Development of Pharmacotherapies for Drug Addiction: a Rosetta Stone Approach

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Development of pharmacotherapies for drug addiction: a Rosetta Stone approach

George F. Koob*, G. Kenneth Lloyd‡ and Barbara J. Mason* Abstract | Current pharmacotherapies for addiction represent opportunities for facilitating treatment and are forming a foundation for evaluating new medications. Furthermore, validated animal models of addiction and a surge in understanding of neurocircuitry and neuropharmacological mechanisms involved in the development and maintenance of addiction — such as the neuroadaptive changes that account for the transition to dependence and the vulnerability to relapse — have provided numerous potential therapeutic targets. Here, we emphasize a ‘Rosetta Stone approach’, whereby existing pharmacotherapies for addiction are used to validate and improve animal and human laboratory models to identify viable new treatment candidates. This approach will promote translational research and provide a heuristic framework for developing efficient and effective pharmacotherapies for addiction.

Addiction Drug addiction is a chronically relapsing disorder to emulate different components of addiction, some 2 This term can be used character ized by a compulsion to seek and take a drug, of which are still evolving . Second, there is a dynamic interchangeably with substance loss of control in limiting intake and emergence of a approach to the process of validation, with changes being dependence (as currently negative emotional state (for example, dysphoria, anxiety discovered and implemented at both ends. New targets defined by the Diagnostic and 1 Statistical Manual of Mental and irritability) when access to the drug is prevented . from neurobiology will feed forwards through the system Disorders, 4th edition) to refer An important goal of current neurobiological research is and new medications will feed backwards, regardless of to a final stage of a usage to understand the molecular, neuropharmacological and whether these medications are derived from the feed process. Clinically, the neurocircuitry changes that mediate the transition from forward process, clinical experience or serendipity. Third, occasional but limited use of occasional, controlled drug use to the loss of behavioural symptoms or components of the addiction cycle provide a a drug with the potential for abuse or dependence is distinct control over drug seeking and drug taking that defines face-valid model that facilitates the creation of new animal from the emergence of chronic addiction. In this Review, we suggest that a and human laboratory models (for example, the animal addiction. combination of validated animal models for addiction, model of compulsivity and drug seeking in the context neurobiological targets derived from such models, and of aversive consequences, or the human model of brain translation to and from the clinical domain provides a imaging in the context of cueinduced imagery3–5). heuristic framework for the development of pharmaco *Committee on the Neurobiology of Addictive therapies for addiction. Moreover, the application of The addiction cycle Disorders, The Scripps known treatments for addiction to existing animal A useful psychiatrybased motivational framework that Research Institute, and human laboratory models can provide an evolving integrates well with animal models of addiction is the 10550 North Torrey Pines ‘Rosetta Stone approach’ for accelerating the translation concept that drug addiction has aspects of both impulse Road, SP30‑2400 La Jolla, kleptomania California 92037, USA. of newly identified targets to pharmacotherapies for control disorders (such as ) and compulsive ‡Research and Development, addiction (BOX 1; FIG. 1). disorders (such as obsessive–compulsive disorder). It Nereus Pharmaceuticals, A key element of this approach will be to prevent has been suggested that, as an individual moves from 10480 Wateridge Circle, predictions from animal models being limited by the con an impulsive disorder to a compulsive disorder, a shift San Diego, California structs of the models themselves. Several aspects of the from positive reinforcement to negative reinforcement 92121, USA. 1 Correspondence to G.F.K. Rosetta Stone approach address this issue. First, because drives the motivated behaviour within a cycle compris e‑mail: [email protected] no single animal or human laboratory model exists for ing three stages: binge–intoxication, withdrawal–negative doi:10.1038/nrd2828 all of the aspects of addiction, various models are used affect, and preoccupation–anticipation.

Box 1 | Disease concept: addiction as a treatable disease Animal models for the binge–intoxication stage of the addiction cycle incorporate drug reinforcement and Addiction is a brain disease, and is defined as a chronically relapsing disorder of include drug and alcohol selfadministration. For the compulsive drug use. Advances in our understanding of the neurobiology of addiction withdrawal–negative affect stage, animal models exist have given substantial support to the disease basis for addiction. Changes in specific for the somatic signs of withdrawal for almost all drugs neuronal and neurochemical circuits have been identified that correspond to different components of the addiction cycle. Perhaps more importantly, these changes are long of abuse. However, more relevant to addiction are the lasting and in some cases can be permanent. One goal of medications development animal models of components of the motivational signs for addiction is to reverse or compensate for such pathological effects. of withdrawal and the negative reinforcing effects of The concept of addiction as a disease is also supported by overwhelming evidence dependence, which are beginning to be used to explore that addiction leads to brain pathology from a functional perspective, and this how the nervous system is involved in motivation and pathology is manifested by reversible, and possibly some irreversible, brain changes. adapts to drug use. These include anxietylike responses, In the United States alone, illicit-drug abuse and addiction costs society US$180.9 conditioned place aversion (a form of place conditioning), 159 160 billion per year ; in addition, alcoholism costs $180 billion and tobacco addiction elevated reward thresholds and withdrawalinduced 161 costs $167 billion . increases in drug selfadministration. For the preoc From the perspective of treatment, relapse rates for addiction with abstinence as cupation–anticipation (craving) stage, models include a goal are high: generally 90% without treatment after 1 year. However, such relapse rates for addiction are similar to those for other chronic relapsing disorders, such as drug, cue and stressinduced reinstatement of drug diabetes, hypertension and asthma162. Treatments for addiction have limited success, seeking behaviour. Animal models of craving can also often only doubling the number of individuals that do not relapse after 1 year. include the conditioned rewarding effects of drugs of However, even capturing 10% of subjects per year could afford considerable savings abuse, measures of the conditioned aversive effects of in human suffering and societal cost. Appropriately monitored replacement withdrawal, and signs and symptoms of protracted treatments, such as methadone and buprenorphine, have a relatively high success abstinence6,7. rate in terms of reducing or eliminating illicit use of opioids. Furthermore, recent successes with naltrexone, acamprosate, buprenorphine and varenicline hold Neurobiological targets in addiction promise for future medications development for addiction. Neurocircuitry of addiction. A crucial issue for the development of treatments for addiction is that selec tion of relevant targets should be informed by an Face-valid model Animal models relevant to the addiction cycle. Animal empirical understanding of the neurobiology of addic 7 A model that looks or seems models of addiction have outstanding face validity (for tion . Three neurobiological circuits have been iden to be a valid representation of example, for intravenous selfadministration) and reca tified that have heuristic value for the study of the what it purports to measure. pitulate aspects of the condition in humans. They also neurobiological changes associated with the development (FIG. 2) Kleptomania have substantial construct validity (for example, deregu and persistence of drug dependence . A classic impulse control lated stress responsivity during drug withdrawal), that The circuitry related to the origin and terminal regions disorder in which there is an is, explanatory power or functional equivalence for the of the mesocorticolimbic dopamine system, which increase in tension before condition in humans. Although no animal model fully includes signalling by dopamine and opioid peptides, is a stealing an object or objects reproduces addiction in humans, such models do permit crucial mediator of the positive reinforcing effects of drugs that are not needed and relief after the act, but little or no investigation of elements of the drug addiction process associated with the binge–intoxication stage of the addic 8 regret or self-reproach. that can be defined by models of addiction symptoms tion cycle .The preoccupation–anticipation (craving) stage within the three stages of the addiction cycle. Different involves key glutamatergic projections to the extended animal models for the study of the neurobiology of amygdala and nucleus accumbens from the prefrontal addiction can be superimposed on these three stages, cortex (for druginduced reinstatement of drug seeking) collectively reproducing the pathological state known as and from the basolateral amygdala (for cueinduced rein addiction1 (TABLE 1). statement of drug seeking)9. Compulsive drugseeking behaviour is thought to engage ventral striatal–ventral pallidal–thalamic–cortical loops that could subsequently Novel compounds New use of approved drugs engage dorsal striatal–dorsal pallidal–thalamic–cortical loops10, both of which are exaggerated by concomitant decreased activity in reward circuits11,12. The neural sub Animal screening studies: Human laboratory studies: strates and neuropharmacological mechanisms for the • multiple models • multiple dependent variables negative motivational effects of the withdrawal–negative • comparison with • comparison with reference affect stage of the addiction cycle may involve not only reference compounds compounds disruption of the neural systems implicated in the positive reinforcing effects of drugs, but also recruitment of brain stress systems13. Common responses during acute with Phase II clinical trials drawal from the main drugs of abuse include decreased dopaminergic activity, an activated pituitary–adrenal Figure 1 | The ‘Rosetta Stone approach’ to drug development. A crucial aspect of the proposed Rosetta Stone approach is the dynamic feedback from animal models and stress response and an activated brain stress response with clinical data which can be used to identify treatments for drugNatur addictione Reviews that | Drug are Disc likelyovery activated extrahypothalamic corticotropin-releasing factor to succeed in clinical trials and to facilitate further development of animal and human (CRF) systems in the amygdala. However, repeated cycles models. These data may ultimately provide a rational basis for combination therapies of addiction lead to a blunted pituitary–adrenal response such that multiple components of the addiction cycle can be treated by a given and a sensitized extrahypothalamic CRF stress system pharmacological strategy. response in the amygdala13.

