Anti-relapse medications: Preclinical models for drug addiction treatment

Pharmacology & Therapeutics 124 (2009) 235–247

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Pharmacology & Therapeutics

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Associate editor: F. Tarazi

Anti-relapse medications: Preclinical models for drug addiction treatment

Noushin Yahyavi-Firouz-Abadi, Ronald E. See ⁎Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA

Abbreviations: BLA, basolateral amygdala; CPP, cdmPFC, dorsomedial prefrontal cortex; DA, dopamineGlu, glutamate; NAc, nucleus accumbens; VTA, ventral t⁎ Corresponding author. Department of Neurosciences

Medical University of South Carolina, Charleston, SC 29fax: 843 792 4423.

E-mail address: [email protected] (R.E. See).

0163-7258/$ – see front matter © 2009 Elsevier Inc. Aldoi:10.1016/j.pharmthera.2009.06.014

a b s t r a c t
a r t i c l e i n f o
Keywords:
CocaineDrug screeningMethamphetamineReinstatementRelapseSelf-administration
Addiction is a chronic relapsing brain disease and treatment of relapse to drug-seeking is considered themost challenging part of treating addictive disorders. Relapse can be modeled in laboratory animals usingreinstatement paradigms, whereby behavioral responding for a drug is extinguished and then reinstated bydifferent trigger factors, such as environmental cues or stress. In this review, we first describe currently usedanimal models of relapse, different relapse triggering factors, and the validity of this model to assess relapsein humans. We further summarize the growing body of pharmacological interventions that have shownsome promise in treating relapse to psychostimulant addiction. Moreover, we present an overview on thedrugs tested in cocaine or methamphetamine addicts and examine the overlap of existing preclinical andclinical data. Finally, based on recent advances in our understanding of the neurobiology of relapse andpublished preclinical data, we highlight the most promising areas for future anti-relapse medicationdevelopment.

© 2009 Elsevier Inc. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2352. Animal models of relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2363. Drugs tested as anti-relapse medications in animal models . . . . . . . . . . . . . . . . . . . . . . . . 2364. Drugs tested for the treatment of psychostimulant addiction in humans . . . . . . . . . . . . . . . . . . 2365. Summary and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

238241243243

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237244

1. Introduction

Drug addiction is a chronic relapsing disorder, characterized bycompulsive drug-taking and drug-seeking behaviors, despite negativeconsequences (Jaffe, 1990; O'Brien & McLellan, 1996). In addiction orsubstance use disorders, relapse is defined as a return to drug-seeking/taking behavior after a period of self-imposed or forcedabstinence. Addicts often have a persistent vulnerability to relapse todrug use after days or even years of abstinence, and prevention ofrelapse to drug-taking behavior is considered to be the most difficult

onditioned place preference;; GABA, γ-Aminobutyric acid;egmental area., BSB416B, 173 Ashley Avenue,425, USA. Tel.: 843 792 2487;

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aspect in the treatment of addiction (O'Brien, 1997). Treatment ofaddiction usually starts with medical and psychosocial assessmentsand relieving withdrawal symptoms (detoxification) that help thepatient to achieve a drug-free state. However, the most importantissue in addiction treatment is prevention of relapse to drug-taking(O'Brien, 2006). If drug-taking does not resume, homeostaticmechanisms are thought to gradually readapt to the pre-addictivestates (LeBlanc et al., 1969) and many of the enduring effects of priordrug use may fade with time.

Despite clinical progress in treating the physical withdrawalsyndromes produced by abstinence from opiates, alcohol, and nicotine,successful treatments for all drug addictions are either completelylacking or clearly inadequate in terms of controlling the core addictionproblems of drug craving and relapse (Nestler, 2002). Moreover, drugsof abuse produce pathological changes to the brain that can endureeven after long-term cessation of drug use (Hyman & Malenka, 2001;Kalivas & O'Brien, 2008). Consequently, recent preclinical research hasfocused on identifying long-lasting neuroadaptive changes and

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236 N. Yahyavi-Firouz-Abadi, R.E. See / Pharmacology & Therapeutics 124 (2009) 235–247

environmental and neurobiological mechanisms underlying drugrelapse. These efforts may lead to recognition of new treatmentmodalities to prevent relapse. Moreover, recent approaches for thetreatment of relapse in patients involve novel pharmacotherapies inaddition to traditional counseling and psychotherapy (O'Brien, 2008).These medications may be used to blunt the strength of conditionedreflexes that lead to relapse and to enhance the development of newmemories related to natural rewards. Prevention and treatment withvaccines represent another experimental approach that is underinvestigation in clinical trials (Martell et al., 2005; Sofuoglu & Kosten,2006). In this review, we will discuss preclinical findings on medica-tions that may reduce relapse to drug use, as well as relevant clinicaldata.

