46. Goldstein A, Kalant H (1990) Drug policy: Striking the right balance. Science 249: 1513–1521.A. GoldsteinH. Kalant1990Drug policy: Striking the right balance.Science24915131521
  47. 47. Carlezon WA Jr, Wise RA (1996) Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex. J Neurosci 16: 3112–3122.WA Carlezon JrRA Wise1996Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex.J Neurosci1631123122
  48. 48. Hondo H, Yonezawa Y, Nakahara T, Nakamura K, Hirano M, et al. (1994) Effect of phencyclidine on dopamine release in the rat prefrontal cortex; An in vivo microdialysis study. Brain Res 633: 337–342.H. HondoY. YonezawaT. NakaharaK. NakamuraM. Hirano1994Effect of phencyclidine on dopamine release in the rat prefrontal cortex; An in vivo microdialysis study.Brain Res633337342
  49. 49. Ridenour TA (2005) Inhalants: Not to be taken lightly anymore. Curr Opin Psychiatry 18: 243–247.TA Ridenour2005Inhalants: Not to be taken lightly anymore.Curr Opin Psychiatry18243247
  50. 50. Campagna JA, Miller KW, Forman SA (2003) Mechanisms of actions of inhaled anesthetics. N Engl J Med 348: 2110–2124.JA CampagnaKW MillerSA Forman2003Mechanisms of actions of inhaled anesthetics.N Engl J Med34821102124
  51. 51. Mennerick S, Jevtovic-Todorovic V, Todorovic SM, Shen W, Olney JW, et al. (1998) Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures. J Neurosci 18: 9716–9726.S. MennerickV. Jevtovic-TodorovicSM TodorovicW. ShenJW Olney1998Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures.J Neurosci1897169726
  52. 52. Nagele P, Metz LB, Crowder CM (2004) Nitrous oxide (N(2)O) requires the N-methyl-D-aspartate receptor for its action in Caenorhabditis elegans. Proc Natl Acad Sci U S A 101: 8791–8796.P. NageleLB MetzCM Crowder2004Nitrous oxide (N(2)O) requires the N-methyl-D-aspartate receptor for its action in Caenorhabditis elegans.Proc Natl Acad Sci U S A10187918796
  53. 53. Martin JV, Iyer SV, McIlroy PJ, Iba MM (2004) Influence of oxygenated fuel additives and their metabolites on gamma-aminobutyric acidA (GABAA) receptor function in rat brain synaptoneurosomes. Toxicol Lett 147: 209–217.JV MartinSV IyerPJ McIlroyMM Iba2004Influence of oxygenated fuel additives and their metabolites on gamma-aminobutyric acidA (GABAA) receptor function in rat brain synaptoneurosomes.Toxicol Lett147209217
  54. 54. Riegel AC, French ED (2002) Abused inhalants and central reward pathways: Electrophysiological and behavioral studies in the rat. Ann N Y Acad Sci 965: 281–291.AC RiegelED French2002Abused inhalants and central reward pathways: Electrophysiological and behavioral studies in the rat.Ann N Y Acad Sci965281291
  55. 55. Gerasimov MR, Collier L, Ferrieri A, Alexoff D, Lee D, et al. (2003) Toluene inhalation produces a conditioned place preference in rats. Eur J Pharmacol 477: 45–52.MR GerasimovL. CollierA. FerrieriD. AlexoffD. Lee2003Toluene inhalation produces a conditioned place preference in rats.Eur J Pharmacol4774552
  56. 56. Ungless MA, Whistler JL, Malenka RC, Bonci A (2001) Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411: 583–587.MA UnglessJL WhistlerRC MalenkaA. Bonci2001Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons.Nature411583587
  57. 57. Saal D, Dong Y, Bonci A, Malenka RC (2003) Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37: 577–582.D. SaalY. DongA. BonciRC Malenka2003Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons.Neuron37577582
  58. 58. Bellone C, Lüscher C (2006) Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression. Nat Neurosci 9: 636–641.C. BelloneC. Lüscher2006Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression.Nat Neurosci9636641
  59. 59. Phillips PE, Stuber GD, Heien ML, Wightman RM, Carelli RM (2003) Subsecond dopamine release promotes cocaine seeking. Nature 422: 614–618.PE PhillipsGD StuberML HeienRM WightmanRM Carelli2003Subsecond dopamine release promotes cocaine seeking.Nature422614618
  60. 60. Kalivas PW, McFarland K (2003) Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology (Berl) 168: 44–56.PW KalivasK. McFarland2003Brain circuitry and the reinstatement of cocaine-seeking behavior.Psychopharmacology (Berl)1684456
  61. 61. Volkow ND, Li TK (2004) Drug addiction: The neurobiology of behaviour gone awry. Nat Rev Neurosci 5: 963–970.ND VolkowTK Li2004Drug addiction: The neurobiology of behaviour gone awry.Nat Rev Neurosci5963970