Table 1 | Laboratory models of the stages of the addiction cycle New targets for medications development The premise of this Review is that different components Stage of Animal models Human laboratory models addiction cycle of the addiction cycle can be targeted by different medications, selected on the basis of information from Binge– Drug or alcohol self- Self-administration in three key sources. These comprise research into basic intoxication administration172 dependent subjects120,176,177 neurobiological mechanisms for the different stages of Conditioned place Impulsivity178–180 the addiction cycle, the effects of medications approved 6 preference for the treatment of addiction on animal models of the Brain stimulation reward different stages of the addiction cycle (Supplementary thresholds173 information S1 (box)) and clinical studies of medica Increased motivation for self- tions approved for other indications that overlap with administration in dependent specific components of addiction (discussed below) 3,4,174,175 animals (FIG. 2; TABLE 3). Withdrawal– Anxiety-like responses60,72,181 Acute withdrawal125,188,189 The effects of selected compounds acting on specific negative affect Conditioned place Self-medication190–192 neurobiological targets on models of the motiva aversion182 tional components of the addiction cycle that are relevant for pharmacotherapies, using alcoholism as Elevated reward thresholds183 Mood induction57,149 an example, are shown in TABLE 4. It compares novel Withdrawal-induced approaches with two medications currently on the increases in drug self- administration175,184–187 market (naltrex one, and acamprosate (Campral/ Aotal; Merck–Serono/Forest laboratories)). Different 6 132 Preoccupation– Drug-induced reinstatement Drug reinstatement patterns of action on the animal models are thought anticipation Cue-induced reinstatement6 Cue reactivity134,137,139 to reflect actions in different stages of the addiction Stress-induced Emotional reactivity55 cycle. The Rosetta Stone approach places emphasis on reinstatement6 elements of the withdrawal–negative affect stage (the ‘dark side’) of addiction. we propose that this frame Stress-induced craving135,141–143 work is crucial for the neuroadaptations that lead to Resistance to relapse150 changes in motivation and thereby drive addiction Cue-induced brain imaging to maintain an allostatic state12. There is compelling responses5,151,152 evidence that direct antagonism of the reinforcing effects of drugs of abuse, representing the binge– intoxication stage, produces compensatory increases in drug taking, motivational side effects that limit Molecular targets within the brain circuits associated with compliance, or a combination of both. other reviews addiction. Molecular changes at the signal transduction, have focused on animal models of the preoccupation– gene transcription or gene level are thought to provide anticipation (craving) state15. Here, we explore four insights into how the circuits described above become neurotransmitter systems: dopamine, γaminobutyric deregulated and maintain such deregulation, and provide acid (GABA), CRF and glutamate, all of which have several contributions to medications development. Drugs targets that can restore deregulated reward systems, as Obsessive–compulsive of abuse perturb intracellular signal transduction, leading in the withdrawal–negative affect stage, and in some disorder A classic compulsive disorder to changes in nuclear function and rates of transcription cases affect the binge–intoxication stage (dopamine) 14 is one in which obsessions of of certain genes . This leads to altered activity of the and the preoccupation–anticipation stage (glutamate). contamination or harm drive neurons in which such changes occur and ultimately to Although GABA, glutamate and CRF are not new tar anxiety, the reduction of which changes in the function of the associated neural circuits. gets in the treatment of addiction2, targeting these requires repetitive compulsive acts to reduce the anxiety. To date, no medication targets have been identified from and the dopamine system using the framework of molecular targets but, in the future, molecular studies validation described here has the potential to provide Binge may provide the basis for future targets for pharmaco new medications. Any behaviour indulged to therapeutic approaches and a key to understanding the excess. In alcohol abuse, vulnerability to addiction. Dopamine receptor partial agonists. The mesolimbic a binge is defined in the United States as four drinks dopamine system projects from the ventral tegmental for females and five drinks for Animal models of addiction: reverse validity area to basal forebrain sites, the nucleus accumbens and males in a 2-hour period or Several medications are currently on the market for the the central nucleus of the amygdala, and has a key role reaching a blood alcohol level treatment of addiction (FIG. 2; TABLE 2). The validation in motivation. Activation of the mesolimbic dopamine of 0.08 g per 100 ml. procedure termed the Rosetta Stone or reverse validity system is thought to be important for directing behaviour 16 Withdrawal approach uses drugs that are known to be effective in towards salient rewarding stimuli , but may not be A collection of physiological human clinical studies to validate animal models and necessary for hedonic experience17. Therefore, meso signs and symptoms that human laboratory models, and can provide a means of limbic dopamine activity seems to be crucial for the present after the sudden refining such models. For more detailed information reinforcing actions of indirect sympathomimetics, such cessation of drug intake, which can include shaking, on the effects of drugs approved for the treatment of as cocaine and amphetamines, and is involved in, but sweating and anxiety, addiction on established animal models of addiction, not essential for, the reinforcing actions of other drugs depending on the drug. see Supplementary information S1 (box). of abuse, such as opioids and alcohol.

Place conditioning More importantly for our dark side view, dopamin withdrawal and reinstatement, and dopamine partial A procedure for assessing the ergic function is compromised during acute withdrawal agonists with the appropriate neuropharmacological reinforcing efficacy of drugs from all major drugs of abuse18: levels of extracellular and pharmacokinetic profile may be effective in treating using a classical or Pavlovian dopamine decrease in the nucleus accumbens following certain aspects of addiction39. conditioning procedure. 19 Animals typically show a binge of selfadministered cocaine ; animals kept on GABA receptor conditioned place preference a diet of alcohol show a decrease in extracellular levels GABAergic modulators. A antagonists and for an environment associated of dopamine in the nucleus accumbens during with inverse agonists decrease alcohol selfadministration40,41. with the common drugs of drawal20. withdrawal from most major drugs of abuse However, their therapeutic actions are limited by potential addiction in humans and avoid is also associated with decreased firing of dopaminergic side effects involving central nervous system hyperexcit environments associated 21 with aversive states of drug neurons in the ventral tegmental area . ability. By contrast, GABA receptor agonists or modu withdrawal (that is, they show Given the role of dopamine in the acute reinforcing lators can block drugseeking behaviour through their conditioned place aversion). effects of drugs and its deregulation during drug with actions on reward, dependence or both. GABA receptor drawal, a dopamine partial agonist may be an effec modulators that increase GABAergic activity directly or Corticotropin-releasing factor tive treatment in different stages of the addiction cycle. indirectly decrease selfadministration of cocaine, heroin, 42–45 A 41-amino-acid polypeptide A dopa mine receptor partial agonist has antagonist prop nicotine and alcohol in nondependent rats . GABA with wide distribution erties in situations of high intrinsic activity and agonist receptor agonists also block alcohol withdrawal in ani throughout the brain and high properties in situations of low intrinsic activity. Because mals46 and humans, and decrease drinking and certain concentrations in cell bodies of its intermediate efficacy, a dopamine partial agonist components of craving in humans with alcoholism47,48 in the paraventricular nucleus (TABLE 4) GABA receptor of the hypothalamus, the basal acts as an agonist in the absence of dopamine and can . B agonists also block the increased 23–25 forebrain and notably the act as an antagonist in the presence of dopamine , alcohol selfadministration observed during acute with extended amygdala and and would hypothetically have less severe or fewer side drawal in dependent rats at lower doses than those that brainstem. effects than full agonists or antagonists22. Indeed, partial block alcohol selfadministration in nondependent rats,