2. Animal models of relapse

2.1. Methodology

Most of the recent progress in understanding the underlyingmechanisms of addiction and relapse has come from studies withanimal models. Animals readily self-administer most drugs used byhumans and show patterns of drug intake that mimic patterns seen inhuman users (Collins et al., 1984; Caine & Koob, 1993; Deroche-Gamonet et al., 2004). Although no animal model completelysimulates human addiction, a number of laboratories have success-fully developed and applied an animal model, termed the reinstate-ment model, to study factors that underlie relapse. In the learningliterature, reinstatement refers to the resumption of a previouslylearned response (e.g., lever pressing behavior) that occurs when asubject is exposed noncontingently to the unconditioned stimulus(e.g., food or cocaine) after extinction (Bouton & Swartzentruber,1991). Human and experimental animal studies have shown that drugcraving and relapse following extended periods of abstinence arereliably triggered by exposure to: 1) a small, ‘priming’ dose of thedrug, 2) cues previously associated with drug use, or 3) a stressfulevent. Accordingly, laboratory studies in humans have found thatpriming doses of cocaine, heroin, alcohol, or nicotine increased self-reports of craving in users of the respective drugs (Jaffe et al., 1989; deWit, 1996). Moreover, stressful events and exposure to environmentalcues associated with drug-taking behavior are known triggeringfactors to relapse in humans (Shiffman, 1982; Foltin & Haney, 2000;Sinha et al., 2006). Two primary animal models of reinstatement havebeen developed to model relapse to addictive drug-seeking and drug-taking behavior: 1) conditioned place preference (CPP) based onPavlovian conditioning, and 2) self-administration based on operantand Pavlovian conditioning.

2.1.1. Conditioned place preferenceSeveral laboratories have developed reinstatement procedures

using the CPP model in rats and mice. CPP reinstatement paradigmswork on the basis of classical conditioning, as opposed to self-administration paradigms (that are primarily based on instrumentalconditioning) and purportedly models contextual cue-elicited drug-seeking behavior. In this procedure, one compartment is repeatedlypaired with drug injections, while a second distinct compartment ispaired with vehicle. Following training, subjects are given a choicetest between the two compartments. If drug injections are rewarding,the animal will spend more time in the drug-paired environmentduring the test (i.e., a CPP). Then, during the extinction phase, theacquired preference for the drug-paired side is extinguished graduallyby pairing injections of vehicle with both compartments (i.e., drug-associated and vehicle-associated), or by allowing subjects to explorethe drug- and vehicle-associated compartments during daily sessionsin the absence of the drug. Following extinction training, reinstate-ment of conditioned place preference can be induced by exposure todrug or stressors (Wang et al., 2000; Lu et al., 2000; Mueller & Stewart,

2000). The advantage of the CPP reinstatement model is thatnonspecific motor effects of pharmacological manipulations may beless likely to influence behavior as the dependent measure is notoperant-based responding. Moreover, it is methodologically easier,more affordable, can be achieved faster (sometimes by a single drug-context pairing), and is sensitive to relatively low drug doses(Tzschentke, 2007; Aguilar et al., 2009). However, several factorslimit the relevance of this model to compulsive and chronic drug usein humans. First, CPP does not evaluate the primary reinforcing effectsof drugs and drug-taking behavior, as there is no contingent use of thedrug in this model. Related to this problem is the inability todetermine an animal's dynamic changes in drug intake over time.Second, noncontingent drug administration in CPP has differentpharmacokinetic and pharmacodynamic properties than repeatedcontingent drug use in human addicts. Importantly, total exposure tothe drug is relatively low in CPP. Finally, some of the effects of CPPmay reflect state-dependent learning due to discriminative stimuliproperties of the test drug, rather than reinforcing efficacy.

2.1.2. Self-administrationThe most commonly used animal model to study relapse to drug-

seeking is the extinction–reinstatement model following intravenousdrug self-administration. Self-administration models drug-takingbehavior in humans and evaluates the primary rewarding propertiesof drugs. Reinstatement of drug-seeking after extinction implies therestoration of a concrete operant response. In this model, an intra-venous catheter is surgically implanted into a central vein (althoughthe drug can be administered through the oral route, as with ethanol).Drug self-administration (via lever-pressing or nose-poking) istypically continued to reach a stable level of responding. Subsequent-ly, the drug-taking behavior is extinguished by withholding the drugreinforcer (substituting the drug solution with saline or by dis-connecting the infusion pump). After a satisfactory degree ofextinction is achieved (e.g., 20% or less responding during the lastextinction session as compared with the first extinction session), theability of acute exposure to a triggering stimulus (i.e., drug priming,stress, or drug-paired environmental cues) to reinstate operantresponding as a measure of drug-seeking can be determined.Reinstatement is considered to have occurred if the animal respondsat a rate above extinction and shows selectivity on the operandumthat previously delivered the drug (e.g., presses on a previously“active” lever, as opposed to a previously non drug-paired “inactive”lever). Fig. 1 illustrates a schematic graph of the reinstatementparadigm following drug self-administration and extinction.

Reinstatement of drug-seeking has been studied using differentvariations of the reinstatement model (Shalev et al., 2002): between-session,within-sessionandbetween-within-session. In thebetween-sessionparadigm, which is most commonly used, drug self-administration,extinction, and reinstatement tests are conducted during sequentialdaily sessions. In the within-session paradigm, self-administrationtraining (1–2 h), extinction (3–4 h) and reinstatement tests are carriedout on the same day. In the between-within paradigm, self-administra-tion training occurs on different days. However, extinction andreinstatement tests are conducted on the same day after varying daysof withdrawal (Shaham et al., 2003).

A modified relapse model of drug-seeking is one in which animalsundergo forced abstinence in the home cage or an alternate environ-ment without extinction trials following chronic self-administration(Fuchs et al., 2006). This abstinence model may have more directrelevance to addiction in humans, as addicts rarely experience explicitdaily extinction of drug-seeking related to drug-paired cues andcontexts during the withdrawal from drug use. Based on the abovementioned reasons for favoring the self-administration paradigm overCPP, in this review we will focus on studies using the reinstatementmodel in the self-administration paradigm. For a recent review of thereinstatement model in CPP, see Aguilar et al. (2009).