GABA receptor agonists of dopamine D2 receptors dosedependently suggesting an increased sensitivity of this system during A 49 A receptor that is coupled decrease the reinforcing effects of intravenous cocaine the development of dependence . The GABAB agonist to Cl– channels and forms a and amphetamine selfadministration and oral alcohol baclofen has been reported to reduce alcohol craving and receptor complex that selfadministration in nondependent rats26–29. intake in a preliminary doubleblind, placebocontrolled includes recognition sites for In a series of studies, D partial agonists have been trial47. However, GABA agonists currently in therapeutic convulsants, benzodiazepines, 2 B barbiturates and steroids. shown to reverse psychostimulant withdrawal and block use for the relief of flexor spasms in multiple sclerosis have the increase in selfadministration associated with substantial sedative effects at therapeutic doses50. Thus, GABA receptor B extended access to the psychostimulant. A D2 partial another approach is to explore the role of GABA receptor A metabotropic receptor that agonist reversed the motivational deficit that occurs modulators that indirectly facilitate GABA release. regulates K+ and Ca2+ channels through a G protein-coupled during amphetamine and methamphetamine with Gabapentin (Neurontin; Pfizer), an amino acid drawal30,31. Animals with extended access to metham designed as a structural analogue of GABA51, is a novel mechanism. Both GABAA and

GABAB receptors have an pheta mine through intravenous selfadministration show anticonvulsant drug that is also used in the treatment of inhibitory action in the central an increased intake of methamphetamine (escalation neuropathic pain. Gabapentin increases the concentration nervous system and are 32 52 in intake) . A notable effect of the D2 partial agonist of GABA in the brain and GABA release from rat brain thought to mediate the 53 anxiety-decreasing, motor- aripiprazole on methamphetamine selfadministration slices in vitro . It also decreases synaptic transmission 2+ uncoordinating, sedative and was a shift to the right of the dose–response function, in the brain by selectively inhibiting Ca influx through hypnotic effects of alcohol. with a greater effect in rats with higher methampheta voltageoperated Ca2+ channels54 and may be an agonist 55 mine intake associated with extended access. These data of GABAB receptors . again suggest an increased sensitivity to the effects of In animal models of alcohol dependence, gabapentin 32 the D2 partial agonists in dependent rats . has strikingly different effects in nondependent and

Antagonists of the dopamine D3 receptor do not affect alcoholdependent rats, both cellularly and pharmaco baseline cocaine selfadministration, but block responses logically56. In nondependent rats, gabapentin facilitated in a progressiveratio schedule, a measure that is thought GABAergic transmission in the central nucleus of the to reflect a compulsivity component of cocaine seeking. amygdala but did not affect alcohol intake. However,

Additionally, D3 antagonists block cueinduced rein in dependent rats, gabapentin decreased GABAergic statement of cocaine and alcohol selfadministration33. transmission in the central nucleus of the amygdala and

Similarly, D3 partial agonists do not block baseline reduced excessive alcohol intake. Furthermore, gabapen cocaine selfadministration but block cueinduced rein tin suppressed the anxiogeniclike effects of withdrawal statement of selfadministration34 and cueinduced drug from an acute alcohol injection. A possible explana seeking in a secondorder schedule of reinforcement35. tion for these results is that, during the development of

A D3 partial agonist also blocked amphetamineinduced alcohol dependence, neuroadaptive changes occur in the conditioned place preference36. GABAergic system, including a reduced sensitivity and/ 56 D1 antagonists competitively block cocaine self or a downregulation of presynaptic GABAB receptors . administration in rats37, but little work has been done Gabapentin has proved effective in human laboratory

on D1 partial agonists. one study has shown strain studies in decreasing craving, reversing physiological dependent agonist and antagonist effects on cocaine self measures of protracted abstinence and reversing sleep 38 57 administration with a D1 partial agonist in rats . Together, deficits in protracted abstinence , suggesting a key these results suggest that deregulation of dopamine translation from animals to humans and supporting the signalling contributes to the motivational effects of drug translational approach suggested here.

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Preoccupation or anticipation (‘craving’) Withdrawal or negative affect Binge or intoxication Existing medications: Existing medications: Existing medications: • Acamprosate • Methadone • Disulfiram • Bupropion • Buprenorphine • Naltrexone Potential pharmacotherapies: • Varenicline • Methadone • GABA modulators (homeostatic resetters) • Nicotine patch • Buprenorphine • CRF1 antagonists (stress reducers) Potential pharmacotherapies: Potential pharmacotherapies: • Glutamate modulators (habit reducers) • GABA modulators (homeostatic resetters) • Partial agonists of the relevant receptor • CRF1 antagonists (stress reducers) system (intoxication blockers) • κ-opioid antagonists (dysphoria reducer) • Drug vaccines (intoxication blockers)

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73 ▶ REVIEWS REVIEWS

nucleus accumbens decreases activity in the dopamine cocaineinduced place preference in mice93 and blocked system. It is therefore possible that the activation of the stressinduced reinstatement of cocaineseeking behav dynorphin system could contribute to the dysphoric iour in rats94, and CRF is thought to produce its aversive syndrome associated with cocaine dependence90. effect through activation of the dynorphin system92. There Dynorphin activity is also increased by stress91, is also evidence that the link between reinstatement of suggesting a potential interaction with the CRF sys drugseeking behaviour and activation of κopioid recep tem. In mice, forcedswim stress and inescapable foot tors is mediated by CRF95. Thus, the dynorphin–κopioid shock produced place aversions that were blocked by system mimics stressor administration in animals in a κopioid receptor antagonist and dynorphin knock producing aversive effects and inducing drugseeking out92. Blockade of dynorphin activity, either by κopioid behaviour. This aversive response could involve recipro receptor antagonism or by disruption of the prodynor cal interactions with dopamine in the nucleus accumbens phin gene, blocked stressinduced reinstatement of and the extrahypothalamic brain CRF system.

Table 2 | Medications currently on the market for the treatment of drug addiction Name Addiction year of FDA Description approval Disulfiram Alcohol 1954 • An acetaldehyde dehydrogenase (ALDH) inhibitor used to prevent relapse in patients with alcoholism who have stopped drinking193 • Produces an aversive reaction if the subject drinks and has adequate blood levels of disulfiram, presumably owing to increased acetaldehyde in the bloodstream; this is similar to the intense flush reaction of Asians with a deletion of one or two alleles of the ALDH2 gene194 Methadone Opiate 1972 • This long-acting opioid was developed as a substitution treatment for opioid addiction because of its property of being orally active with a long half-life, and became the standard medication for opioid detoxification Naltrexone Alcohol 1994 • A competitive opioid antagonist that has oral bioavailability and and 2005 binds to µ-, δ- and κ-opioid receptors, with a higher affinity for (extended- the µ-opioid receptor release • Decreases heavy drinking in patients with alcoholism and formulation) prevents relapses to heavy drinking195,196; has greater efficacy when combined with associated behavioural treatments, particularly cognitive behavioural therapy Bupropion Nicotine 1997 • An antidepressant with efficacy in smoking cessation197 that has (Wellbutrin/Zyban; beneficial effects on protracted abstinence, consistent with its GlaxoSmithKline) antidepressant properties • Effectively doubles abstinence rates after 1 year198 Buprenorphine Opiate 2002 • An oripavine derivative that is a partial agonist at µ-opioid (Subutex; receptors, κ-opioid receptors and nociceptin receptors and Schering–Plough) an antagonist at δ-opioid receptors • Studies have shown that maintenance therapy with buprenorphine is an effective treatment for opioid dependence • Can be prescribed as a sublingual tablet consisting of buprenorphine or buprenorphine with naloxone (Suboxone; Schering–Plough); the addition of naloxone limits diversion because naloxone is inactive when taken orally, but will block the effects of buprenorphine if the preparation is diverted to intravenous use Acamprosate Alcohol 2004 • An indirect partial agonist of the NMDA glutamate receptor and (Campral/Aotal; an antagonist of metabotropic glutamate receptors, used to Merck–Serono/ prevent relapse in patients with alcoholism who have stopped Forest Laboratories) drinking198,199 • In a clinical trial, treatment efficacy was particularly high in patients who had a clearly identified goal of achieving abstinence, before starting treatment Varenicline Nicotine 2006 • A partial agonist of the α4β2 nicotinic acetylcholine receptor (Chantix/Champix; used for detoxification and treatment of nicotine addiction200 Pfizer) Nicotine Nicotine • Oral slow release nicotine from nicotine chewing gum or replacement lozenges, or percutaneous administration using a nicotine patch therapy facilitates abstinence as an aid to smoking cessation FDA, US Food and Drug Administration; NMDA, N-methyl-d-aspartate.