Fig. 1. Experimental paradigm for reinstatement of drug-seeking behavior showing active (drug-paired) lever presses in representative phases of drug self-administration(acquisition and maintenance), extinction, and reinstatement test days (cue-induced, drug-induced, and stress-induced). Animals undergo extinction sessions in between thereinstatement tests.

237N. Yahyavi-Firouz-Abadi, R.E. See / Pharmacology & Therapeutics 124 (2009) 235–247

2.2. Relapse triggering factors

2.2.1. Drug-induced relapseDrug priming injection has been known for a long time to serve as a

potent stimulus to reinstate extinguished drug-seeking behavior (Gerber& Stretch, 1975; de Wit & Stewart, 1981). Priming injections can inducerelapse both after systemic administration and when administereddirectly into specific brain regions, especially the ventral tegmental area(VTA) and the nucleus accumbens (NAc) (Stewart, 1984; Stewart &Vezina, 1988). Several neurotransmitter systems are involved in theregulation of drug-induced relapse, including dopamine (DA), glutamate(Glu), endogenous opioids, γ-Aminobutyric acid (GABA), and endocan-nabinoids. However, growing evidence reveals a convergence on a finalcommoncorticostriatal glutamatergic substrate (Kalivas&Volkow, 2005).Drug-primed reinstatement involves dorsomedial prefrontal cortex(dmPFC) glutamatergic projections to the NAc core and dopaminergicinnervations of the dmPFC (McFarland & Kalivas, 2001). Cumulativeevidence has shown the critical role of corticostriatal glutamatergictransmission in drug-primed relapse for different drugs of abuse,including cocaine and heroin (Knackstedt & Kalivas, 2009).

2.2.2. Stress-induced relapseIn humans, stressful events can trigger relapse to drug-seeking/

taking behavior (Shiffman, 1982; Shiffman et al., 1996; Sinha et al.,1999). Likewise, stress-induced reinstatement in laboratory animalshas been used as a model to study relapse in human subjects (Erbet al., 1996; Shaham et al., 2000a; Koob & LeMoal, 2001). Stress can beinduced by a variety of precipitating factors, but in animal models,intermittent footshock (Erb et al., 1996; Piazza & Le Moal, 1998;McFarland et al., 2004) or pharmacologically-induced stress (Leeet al., 2004; Shepard et al., 2004; Feltenstein & See, 2006) have beenthe most successfully used stressors in the reinstatement paradigm(Epstein et al., 2006). Neurocircuits involved in stress-triggeredrelapse are thought to include the lateral tegmental noradrenergicnuclei (Shaham et al., 2000b) and their noradrenergic projectionsthrough the ventral noradrenergic bundle (Moore & Bloom, 1979) tothe central nucleus of the amygdala, bed nucleus of stria terminalis,hypothalamus, medial septum, and NAc (for review, see Shaham et al.,2003). As with drug-primed reinstatement, a final common glutama-tergic corticostriatal pathway is engaged during stress-inducedreinstatement (McFarland et al., 2004).

2.2.3. Cue-induced relapseA major factor in relapse to drug-seeking/taking is re-exposure to

sensory cues previously associated with drug-taking. Accordingly,

cue-triggered reinstatement of drug-seeking in animal models hasbeen used as a powerful tool to simulate relapse in human addicts(See, 2002). Different types of cuesmay induce reinstatement of drug-seeking behavior, including discrete cues, discriminative cues, andcontextual cues. In studies on discrete cue-induced reinstatement,each drug delivery is paired with presentation of discrete cues (e.g.,lights or tones). Lever pressing is then extinguished in the absence ofthe cues and reinstated upon re-exposure to the cues. Drug-pairedstimuli can be presented either as conditioned reinforcers and/or asdiscriminative stimuli. In the discriminative cue-induced procedure,rats are trained to self-administer a drug or saline in the presence ofdistinct sets of discriminative stimuli in which one set of stimulisignals drug availability (S+) and the other set of stimuli signalssaline availability (S−). Extinguished lever pressing (produced in theabsence of the discriminative stimuli) can later be reactivated byexposure to the S+ stimuli only (Weiss et al., 2000). For contextualreinstatement (also known as “renewal”), animals first learn to self-administer the drug in the presence of a distinct set of environmentalstimuli (drug-paired context) that act as occasion setters for theavailability of the drug, and drug-reinforced behavior is thenextinguished in the presence of a different context (extinctioncontext). These contexts are different in their tactile, visual, auditory,and/or olfactory features. Re-exposure of the subject to the drug-paired context then reinstates drug-seeking (Crombag et al., 2002;Fuchs et al., 2005).

Dopaminergic and glutamatergic projections from the VTA,basolateral amygdala (BLA), dmPFC, and NAc core appear to be theprimary pathways mediating conditioned-cued reinstatement, al-though a number of other neurotransmitter systems have also beenimplicated (recently reviewed in Feltenstein & See, 2008). Determin-ing the neural circuitry that underlies conditioned-cued reinstate-ment may help to elucidate the neurobiological basis of drug cravingthat addicts experience upon exposure to paraphernalia (e.g.,syringes, needles, smoking pipes) or the context in which theypreviously obtained and consumed the drug. Identification of thedistinct neurocircuits that underlie learned drug–cue associations willhelp discover and test potential anti-craving pharmacotherapies(O'Brien & Gardner, 2005).

In summary, although the neurocircuitries involved in drug-, cue-,and stress-induced reinstatement are distinct in a number of aspects,the cumulative findings indicate that projections from the VTA (allforms of reinstatement), regions of the BLA (cue reinstatement), andthe central amygdala, bed nucleus of the stria terminalis, and NAcshell (stress reinstatement) converge on motor pathways involvingglutamatergic projection from the dmPFC to NAc core that represents


a ‘final common pathway’ for all three types of instigating factors inrelapse (Kalivas &McFarland, 2003; Shaham et al., 2003; Feltenstein &See, 2008). Moreover, enhanced synaptic release of Glu fromterminals of prefrontal cortex neurons following all three triggeringfactors provokes reinstatement of drug-seeking (Knackstedt &Kalivas, 2009). Thus, pharmacological modulation of substrates thatmodulate these circuits may yield potentially useful therapeuticmodalities.

2.3. Validity of the reinstatement model of relapse

A major concern in the interpretation of preclinical results is theability to extend these findings to human subjects. In this section, webriefly describe the validity of reinstatement models. Several detailedreviewson validity assessment of relapsemodels have been previouslywritten on this important issue (Epstein & Preston, 2003; Katz &Higgins, 2003; Epstein et al., 2006). The ability to predict humanbehavior based on animal data is expressed in the predictive validity ofthe available animal models and can reflect a given model's capabilityto find new therapeutic options for human subjects (Willner, 1984;Markou et al., 1993; Geyer & Markou, 1995; Sarter & Bruno, 2002;Epstein et al., 2006). Numerous studies have shown considerablesimilarity of relapse-provoking factors (drugs, drug-associated cues,and stress) between animals and humans (Epstein et al., 2006),indicating a reasonable level of predictive validity for animal models.Nonetheless, the ability of existing animal models to guide newtreatments for humans, particularly for psychostimulant addiction,remains controversial (Katz & Higgins, 2003; O'Brien & Gardner, 2005;McKay et al., 2006). Amajor limitation is the general absence of clinicalstudies that are equivalent in design to basic animalmodel studies. Forinstance, while a common design in the animal model experiments, ahistory of defined abstinence and especially extinction training (alsoreferred to as exposure therapy) rarely exists in subjects enrolled inclinical studies (Conklin & Tiffany, 2002). The reason in part is thatabstinence requires expensive and often unavailable hospitalizations,and extinction procedures have been generally ineffective in sub-stance abusers (Conklin & Tiffany, 2002), although this issue remainsto be settled. In addition, measured outcomes frequently differbetween clinical (changes in drug intake or subjective effects of thedrug) and animal (relapse to drug-seeking behavior) studies (Epstein& Preston, 2003). Furthermore, other factors related to the multifac-torial nature of relapse need to be considered in applying obtainedanimal model data to clinical studies of relapse (Epstein & Preston,2003). For example, blockade of stress-induced reinstatement ofalcohol-seeking in rats by fluoxetine (Le et al., 1999) does notnecessarily result in prevention of relapse in human alcoholicstriggered by other factors (Kranzler et al., 1995). In addition to thelimited parallel design features in basic and clinical studies, many ofthe drugs tested in animal models of reinstatement have simply notyet been tested in clinical trials. This fact makes current criticisms ofthe ability of this model to screen medications premature.

The degree of similarity in the underlying biological mechanismsof behavior between animal and human subjects for a given conditioncan be referred to as construct validity (Sarter & Bruno, 2002; Epsteinet al., 2006). High construct validity, in addition to high predictivevalidity, is important to recognize appropriate drug treatments withthe desired mechanism(s) of action (Russell, 1964; Sarter & Bruno,2002; Epstein and Preston, 2003). In spite of the noticeable homologyin the neuroanatomy of reinstatement of drug-seeking in rats(Feltenstein & See, 2008) and drug craving in human studies asdetermined by in vivo brain imaging (Volkow et al., 2004), muchfuture work is needed in order to establish the construct validity ofreinstatement models of relapse, as is the case for all existing animalmodels of neuropsychiatric diseases (Willner, 1984; Geyer & Markou,1995).

For clinicians, identification of effective pharmacotherapies withlimited side effects and abuse potential by themselves constitutes amajor priority in the transition from animal model studies. Unfortu-nately, several drugs that had been shown to be effective in primaryinvestigations failed in clinical trials. These failures suggest that theanimal models result in a high rate of false positives. As alreadymentioned, this lack of concordance could be largely due to the paucityof relevant clinical data. Clinical trials including extinguishedor formerabstinent drug users are rare, difficult to conduct, and the few that doexist have usually testedmedications never tested in animalmodels ofrelapse. Therefore, while of clear concern, it remains premature toreject the reinstatement model for generation of false positives.

Notably, promising results from the translational use of animalmodel data have been obtained in pharmacotherapy of dependence toheroin using naltrexone (Comer et al., 2006), methadone (Leri et al.,2004), and buprenorphine (Sorge et al., 2005). Similar promisingresults have been seen for two potential treatments for nicotineaddiction: rimonabant, a cannabinoid CB1 receptor antagonist(Fagerstrom & Balfour, 2006), and varenicline, a partial nicotinereceptor agonist (Spiller et al., 2009). Arguably the most successfulresults of a translational approach have been achieved in thetreatment of alcohol dependence, where naltrexone blocks relapseboth in rats (Volpicelli, 1995; Le et al., 1999) and humans (Streeton &Whelan, 2001; Latt et al., 2002) with a history of chronic alcoholconsumption. Clinical usage of acamprosate (Sass et al., 1996;Tempesta et al., 2000) for alcohol dependence was also based onanimal model findings (Spanagel et al., 1996; Holter et al., 1997).However, the efficacy of acamprosate has not been supported in arecent large clinical trial (Anton et al., 2006). As for psychostimulants,the reinstatement model has not yet identified any clearly efficacioustreatments for relapse prevention. However, as we will discuss below,a number of clinical trials have evaluated the therapeutic potential ofdifferent drugs on cocaine dependence and found encouraging resultsin reducing ongoing drug intake, relieving withdrawal symptoms, andprolongation of abstinence.