104 Table 3 | Potential pharmacotherapies derived from preclinical research psychomotor stimulants , and NMDA receptor antago nists also block the longterm potentiation and longterm class candidates depression associated with repeated administration of 105 Dopamine receptor partial • D2 receptor partial agonist (aripiprazole) psychostimulants . Some of these effects have been agonists • D receptor partial agonist 3 linked to increases in AMPA receptors that lack the Modulators of γ-aminobutyric • GABA neurotransmission modulators subunit known as glutamate receptor 2 (GluR2)106. acid (GABA) signalling one prominent hypothesis is that repeated self

Modulators of brain stress • CRF1 antagonist administration of psychostimulants decreases basal systems • Dynorphin antagonist release of glutamate in key brain circuits associated • Neurokinin 1 receptor antagonist with the preoccupation–anticipation (craving) stage Modulators of glutamate • AMPA receptor antagonist (topiramate) of the addiction cycle, but an exaggerated response signalling • NMDA receptor antagonist of glutamate to activity in these circuits could confer • mGluR agonist 107 • mGluR5 receptor antagonist susceptibility to relapse . For example, druginduced reinstatement of drug seeking seems to be mediated by AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; CRF1, corticotropin-releasing factor receptor 1; mGluR, metabotropic glutamate receptor; NMDA, N-methyl-d-aspartate. a glutamatergic projection from the prefrontal cortex to the nucleus accumbens9. Cueinduced reinstatement of drug seeking involves a glutamatergic projection to Administration of a κopioid receptor antagonist the nucleus accumbens from both the basolateral amy had no effect on baseline selfadministration of limited gdala and the ventral subiculum108,109. In addition, in access cocaine or heroin in primates96, but blunted the cocainetreated mice, there was less strengthening of increased selfadministration of cocaine in rats with synaptic transmission in ventral tegmental area slices extended access to the drug (S. wee et al., in the press). from mice that lacked mGluR1 or the NMDA receptor A κopioid receptor antagonist also selectively blocked subunit NR1 in dopamine neurons, suggesting a direct the increase in ethanol selfadministration associated dopamine neuron target produced by glutamatergic with withdrawal in alcoholdependent rats97. plasticity110. Neuromodulatory systems that oppose the actions Additional evidence that AMPA or kainate receptors of CRF in modulating stress and emotional behaviour mediate glutamate modulation in addiction comes from could also be future targets for addiction treatment. a ‘top–down’ perspective. Clinical trials of topiramate, These include neuropeptide Y and nociceptin systems, in an anticonvulsant with some glutamate antagonist which agonists reduce the excessive drinking associated activity, have reported decreases in drinking behaviour with alcohol dependence98,99. Targeting the receptor sys in alcohol dependence and improvements in quality of tem for substance P, known as the neurokinin 1 receptor life, but with significant adverse effects on memory and (NK1R; also known as TACR1) system, which modulates concentration111,112. In preclinical studies, topiramate emotional states, provides an example of a translational decreased alcohol consumption and preference113 and approach100. NK1Rknockout mice backcrossed onto a decreased stressinduced increases in alcohol consump highdrinking strain of mice showed a major decrease tion and preference in mice114. However, topiramate also in voluntary alcohol consumption, and recently detoxi decreased saccharin preference, increased water intake fied subjects with alcohol dependence and treated with and failed to block conditioned place preference to alco an NK1R antagonist showed decreased craving, blunted hol113,115. Together, these results suggest that topiramate cortisol responses and decreased functional magnetic can interact with both withdrawalinduced negative resonance imaging (fMRI) responses to affective stimuli. affective states and the rewarding effects of ethanol. This suggests that NK1R may be a viable therapeutic target Pharmacological agents that modulate glutamate for the treatment of the dark side of addiction. function may not only have a role in the basal hypoexcita bility or hyperexcitability of glutamatergic systems during Glutamate modulators. Glutamate is thought to have protracted abstinence, depending on the drug of abuse, several roles in the neurobiology of addiction, many of but may also decrease drug and cueinduced reinstate which provide potential targets for medications develop ment of drug selfadministration. To this end, antagonists ment. At low doses, ethanol may act as an NMDA of AMPA receptors, NMDA receptors and metabotropic (Nmethyldaspartate) receptor antagonist, which could glutamate receptor 5 (mGluR5), and agonists of mGluR2 contribute to the acute rewarding effects of ethanol102. and mGluR3, all of which decrease glutamate function, Acute and protracted abstinence from ethanol described have been shown to block cueinduced reinstatement of in alcohol dependence models seems to involve over drug selfadministration116–119. active glutamatergic systems, which are thought to be Given the side effects associated with direct gluta a target for the therapeutic effects of acamprosate39,102,103 matergic antagonists, drugs that modulate the system (TABLE 4). may be more promising candidates for the treatment of Glutamate has also long been associated with the addiction. Agents that can restore homeostasis to systems neuro plasticity that is important for behavioural sensitization associated with both the withdrawal–negative affect (dark Behavioural sensitization to drugs of abuse, particularly psychostimulants. AMPA side) stage and the preoccupation–anticipation (crav An increased drug-induced locomotor response or drug (αamino3hydroxy5methyl4isoxazole propionic ing) stage would be optimal. Studying the withdrawal– reward response with repeated acid) receptor antagonists and NMDA receptor antago negative affect stage of the addiction cycle reveals numerous administration. nists block the development of locomotor sensitization to targets for pharmacotherapy development for addiction.

Table 4 | Effects of drugs on animal models of the motivational components of the addiction cycle* Naltrexone Acamprosate cRF Noradrenaline gABA Metabotropic receptor receptor receptor glutamate antagonist antagonist modulator receptor agonist Baseline drinking ↓201 No effect202 No effect75 ↓80 ↓203 ↓204 Dependence- ↓98 ↓205 ↓75 ↓80 ↓56 Not determined induced drinking cue-induced ↓206 ↓207 No effect206 Not determined ↓208 ↓117 reinstatement Stress-induced No effect206 Not ↓206 ↓209 Not ↓117 reinstatement determined determined *Using alcoholism as an example. CRF, corticotropin-releasing factor; GABA, γ-aminobutyric acid.

A similar case can be made for the preoccupation–antici none has proved reliably effective in clinical trials123. pation stage using the neurobiological targets identified To date, little or no work has been done on treatments for here7. However, in both domains, a limiting step for clini marijuana dependence. cal development is the progression from identifying pre other measures, such as impulsivity, could be con clinical targets to testing in humans. sidered endophenotypes of the binge–intoxication stage and have some potential for predicting which pharma Human laboratory studies cotherapies could have efficacy for addiction treatment. A crucial step in medications development is the sub Impulsivity can increase the probability that an individual mission of an investigational new drug (IND) applica will engage in initial drug intake, and the subsequent tion to the uS Food and Drug Administration (FDA), effects of the drug on impulsivity may increase impulsive or its equivalent in other countries, so that the drug can behaviours that facilitate further drug use, prolonging be tested in humans. See Supplementary information the binge or even provoking relapse (discussed below). S2 (box) for further information regarding INDs for Various tasks have been used to assess impulsivity, pharmacotherapies for the treatment of addiction. including delayed discounting (that is, whether subjects Human laboratory studies provide a potentially show a relative preference for smaller, more immediate power ful means of exploring treatment targets for spe rewards over larger, more delayed rewards), behavioural cific components of the addiction cycle without the inhibition (for example, the Stop Task124) and attentional need for expensive doubleblind, placebocontrolled measures (that is, whether subjects show increased vari trials. They can potentially predict efficacy measures of ability in performance in a simple reaction time task that potential treatments for each stage of the addiction cycle reflects ‘lapses in attention’). (TABLES 1,4). Although the predictive validity of human laboratory models remains to be determined, ongoing The withdrawal–negative affect stage. For the with studies with established medications for addiction can drawal–negative affect stage, negative reinforcement be used in a Rosetta Stone approach to evaluate the mechanisms are in operation. Numerous human labo validity of animal and human models. Human labora ratory measures of acute withdrawal have proved to be tory models can also then serve as a springboard for the sensitive to drug substitution125. In the laboratory, mari development of new pharmacotherapies. juana withdrawal is alleviated by marijuana smoking or by administration of oral Δ9tetrahydrocannabinol The binge–intoxication stage. For the binge–intoxica (THC)126. Cognitive measures are sensitive to withdrawal tion stage of the addiction cycle, selfadministration pro effects of drug dependence during acute and protracted cedures for cocaine, heroin and marijuana in humans abstinence, and can be considered to be another endo have been established largely using operant responding phenotype of the addiction process that could be used in paradigms, in which participants who are dependent on medication screening127 (TABLE 1). Nicotine can improve a drug make a behavioural response such as pressing a cognitive processing and reduce negative affect128. The key on a computer to receive the drug120. As in animal cascade of stress hormone interactions with drugs of models, heroin selfadministration is reduced by all abuse — which can facilitate the binge–intoxication three medications approved by the FDA to treat opioid stage, exaggerate the withdrawal–negative affect stage, dependence — methadone, naltrexone and buprenor and cause sensitization to stressinduced relapse — may phine (Subutex; Schering–Plough) — supporting the all be amenable to human laboratory studies129. predictive validity of the animal models121,122. However, for cocaine, support for the validity of these models is The preoccupation–anticipation (craving) stage. For less robust. A range of medications have been shown to the preoccupation–anticipation stage, three main exter Endophenotype reduce the subjective effects and craving associated with nal factors (priming doses of drug, drugassociated Measurable components, unseen by the unaided eye, cocaine but do not decrease cocaine selfadministration cues and stressor exposure) and two internal factors 120 along the pathway between itself . These results are consistent with clinical data (the malaise of protracted abstinence and an associated disease and genotype. showing that, of more than 60 medications tested, state of stress that contributes to malaise) are thought to

contribute to relapse. Several human laboratory pro alcohol or nicotine146,147. Preliminary results suggest

cedures have been developed to reflect these aspects of that an α2adrenoceptor agonist and an antagonist of the preoccupation–anticipation stage. Drug reinstate sympathetic signalling, but not naltrexone, significantly ment has been developed in human laboratory models, decreased stressinduced opioid craving in subjects notably for alcohol and tobacco addiction. Priming dependent on opioids148. These results support the con induced drinking in alcoholdependent subjects in a struct and predictive validity of this laboratory model barlike setting was greater than in social drinkers and for stressinduced craving. Future studies crossreferencing was selectively decreased in the alcoholdependent pharmacological probes from the animal and human groups by administration of opioid antagonists130. studies should provide an excellent basis for translational Similar results were observed in individuals who were advances. dependent on alcohol, had a family history of alcohol exploration of the interaction of cue exposure with dependence and received a priming dose of alcohol131, emotional states during protracted abstinence has pro and in cigarette smokers primed with five cigarettes132. vided a novel approach to the study of cue reactivity in exposure to alcohol cues, such as the sight or smell alcohol craving57,149. A sample of nontreatmentseeking of alcoholic beverages using the cue reactivity paradigm, subjects with alcohol dependence was exposed to reliably increases the urge to drink alcohol, salivation affective stimuli that had positive or negative valence and attention to cues57,133,134. Furthermore, cue reactivity (that is, they produced emotional responses that were can predict treatment outcome135 and has been validated positive or negative in nature) and then to a beverage in some cases using medications that successfully treat cue but with no opportunity to selfadminister alcohol. alcohol dependence. For example, naltrexone, but not Cue reactivity was measured using subjective measures topiramate, blocked cue reactivity in subjects with alco of craving, measures of emotional reactivity and psycho hol dependence134,136, and nicotine replacement therapy physiological measures. Alcohol exposure and both posi decreased craving associated with smoking cues137. other tive and negative emotional cues had the expected effects drugs not currently in therapeutic use for addiction have on subjective and emotional reactivity, and related effects shown positive results with cueinduced reactivity para on psychophysiological measures57. Gabapentin signifi digms, including carbamazepine (Tegretol; Novartis) for cantly decreased subjective craving and craving that was alcohol138 and amantadine for cocaine139. affectively evoked, and improved several measures of Stress responses, including changes in the activities sleep quality57. These results suggest that affective prim of the hypothalamic–pituitary–adrenal axis and extra ing, combined with alcohol cue exposure, could provide a hypothalamic brain stress systems, affect all phases of the powerful means to evaluate potential pharmacotherapies addiction cycle but may be particularly relevant to both for addiction treatment. the withdrawal–negative affect stage and the preoccupa Another novel approach involves measuring resistance tion–anticipation stage. Stress and stressors have also been to relapse in humans. The ‘smoking lapse behaviour’ associated with relapse and vulnerability to relapse129,140. model allows the measurement of two crucial features Negative affect, stress or withdrawalrelated distress also of relapse: the ability to resist the first cigarette and sub increases drug craving57,135,141,142. Both stress and drugs of sequent smoking behaviour150. Subjects with nicotine abuse activate the hypothalamic–pituitary–adrenal axis, dependence are first exposed to precipitants of smoking but the glucocorticoid response becomes blunted with relapse, such as alcohol, stress and nicotine deprivation, chronic highdose drug use. High glucocorticoid tone can, and then their ability to resist smoking when presented in turn, drive the brain stress systems in the amygdala129. with their preferred brand of cigarettes is measured150. Thus, drugs of abuse can trigger a cascade of stress hor This model remains to be validated with existing anti mone interactions that can facilitate the binge–intoxica craving medications but provides an intriguing exten tion stage and exacerbate the withdrawal–negative affect sion of cue reactivity studies that could be useful as stage. They may also cause hypersensitivity of brain stress an intermediary step between preclinical models and systems that contribute to maintaining the withdrawal– clinical trials. negative affect stage and sensitize the individual to stress An evolving area in human laboratory relapse models induced relapse. All of these changes may be amenable to is the measurement of neural correlates of cues for study in humans in a laboratory setting. relapse. Increased functional brain activation elicited Stressrelated responses and stressinduced craving by drugassociated cues, as measured in brain imaging have been elicited in individuals with an addiction studies, may correlate with an increased risk of relapse. using a new model of stressinduced responsivity with Cueinduced functional activation of the brain can be an emotional imagery paradigm142 based on the early assessed by measuring changes in cerebral blood flow work of lang and colleagues143. In this paradigm, indi with positron emission tomography or single photon viduals using the higher amounts of cocaine and alcohol emission computed tomography, or by combining and subjects recovering from an alcohol dependence blood flow measurements with fMRI. Core regions showed greater craving and physiological responses activated in most studies include the anterior cingulate, to stressors than control social drinkers144. Perhaps of orbitofrontal cortex, basolateral amygdala, ventral stria greatest importance in terms of paradigm validation, tum and dorsal striatum5. Strong cueinduced activa stressinduced cocaine craving in the laboratory could tion of similar regions, including the ventral striatum, be used to accurately predict time to relapse145. Similar dorsal striatum, medial prefrontal cortex and anterior results have been observed for subjects dependent on cingulate, has been observed in subjects with alcohol

In a separate series of studies, an association was Box 2 | Genetic association studies — two examples found between single nucleotide polymorphisms of the