3. Drugs tested as anti-relapse medications in animal models

Over the past several years, a growing number of investigationshave assessed the effects of different drugs on reinstatement of drug-seeking behavior using self-administration and relapse. One broadapproach has been the determination of the neurocircuitries under-lying various types of reinstatement to drug-seeking as produced bycues, stress, or drugs. Therefore, these studies have examined theeffects of direct pharmacological interventions in specific brain regions(usually localized receptor antagonism or inhibition) on drug-takingand drug-seeking. Other studies have adopted approaches to screenpotential medications that may block the acquisition, maintenance, orreinstatement of drug-taking and drug-seeking. Since relapse preven-tion is themost difficult and critical part of addiction treatment, animalmodel studies of possible anti-relapse medications will continue to bea major focus of preclinical research. At the current time, mostprevious studies in animal models have focused on cocaine self-administration and relapse. Although some studies have been carriedout in primates, most of the existing data comes from studies in rats.We have summarized the studies that have evaluated potentialmedications for relapse to cocaine-seeking in Tables 1 and 2,categorized based on their mechanisms of action. Table 1 includesthe studies that have assessed systemic administration of monoam-inergic drugs on reinstatement of cocaine-seeking, which includesdrugs with primary receptor selectivity for central DA, serotonin, and/or norepinephrine systems. Table 2 summarizes results from otherclasses of drugs, including compounds that act on Glu, GABA, opioid,cannabinoid, and other neurotransmitters or neuromodulators. Asseen in Tables 1 and 2, themost commonly studied drugs to date act onDA, Glu, or serotonin systems. Drugs were administered systemically

Table 1Effects of different systemic monoaminergic (dopamine, serotonin, norepinephrine) drugs on the reinstatement of cocaine-seeking in rats induced by cocaine, cue, stress, or context.

Class of drug Drug Route and dose Effect Reference

Dopamine ABT-431 (D1 agonist) 1 or 3 mg/kg, s.c. ↓ cocaine Self et al., 2000SKF-81297 (full D1 agonist) 3 mg/kg, s.c. ↓ cue, ↓ cocaine Alleweireldt et al., 2002, 2003SKF-38393 (partial D1 agonist) 3 mg/kg, s.c. ↔ cue Alleweireldt et al., 2002SCH-23390 (D1 antagonist) 10 µg/kg, s.c. ↓ cue Alleweireldt et al., 2002

5 or 10 µg/kg, s.c. ↓ context Crombag et al., 20021–10 µg/kg, s.c. ↔ cocaine Schenk and Gittings, 2003

LEK-8829 (D1 agonist/D2 antagonist) 0.1–1 mg/kg, i.v. ↓ cocaine Milivojevic et al., 2004Eticlopride (D2 antagonist) 0.3 mg/kg, i.p. ↓ cocaine Schenk and Gittings, 2003Raclopride (D2 antagonist) 0.1 or 0.3 mg/kg, s.c. ↓ cue Cervo et al., 2003

50 or 100 µg/kg, s.c. ↓ context Crombag et al., 2002Haloperidol (D2 antagonist) 0.2 mg/kg, p.o. ↓ cue Gal and Gyertyan, 2006Aripiprazole (partial D2 agonist) 0.1–15 mg/kg, i.p. ↓ cue Feltenstein et al., 2007

0.25–15 mg/kg, i.p. ↓ cocaine Feltenstein et al., 2007Levo-tetrahydropalmatine (l-THP)(D1/D2 antagonist)

3.75 or 7.5 mg/kg, i.p. ↓ cocaine Mantsch et al., 200720 mg/kg, i.p. ↓ cocaine Xi et al., 2007

BP897 (D3 partial agonist/D2 antagonist) 1–3 mg/kg i.p. ↓ cue Cervo et al., 2003; Gilbert et al., 2005;Gal and Gyertyan, 2006

S33138 (partially selective D3 antagonist) 0.156–2.5 mg/kg, p.o. ↓ cocaine Peng et al., 20091-methyl-1,2,3,4-tetrahydroisoquinoline 50 mg/kg, i.p. ↓ cocaine Antkiewicz-Michaluk et al., 2007RGH-237 (D3 partial agonist) 10 or 30 mg/kg, p.o. ↓ cue Gyertyan et al., 20077-OH-DPAT (D3 agonist) 0.1 or 0.3 mg/kg, i.p. ↓ cue Cervo et al., 2003

1 or 3 mg/kg, i.p. ↑ cue Cervo et al., 2003SB-277011-A (selective D3 antagonist) 5–30 mg/kg, i.p. or p.o. ↓ cue Gilbert et al., 2005; Gal and Gyertyan,

2006; Cervo et al., 20073–24 mg/kg, i.p. ↓ cocaine Vorel et al., 2002; Xi et al., 20053–12 mg/kg, i.p. ↓ stress (footshock) Xi et al., 2004