µ-opioid receptor gene that encodes CRF1 and binge drinking in adoles • In transfected AV-12 cells, A118G substitution leads to increased receptor affinity cents and in adults with an alcohol dependence155. one for β-endorphin154 of these single nucleotide polymorphisms, R1876831, • A118G substitution is associated with higher pain thresholds and greater is located in an intron that could potentially influence requirements for opioid medication163 (BOX 2) transcription of the gene that encodes CRF1 . • Subjects with A118G substitution show greater response to alcohol and opioid antagonists164,165 Clinical trials: challenges and opportunities • A118G substitution does not predict vulnerability to alcoholism166 Doubleblind, placebocontrolled trials with random • Subjects with the A118G single nucleotide polymorphism had a significantly greater assignment to treatments are the accepted standard for cortisol response to naloxone167 determining pharmacotherapy efficacy. A number of unique features of clinical trials for medications to treat corticotropin-releasing factor receptor 1 (cRF ) 1 addiction need to be emphasized. These include a lack • Adolescent subjects homozygous for the C allele of R1876831 drank more alcohol per of consensus about clinically relevant outcome measures, occasion and had higher lifetime rates of heavy drinking in response to negative life events than subjects carrying the T allele168 admission criteria and methods for detecting relapse to use of substances between study visits. Additionally, • Increased expression of CRF is associated with higher intake of ethanol in animal 1 general issues related to medication compliance, placebo studies169,170 response and dropout rates present challenges for the • CRF antagonists block increased ethanol intake associated with acute withdrawal 1 design of clinical trials in addiction. There are also and protracted abstinence in animal studies75,170 safety and tolerability issues that are specific to addic tion, including the potential interaction of alcohol or other substances of abuse with the pharmacotherapy dependence who have repeatedly suffered relapses151,152. under study. even more intriguingly, reduced functional activation of the ventral striatum in response to cues that signal Outcome measures. The choice of the outcome for nondrug rewards was observed in individuals with which a pharmacotherapy is likely to show efficacy may alcoholism, suggesting a shift in incentive salience to be guided by results from preclinical models of addiction drugrelated cues153. Imaging studies may therefore and human laboratory studies. For example, naltrexone provide unique insights into subjects who exhibit the is thought to reduce the rewarding effects of drinking most dramatic functional activation in response to such that the individual with an alcohol dependence is cues and, by extrapolation, the subjects who are more no longer motivated to drink heavily. An outcome of likely to relapse. Future studies will need to explore reduced heavy drinking, as opposed to complete absti pharmaco therapeutic approaches to normalizing such nence, is well characterized for naltrexone in human cueinduced responses and whether such measures will laboratory models involving alcohol administration predict therapeutic efficacy in treatment100. and in clinical trials with subjects that are nonabstinent. Conversely, medications such as acamprosate or gaba Genetic variations and medications development pentin, which are thought to support abstinence from widespread attempts are being made to identify genetic alcohol by normalizing activity in a brain pathway that markers for addiction. However, a more exciting possi has become chronically deregulated, have shown efficacy bility is that certain single nucleotide polymorphisms in human laboratory models of cue reactivity but not may predict vulnerability to certain subtypes of excessive in alcohol administration models, and have primarily drinking syndromes and, of particular relevance to this shown efficacy on abstinence outcomes in clinical trials Review, may predict responsiveness to pharmacothera (see below). pies in the treatment of alcoholism. Animal and human Historically, the rate of complete abstinence has been studies are beginning to realize this potential opportunity. the primary outcome measure of pharmacotherapy effi Genetic association studies have focused on two path cacy. However, clinically relevant abstinenceoriented ways: one representing the reward side of addiction (the outcomes also include latency to first lapse, percentage μopioid peptide system) and one representing the dark of abstinence days over the study duration, longest dura side of addiction (the CRF brain stress system). The tion of abstinence during the study, abstinence at the end human μopioid receptor is encoded by the OPRM1 of the study (as indicative of behaviour likely to continue gene and is a primary candidate for causing the phar after the study) and statistical modelling of the trajectory macogenetic variability of the clinical effects of opioid of abstinence over the course of the study. Depending on drugs and opioid receptor antagonists in the treatment the pharmacokinetic properties of the medication (for of addiction. Mutations in OPRM1 have been found in example, time to achieve steadystate serum concentra the promoter, coding regions and introns of the gene. tions), it may be necessary to specify a grace period during one mutation that has received considerable attention which a lapse may occur that would not normally be is the A118G single nucleotide polymorphism, which considered in efficacy determinations. Alternatively, causes an amino acid substitution of asparagine with to ensure an abstinent starting point across all patients, aspartate at position 40 of the μopioid receptor protein detoxification and a brief abstinent interval (for example, (Asn40Asp)154 (BOX 2). 2–5 days) may be required before randomization.

Harm reduction and nonhazardous use of substances transferrin levels in the case of alcohol) have sensitivity are alternative end points for patients that do not have and/or specificity limitations that can contribute to inac abstinence as their treatment goal. Related outcomes may curate estimations of use. A standardized interview using include time to first heavy use, percentage of heavy use a calendar format, typically a variation on the timeline days during the study or statistical models of the trajectory followback interview158, uses prompts such as weekend of heavy use days over the course of the study. versus weekdays, paydays or holidays to assess quantity and frequency of substance use between study visits. Admission criteria. Admission criteria related to pre Periodic interviews with collateral informants such as randomization substance use or abstinence vary as a close friends or relatives of the subject can also be used function of the stage of the addiction cycle that a in conjunction with biological measures to validate pharmaco therapy is thought to target. To show efficacy, the subject’s timeline followback interview selfreport pharmacotherapies that are thought to support abstinence measures of substance use. If discrepancies between through normalization of a brain pathway deregulated sources cannot be resolved, the most negative outcome is by discontinuation of the addictive substance require a typically assumed to be accurate. study sample that has achieved a minimal period of absti nence before randomization (usually 2–5 days to avoid Medication compliance. Medication noncompliance is the effects of acute withdrawal). Conversely, pharmaco not a common factor that influences outcomes in clinical therapies that are predicted to decrease heavy or hazard trials involving addiction. when it occurs, factors such ous use may require a nonabstinent sample with a high as drug tolerability should be assessed if standard meas prerandomization rate of heavy use to show efficacy. ures to ensure compliance have been implemented. Such Safety considerations specific to a medication also measures can include packaging medication in blister influence admission criteria. For example, subjects with cards with day and time of day indicated for each dose, an addiction, especially those dependent on alcohol, identifying frequently missed doses by reviewing unused frequently present for treatment with pathologically medication at every visit or using multiple event monitoring elevated liver function test values. Trials of pharmaco system cap data, linking missed dosing with an activity therapies that are associated with hepatotoxicity (for of daily living, such as meals or brushing teeth, and a example, naltrexone) typically exclude patients with liver suggestion to affirm a commitment to recovery with function test results that are more than three times the every dose. upper limit of the normal range. However, such necessary exclusion criteria may also limit the dependence severity Premature study termination. Part of the definition of in the study sample and the extent to which clinically substance dependence by the Diagnostic and Statistical relevant generalizations can be made. Although women Manual of Mental Disorders, 4th edition (DSM IV) is with childbearing potential are often omitted from clinical an increased risk of relapse, impaired impulse control trials, this group needs to be represented in clinical trials and psychosocial difficulties. Not surprisingly, there of substance dependence because gender can affect drug fore, trials of substance dependence may involve higher efficacy. For example, longacting injectable naltrexone dropout rates than clinical trials of treatments for other showed efficacy in males but not in females in a multi psychiatric disorders. Therefore, incorporating strate centre trial of alcohol dependence156. gies to enhance study completion in order to adequately assess use, safety and efficacy of a pharmacotherapy is Measures of substance use. Measures of substance use important. Such strategies can include a flat rate of mon are another unique aspect of clinical trials for pharmaco etary compensation to offset transportation expenses at therapy development for addiction. urine dipsticks and each visit and a lump sum payment for trial completion handheld analysers of alcohol or carbon monoxide in that is sufficient to be motivating but not coercive, the expired breath can provide an immediate indication of offer of a ~uS$5 value coupon at each visit or system drug use, drinking and cigarette smoking, respectively, atic acknowledgement of the gains the subject is making at the time of a clinical trial research visit. However, (for example, income saved on days of abstinence that most substances of abuse and their active metabolites was previously spent on substances or normalization of (if any) have short halflives, and their use cannot be liver function tests). obtaining comprehensive contact assessed in breath, urine or plasma during the interval information is also prudent. between study visits. one exception is Δ9THC, the primary metabolite of cannabis, which can be present Conclusions and future directions in urine for 1 month after use, potentially resulting in The uS National Institutes of Health (NIH) has promoted an underestimate of abstinence if detected. Because many of the elements required for the development of of such a long halflife, urinary Δ9THC levels can be pharmacotherapies for addiction. To our knowledge, normalized to the urinary creatinine concentration to equivalent programmes do not exist in europe, and should reduce variability in drug measurement owing to urine be encouraged. Areas of success include tremendous Multiple event monitoring dilution157; abstinence is reflected by a reduction in the breakthroughs in the basic neurobiology of addiction, system cap Δ9THC/creatinine ratio across visits. the successful development and validation of behavioural Caps on pill bottles with built-in microelectronics that record Available biomarkers of substance use between study and pharmacological treatments of addiction (such as each date and time the cap is visits (for example, γglutamyl transpeptidase levels, buprenorphine, supported by the National Institute on removed. mean corpuscular volume and carbohydratedeficient Drug Abuse (NIDA), and naltrexone, supported by the