NGB 2904 (D3 antagonist) 0.1–5.0 mg/kg, i.p. ↓ cue Gilbert et al., 2005; Xi and Gardner, 2007↓ cocaine Xi et al., 2006b; Xi and Gardner, 2007

Serotonin RU24969 (5-HT(1B/1A) agonist) 1 or 3 mg/kg, s.c. ↓ cue, ↓ cocaine Acosta et al., 2005SB 216641 (5-HT(1B) antagonist) 2.5–7.5 mg/kg, i.p. ↓ cue Przegalinski et al., 2008

↓ cocaineWAY 100,635 (5-HT(1A) antagonist) 0.1–1.0 mg/kg, s.c. ↔ cue Cervo et al., 2003; Burmeister et al., 2004

0.1–1.0 mg/kg, s.c. ↓ cocaine Schenk, 2000; Burmeister et al., 2004GR 127935 (5-HT(1B) antagonist) 2.5–10 mg/kg, s.c. ↓ cue Przegalinski et al., 2008

↓ cocaineRo 60-0175 (5-HT(2B/C) agonist) 0.1–1 mg/kg, i.p. ↓ cue Burbassi and Cervo, 2008

↓ stress Fletcher et al., 20080.3–3 mg/kg, s.c. ↓ context Fletcher et al., 2008

SB 242,084 (5-HT(2C) antagonist) 1.0 mg/kg, i.p. ↔ cue Burmeister et al., 2004↔ cocaine

Ketanserin (5-HT(2A/C) antagonist) 10.0 mg/kg, i.p. ↓ cue Burmeister et al., 2004↔ cocaine

M100907 (volinanserin) (5-HT(2A) antagonist) 0.5 mg/kg, s.c. ↓ cocaine Fletcher et al., 20020.001–0.8 mg/kg, i.p. ↓ cue Nic Dhonnchadha et al., 2009

SR 46349B (5-HT(2A) antagonist) 0.5–1 mg/kg, s.c. ↓ cue Filip, 2005↓ cocaine

SDZ SER-082 (5-HT(2C) antagonist) 0.25–1 mg/kg, i.p. ↔ cue Filip, 2005↔ cocaine

MK 212 (5-HT(2C/2B) agonist) 1.0 mg/kg, i.p. ↓ cue Neisewander and Acosta, 2007↓ cocaine

Ritanserin (5-HT(2) antagonist) 1.0 or 10.0 mg/kg, i.p. ↔ cocaine Schenk, 2000Fluoxetine (5-HT reuptake inhibitor) 10.0 mg/kg, i.p. ↓ cue Burmeister et al., 2003

↔ cocaine30 mg/kg, i.p. chronic ↔ cocaine Baker et al., 2001

↓ contextD-fenfluramine (SRI/releaser) 3.0 mg/kg, i.p. ↓ cue Burmeister et al., 2003

↔ cocaineNorepinephrine Clonidine (alpha2 agonist) 20 or 40 µg/kg, i.p. ↓ stress Erb et al., 2000

↔ cocaineLofexidine (alpha2 agonist) 50–200 µg/kg, i.p. ↓ stress Erb et al., 2000

↔ cocaine0.1 or 0.2 mg/kg, i.p. ↓ stress (speedball) Highfield et al., 2001

↔ cue (speedball)Guanabenz (alpha2 agonist/lowaffinity imidazoline1 ligand)

0.64 mg/kg, i.p. ↓ stress Erb et al., 2000↔ cocaine

Prazosin (alpha1 antagonist) 0.3 mg/kg, i.v. ↓ cocaine Zhang and Kosten, 2005Yohimbine (alpha2 antagonist) 1.25 mg/kg, i.p. (extinction) ↔ stress (footshock) Kupferschmidt et al., 2009


via different routes of administration (i.p., s.c., and p.o.). In a fewstudies, drug treatment was chronic (e.g., daily) or via a minipumpinfusion. Moreover, in a few cases, discrepancies exist in the results ofdifferent studies conducted on the same drug that could be due todifferent dosage, pretreatment timing, and/or route of administration.

In addition to cocaine studies, a limited number of studies haveassessed the effects of various drugs on the reinstatement ofmethamphetamine-seeking, and these are summarized in Table 3.

It is noteworthy that most of the existing studies on putative anti-relapse medications have only evaluated the effects of acute drug

Table 2Effects of non-monoaminergic classes of drugs on the reinstatement of cocaine-seeking in rats induced by cocaine, cue, stress, or context.


Glutamate (inotropic) 6-cyano-7-nitro-quinoxaline-2,3-dione(CNQX) (AMPA/kainate antagonist)

3 mg/kg, i.p. ↓ cue Backstrom and Hyytia, 2006

NBQX (AMPA/kainate antagonist) 5 mg/kg, i.p. ↓ cue Backstrom and Hyytia, 2006L-701,324 (NMDA/glycinesite antagonist)

1.25 or 2.5 mg/kg, i.p. ↓ cue Backstrom and Hyytia, 2006

CGP 39551 (NMDA antagonist) 2.5–10 mg/kg, i.p. ↔ cue Backstrom and Hyytia, 2006D-CPPene (competitiveNMDA antagonist)

3 mg/kg, i.p. ↓ cue Bespalov et al., 2000

Memantine (low-affinityNMDA channel blocker)

10 mg/kg, i.p. ↔ cue Bespalov et al., 2000

Glutamate (metabotropic) 2-methyl-6-(phenylethynyl)-pyridine(MPEP) (mGluR5 antagonist)

2.5 or 5 mg/kg, i.p. ↓ cue Backstrom and Hyytia, 2006

MTEP, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]piperidine (mGluR5 antagonist)

0.3–10 mg/kg, i.p. ↓ cocaine Martin-Fardon et al., 2009

LY379268 (mGluR2/3 agonist) 1 or 3 mg/kg, i.p. ↓ cocaine Peters and Kalivas, 2006Glutamate (other) N-acetylcysteine (activates

cystine-glutamate exchange)100 mg/kg, i.p. ↓ cocaine Baker et al., 2003a,b60 mg/kg, s.c. Moran et al., 200560 mg/kg, i.p. (dailyin self-administration)

Madayag et al., 2007

Acamprosate 300 mg/kg, i.p. ↓ cocaine, ↓ cue Bowers et al., 2007GABA Baclofen (GABAB agonist) 1.25 or 2.5 mg/kg, i.p. ↓ cocaine Campbell et al., 1999

2.5–5 mg/kg, i.p. ↓ cocaine Filip et al., 2007b; Filip et al., 2007c5 mg/kg, i.p. ↓ cue Filip and Frankowska, 2007

SCH 50911 (GABAB antagonist) 10 mg/kg, i.p. ↓ cocaine Filip and Frankowska, 2007↓ cue

SKF 97541 (GABAB agonist) 0.03–0.3 mg/kg, i.p. ↓ cocaine Filip and Frankowska, 2007↓ cue

CGP 7930 (GABAB allostericpositive modulator)

30 mg/kg, i.p. ↓ cocaine Filip and Frankowska, 200710 or 30 mg/kg, i.p. ↓ cue

Gabapentin (cyclic GABA analogue) 10–30 mg/kg, i.p. ↔ cocaine Filip et al., 2007c25–200 mg/kg, i.p. Peng et al., 2008b

Tiagabine (GABA reuptake inhibitor) 10 mg/kg, i.p. Nonsignificant Filip et al., 2007c↓ cocaine

Vigabatrin (gamma-vinyl GABA)(irreversible inhibitor of GABAtransaminase and reuptake)

150–250 mg/kg, i.p. ↓ cocaine Filip et al., 2007c25–300 mg/kg, i.p. Peng et al., 2008a

Alprazolam 2 or 4 mg/kg, i.p. ↓ cue Goeders et al., 2009Oxazepam 20 or 40 mg/kg, i.p. ↓ cue Goeders et al., 2009

Opioid JDTic (kappa antagonist) 10 or 30 mg/kg, s.c. ↓ stress (footshock) Beardsley et al., 2005↔ cocaine

Naltrexone 0.25–2.5 mg/kg, s.c. ↓ cue Burattini et al., 20081.6 or 3.2 mg/kg, s.c. ↔ cocaine Comer et al., 19933 mg/kg, s.c. ↓ cocaine Gerrits et al., 2005

Buprenorphine 0.025–0.4 mg/kg, i.v. ↓ cocaine Comer et al., 19933 mg/kg/day, minipump s.c. ↓ cocaine Sorge et al., 2005

↔ stress (footshock)Etonitazene (opioid agonist) 2.5 or 5.0 µg/kg, i.v. ↓ cocaine Comer et al., 1993Methadone 30 mg/kg/day, minipumps ↓ cocaine and heroin

in mixed self adminLeri et al., 2004

↔ stressNociceptin/orphanin FQ (NC)(endogenous ligand of theopioid receptor-like1 (ORL1)

0.1–2.0 µg/kg, i.c.v. ↓ stress (footshock) Martin-Fardon et al., 2000

BD1047 (sigma1 antagonist) 20 or 30 mg/kg, i.p. ↓ cocaine Martin-Fardon et al., 2007U69593 (kappa-opioid agonist) 0.32 mg/kg, s.c. ↓ cocaine Schenk et al., 1999, 2000

Cannabinoid Rimonabant (CB1antagonist/partial agonist)

10 mg/kg, i.p. ↓ cocaine Filip et al., 20065 or 10 mg/kg, i.p. ↓ cue

AM251 (CB1 antagonist) 1–10 mg/kg, i.p. ↓ cocaine Xi et al., 2006aWIN 55,212-2 (CB agonist) 0.3 mg/kg, i.p. ↑ cue Gonzalez-Cuevas et al., 2007

3 mg/kg, i.p. ↔ cue

Hormones Progesterone 0.5 mg/kg, s.c. ↓ cocaine inovariectomized rat

Anker et al., 2007

↓ cocaine in estrousfemales

Anker et al., 2009Feltenstein et al., 2009

Estradiol benzoate 0.05 mg/kg, s.c. ↑ cocaine inovariectomized rat

Anker et al., 2007Larson et al., 2005

Dehydroepiandrosterone (DHEA) 2 mg/kg, i.p. ↓ cocaine Doron et al., 2006Diarylpropionitrile(ERbeta-selective agonist)

1 mg/kg, i.p. ↑ cocaine Larson and Carroll, 2007

Propyl-pyrazole-triol (PPT)(ERalpha-selective agonist)

1 mg/kg, i.p. ↔ cocaine Larson and Carroll, 2007

Corticosterone 50 mg pellets, p.o. ↓ stress (food deprivation)in adrenalectomized rats

Shalev et al., 2003

Allopregnanolone 15 or 30 mg/kg, s.c. ↓ cocaine Anker et al., 2009


Table 2 (continued)