National Institute on Alcohol Abuse and Alcoholism investigations in this area of disease are merited. Increased (NIAAA)), and improved infrastructure for some aspects interaction with NIH in general to pool resources could of pharmacotherapy development. For example, NIDA reduce some of the developmental costs for industry, and has established an extensive clinical trials network (see some mechanisms are clearly underway in the form of Further information for a link to the NIDA clinical trials small business innovation research grants and small busi network website). However, tremendous resources have ness technology transfer grants (see Further information been devoted to the development of pharmacotherapies for a link to the Small Business Innovation Research for cocaine addiction, with little or no success reported (SBIR) and Small Business Technology Transfer (STTR) to date2. It is hoped that the burgeoning use of human programmes). However, more efforts could be made by laboratory studies, outlined above, and the Rosetta Stone industry to partner with the NIH for the development of approach linking human and animal studies promoted medications for addiction treatment. Furthermore, the here will yield better results. pharmaceutical industry should consider allowing com A relevant issue is therefore how the NIH can do more pounds that have been granted IND status but which to help. Several suggestions can be provided on the basis they are no longer developing to be used in proofof of this Review. These include developing a more balanced concept human laboratory studies of addiction. portfolio at the preclinical and clinical stage regarding Thus, there is substantial potential for the development which drugs of abuse should be studied and expanding of future pharmacotherapies for addiction. Medications the development and validation of human laboratory currently on the market for this indication have not studies for potential medications. A major bottleneck only provided information on the opportunities for for testing new medications is obtaining IND approvals facilitating treatment but are also forming a means to for new drugs for human laboratory studies and Phase II evaluate future medications. A combination of validated clinical trials. A core facility like that of the NIDA clinical animal models of addiction and a surge in understanding trials network should be considered for pooling resources the neuro circuits and neuropharmacological mechanisms for IND development, not only by NIDA and NIAAA, involved in the development and maintenance of addic but by all central nervous systemrelated NIH institutes. tion through basic research has provided numerous viable of crucial importance is a scientifically determined and targets for future medications. New neurobiological clinically relevant ‘decision tree’ of which drugs should targets will be derived from this basic research on addic go forward. Such a decision tree could be built on the tion, with a focus on the neuroadaptive changes that framework elaborated here, by incorporating a Rosetta account for the transition to dependence and the vulner Stonelike validation into the strategic planning of the ability to relapse, possibly within a genetic context. we NIH to facilitate translational research. propose that the Rosetta Stone framework outlined here Another key element is that the pharmaceutical could provide a heuristic approach for efficient and effec industry must consider that pharmacotherapies to target tive development of pharmacotherapies for addiction, addiction are potentially profitable. Recent success and promote the flourishing of translational research with acamprosate and varenicline (Chantix/Champix; interactions among independent investigators, the NIH Pfizer) should provide some indication that further and private industry.

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The and Addiction Research and National Institutes of Health polymorphism at the mu-opioid receptor locus modulatory effects of nicotine on parietal cortex activity grants AA12602, AA08459, (R37)AA014028 and AA06420 (OPRM1). Am. J. Med. Gen. B Neuropsych. Genet. in a cued target detection task depend on cue from the National Institute on Alcohol Abuse and Alcoholism, 118B, 60–65 (2003). reliability. Neuroscience 137, 853–864 (2006). DA04043, DA04398, (P20)DA024194 and DA10072 from 168. Blomeyer, D. et al. Interaction between CRHR1 gene 193. Christensen, J. K., Moller, I. W., Ronsted, P., the National Institute on Drug Abuse, DK26741 from the and stressful life events predicts adolescent heavy Angelo, H. R. & Johansson, B. Dose-effect relationship National Institute of Diabetes and Digestive and Kidney alcohol use. Biol. Psychiatry 63, 146–151(2008). of disulfiram in human volunteers. I: Clinical studies. Diseases, and 17RT-0095 from the Tobacco-Related Disease 169. Hansson, A. C. et al. Variation at the rat Crhr1 locus Pharmacol. Toxicol. 68, 163–165 (1991). Research Program from the State of California. The opinions and sensitivity to relapse into alcohol seeking induced 194. Goedde, H. W., Agarwal, D. P. & Harada, S. in expressed in this article by G.K.L. are as an individual and not by environmental stress. Proc. Natl Acad. Sci. USA Isozymes: Current Topics in Biological and Medical as an employee of Nereus Pharmaceuticals. 103, 15236–15241 (2006). Research: Cellular Localization, Metabolism, and 170. Sommer, W. H. et al. Upregulation of voluntary alcohol Physiology Vol. 8 (eds Rattazzi, M. C., Scandalios, J. G. Competing interests statement intake, behavioral sensitivity to stress, and amygdala & Whitt, G. S.) 175–193 (Liss, New York, 1983). The authors declare competing financial interests: see web crhr1 expression following a history of dependence. 195. Volpicelli, J. R., Alterman, A. I., Hayashida, M. & version for details. Biol. Psychiatry 63, 139–145 (2008). O’Brien, C. P. Naltrexone in the treatment of alcohol 171. Koob, G. F., Everitt, B. J. & Robbins, T. W. in dependence. Arch. Gen. Psychiatry 49, 876–880 Fundamental Neuroscience 3rd edn (eds Squire, L. G.et (1992). DATABASES al.). 987–1016 (Academic Press, Amsterdam, 2008). 196. O’Malley, S. S. et al. Naltrexone and coping skills Entrez Gene: 172. Collins, R. J., Weeks, J. R., Cooper, M. M., Good, P. I. therapy for alcohol dependence: a controlled study. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene & Russell, R. R. Prediction of abuse liability of drugs Arch. Gen. Psychiatry 49, 881–887 (1992). OPRM1 using IV self-administration by rats. 197. Hurt, R. D. et al. A comparison of sustained-release UniProtKB: http://www.uniprot.org Psychopharmacology 82, 6–13 (1984). bupropion and placebo for smoking cessation. N. Engl. κ-opioid receptor | μ-opioid receptor | CRF1 | D2 | D3 | NK1R 173. Kornetsky, C. & Bain, G. in Modern Methods in J. Med. 337, 1195–1202 (1997). Pharmacology: Testing and Evaluation of Drugs of 198. Mason, B. J. Acamprosate and naltrexone treatment FURTHER INFORMATION Abuse Vol. 6 (eds Adler, M. W. & Cowan, A.) 211–231 for alcohol dependence: an evidence-based risk- NIDA clinical trials network: http://www.nida.nih.gov/ctn/ (Wiley-Liss, New York, 1990). benefits assessment. Eur. Neuropsychopharmacol. 13, Small Business Innovation Research (SBIR) and Small 174. Tornatzky, W. & Miczek, K. A. Cocaine self- 469–475 (2003). Business Technology Transfer (STTR) programmes: administration “binges”: transition from behavioral and This paper provides an evidence-based risk–benefit http://grants.nih.gov/grants/funding/sbirsttr_programs.htm autonomic regulation toward homeostatic dysregulation assessment of acamprosate and naltrexone in the in rats. Psychopharmacology 148, 289–298 (2000). treatment of alcohol dependence. The safety of the SUPPLEMENTARY INFORMATION 175. Ahmed, S. H. & Koob, G. F. Transition from moderate two drugs in combination is supported by two See online article: S1 (box) | S2 (box) to excessive drug intake: change in hedonic set point. independent double-blind studies, suggesting that All liNkS ARe AcTive iN THe oNliNe PDF Science 282, 298–300 (1998). combination treatment is a realistic goal.

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Supplementary information S1 (box)

Disulfiram—alcoholism Disulfiram is an inhibitor of aldehyde dehydrogenase and is used in the treatment of alcoholism to suppress drinking and prevent relapse. It has a variable therapeutic effect but can be effective under conditions of compliance1. In animal studies, disulfiram decreases alcohol intake, but tolerance develops to the suppression with chronic intake2, and the drug has anxiogenic-like effects3. Both characteristics are possibly relevant for its therapeutic use.

Methadone—opioid addiction Methadone is a mu-opioid agonist with a long oral half-life in humans (22-30 h; racemic mixture used in the clinic) and has been an effective pharmacotherapy for over 40 years for the treatment of opioid addiction4. Methadone has a much shorter half-life in animals. Chronic 5 day treatment in nondependent rhesus monkeys with had little effect on heroin choice functions but prevented withdrawal-associated increases in heroin choice5. Using a slow-release minipump to mimic the pharmacokinetic profile of humans, methadone also blocked cocaine seeking in rats measured by conditioned place preference, responding on a progressive-ratio schedule, and reinstatement at doses that do not have effects on locomotor activity, food intake, or pain responsivity6-8. Human laboratory studies support the clinical observation that persistent heroin use may be reduced by providing larger methadone maintenance doses because such doses completely block the subjective effects of heroin and produce greater withdrawal suppression during outpatient periods9.

Acamprosate—alcoholism Acamprosate is a modulator of hyperglutamatergic function either via an action on the N-methyl-D-aspartate (NMDA) receptor or via an action on metabotropic glutamate receptors10. The preclinical data that led to the clinical studies on acamprosate began with a series of studies in Europe on the effects of acamprosate on excessive drinking in rats. Acamprosate injected chronically decreased alcohol drinking in rats selected for excessive drinking11 and decreased alcohol drinking in dependent rats12. Subsequently, acamprosate was shown to selectively block the increased alcohol drinking associated with withdrawal and alcohol deprivation13-16. Although at high doses acamprosate had effects on baseline drinking in general, the excessive drinking associated with dependence and withdrawal was much more sensitive to the effects of acamprosate.

Naltrexone—alcoholism Naltrexone, a competitive opioid antagonist, has long been known to decrease alcohol consumption in animal models. In an early study, intramuscular administration of naltrexone decreased intravenous alcohol self-administration in rhesus monkeys17. Subsequently, it has been shown to decrease alcohol drinking and self-administration in a variety of animal models18-25. Brain sites particularly effective in the actions of opioid antagonists on alcohol self-administration include the nucleus accumbens, central nucleus of the amygdala, and ventral tegmental area26-28. Human studies have suggested that opioid antagonists may be involved in the direct reinforcing effects of alcohol and also may blunt the urge to drink elicited by presentation of alcohol-related cues in alcoholics29. Naltrexone has been shown to reduce craving for alcohol in a human laboratory study, and this effect may be related

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to its ability to activate the hypothalamic-pituitary-adrenal axis30. Similar results have been observed in a rat model of cue-induced reinstatement in which reexposure to an olfactory stimulus that signaled the availability of alcohol self-administration produced strong reinstatement of responding after extinction31,32. This reinstatement was blocked by systemic administration of naltrexone and a selective mu and δ opioid receptor antagonist. Nalmefene is an orally active opioid antagonist with high affinity for both and κ-opioid receptors. It was shown to decrease heavy drinking in alcoholics in a double-blind, placebo-controlled clinical trial33. Nalmefene is now marketed in parts of Europe for the treatment of alcoholism. Moreover, the efficacy of nalmefene has led to preclinical studies showing greater efficacy in dependent than nondependent animals34 and has increased interest in dynorphin or κ opioid targets for the treatment of alcoholism (see dynorphin discussion below).

Buprenorphine—opioid addiction Buprenorphine, a partial opioid agonist, is an effective maintenance pharmacotherapy for the treatment of opioid addiction35. It has pharmacological properties that provide for a good safety profile, low physical dependence, and flexibility in dose scheduling36,37. The finding that buprenorphine dose-dependently decreased heroin intake in heroin-dependent animals is consistent with predictive validity for the self- administration dependence model38-40. Interestingly, the doses selected for buprenorphine were effective in reducing the self-administration of other drugs of abuse in rats41-44. Buprenorphine decreases intravenous heroin self-administration in human laboratory studies45. From the perspective of the abuse potential of buprenorphine itself, it has reinforcing, discriminative stimulus, and physical dependence-producing effects but is less efficacious than morphine46. Buprenorphine maintains lower breakpoints than full agonists in progressive-ratio self-administration procedures47. Withdrawal from the drug is characterized by a mild morphine-like abstinence syndrome in animals and humans48,49. Buprenorphine may suppress or precipitate withdrawal in animals maintained on chronic administration of a mu agonist48; lower doses suppressed spontaneous withdrawal signs, and higher doses precipitated a mild abstinence syndrome.

Bupropion—tobacco addiction Bupropion, an antidepressant with actions that facilitate dopamine and norepinephrine neurotransmission but not serotonin neurotransmission, has efficacy in smoking cessation treatment. Buprenorphine attenuates nicotine withdrawal in rats50, in which it decreases mecamylamine-precipitated signs of withdrawal and mecamylamine-precipitated place aversions. Bupropion also dose-dependently attenuated the spontaneous nicotine abstinence syndrome50 and reversed nicotine withdrawal effects in contextual fear conditioning51. Perhaps directly relevant to its therapeutic uses, bupropion attenuated the elevation in brain stimulation reward thresholds observed during nicotine withdrawal52,53. Bupropion decreases nicotine self-administration, an effect amplified with repeated administration54. In another study, although bupropion decreased nicotine self-administration, it failed to block cue-induced reinstatement of responding55.

Varenicline—tobacco addiction Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, has efficacy in

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smoking cessation treatment and when combined with nicotine, decreases dopamine release in the nucleus accumbens in vivo by itself and has less efficacy than nicotine in stimulating dopamine release56. Varenicline partially generalizes to nicotine in a drug discrimination study, consistent with its partial agonist mechanism of action57.

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Supplementary information S2 (box)

Investigational new drug application Several aspects of an investigational new drug (IND) application are unique for drugs to be developed for the treatment of addiction. One unique aspect is that the pharmaceutical industry is likely to have other indications for a drug that may be of

significant value to addiction (see discussion of CRF1 antagonists in the main Review). Such a situation has both advantages and disadvantages. The disadvantage is obvious—addiction trials could be seen as counterproductive to the main commercial goal and thus be delayed or eliminated from development. Nevertheless, a reliable mechanism for generating INDs is to have an investigator initiate an IND application on a drug that already has another indication. Approval for studies on addiction is relatively straightforward if the drug is approved for other indications as long as the dose range required for addiction treatment is in the same dose range as the approved medication. This process will also work for drugs approved outside of the United States. A key element and critical point for medications development is submitting an IND application to the FDA, or its equivalent in other countries, so that the drug can be tested in humans. The International Commission on Harmonisation (ICH) developed strict regulations and requirements that have been mandated by the FDA for the testing of a substance (drug) for a previously unapproved therapeutic indication by an investigator. ICH guidelines have also been incorporated by regulatory agencies in most other countries, resulting in a high degree of consistency in the requirements for chemistry, manufacturing, control, safety, and toxicology prior to testing of a drug in humans. In the U.S., the application for the initial clinical testing of a compound by an individual is governed by the sponsor-investigator submission of an IND application. This process involves FDA Forms 1571 and 1572 (complete instructions can be found at http://www.fda.gov/cder/regulatory/applications/ind_page_1.htm; accessed October 10, 2008). The data that must be supplied, in addition to the proposed clinical trial protocol and information on the investigators, include detailed information on the chemistry (i.e., synthesis, formulation, stability), toxicology, pharmacology, and prior human studies.

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