Other systems SB-334867 (orexin1 antagonist) 30 mg/kg, i.p. ↓ stress (footshock) Boutrel et al., 2005D-Phe CRF12-41 (CRF antagonist) 0.1–1 µg/kg, i.c.v. ↓ stress (footshock) Erb et al., 1998

0.1 or 1 µg/kg, i.c.v. ↓ cocaineCP-154,526 (CRF1 antagonist) 20 mg/kg, i.p. ↓ cue Goeders and Clampitt, 2002

5–20 mg/kg, i.p. ↓ cocaine Przegalinski et al., 200515 or 30 mg/kg, s.c. ↓ stress (footshock) Shaham et al., 1998

RP 67580 (neurokinin 1 antagonist) 0.1–2.5 nmol, i.c.v. ↔ cocaine Placenza et al., 2005GR 82334 (neurokinin 1 antagonist) 2–50 pmol, i.c.v. ↔ cocaine Placenza et al., 2005Albu-CocH enzyme (humanbutyrylcholinesterase (BChE) fusionwith human serum albumin)

2 mg/kg, i.v. ↓ cocaine Brimijoin et al., 2008

SR142948 (neurotensinreceptor antagonist)

10 µg/kg, i.p. ↓ cocaine Torregrossa and Kalivas, 2008

1-methyl-1,2,3,4-tetrahydroisoquinoline(1MeTIQ)

25–50 mg/kg, i.p. ↓ cocaine Filip et al., 2007a↔ cue

Ketoconazole (adrenal steroidsynthesis inhibitor)

25 mg/kg, i.p. ↓ cue Goeders and Clampitt, 200250 mg/kg, i.p. ↔ cocaine Mantsch and Goeders, 1999b25 or 50 mg/kg, i.p. ↓ stress Mantsch and Goeders, 1999a

2E2 (anti-cocaine monoclonalantibody (mAb))

120 mg/kg, i.v. ↓ cocaine Norman et al., 2009

L-NG-nitroarginine methylester (L-NAME) (nitric oxidesynthase inhibitor)

50 mg/kg, i.p. ↓ cocaine Orsini et al., 2002


administration on different forms of reinstatement. Only a small num-ber of available studies have administered drugs in a chronic regimenduring the period of cocaine self-administration or prior to reinstate-ment. The use of repeated drug administration provides a much morehomologous approach, as treatment regimens in humans almost alwayscontinue for multiple days or even more prolonged time periods. In afewpreclinical studies, drugswere chronically administeredbefore eachself-administration session and acutely on reinstatement tests withdifferent results. For example, acute administration of acamprosateblockedboth cocaine- and cue-induced reinstatement; however, chron-ic daily administration of acamprosate prior to each self-administrationsession had no effect on cocaine intake (Bowers et al., 2007). In anotherstudy, adenosine agonists exerted inhibitory effects on drug-takingduring self-administration, but facilitated the reinstatement of cocaine-seeking (Knapp et al., 2001). These results likely relate to the differencesin the neurocircuitry underlying self-administration, extinction, andreinstatement. Some recent studies have tested repeated drug admin-istration prior to reinstatement testing. Gonzalez-Cuevas et al. (2007)administered a cannabinoid agonist (WIN 55,212-2) subchronicallyduring abstinence and observed enhanced context- and cue-inducedreinstatement of cocaine-seeking with higher doses, but no effect withlowerdoses. In addition, chronicfluoxetine treatmentduringabstinenceattenuated cue-, but not cocaine-induced reinstatement of cocaine-seeking (Baker et al., 2001). Moreover, rats maintained chronically onmethadone (Leri et al., 2004) or buprenorphine (Sorge et al., 2005)

Table 3Effect of systemic administration of different drugs on the reinstatement of methamphetam

Drug Dose and rout

SR141716A (CB1 antagonist) 3.2 mg/kg, i.p.1 mg/kg, i.p.

Delta8-tetrahydrocannabinol (THC) (cannabinoid agonist) 3.2 mg/kg, i.p.AM251 (CB1 antagonist) 0.032–0.32 mgDiclofenac (cyclooxygenase inhibitor) 3.2 or 10 mg/kNaltrexone 1 mg/kg, i.p.

3.2 mg/kg, i.p.Ondansetron (5-HT3 antagonist) plus pergolide (dopamine agonist) 0.2 mg/kg, s.c.MTEP (mGluR5 antagonist) 1 or 3 mg/kg,Lobeline 1 or 3 mg/kg,Nicotine 0.1 or 0.32 mgDonepezil (acetylcholinesterase inhibitor) 0.1 or 0.32 mgKetoconazole (adrenal steroid synthesis inhibitor) 25–100 mg/kgCP-154,526 (CRF1 antagonist) 20 or 40 mg/k

showed reductions in both heroin- and cocaine-induced reinstatementof drug-seeking. Finally, chronic N-acetylcysteine administration duringdaily extinction sessions led to enduring inhibition of cue- and heroin-induced reinstatement of heroin-seeking (Zhou&Kalivas, 2008). Futuretesting and development of anti-relapse medications will requirecareful assessment of chronic dosing regimens at various timepointsand for various forms of relapse.

4. Drugs tested for the treatmentof psychostimulant addiction in humans

Currently, no medications have been approved by the Food andDrug Administration (FDA) for the treatment of psychostimulantaddiction. Several clinical studies have been conducted on possiblemedications that might be efficacious in the treatment of cocaine/methamphetamine addiction. Table 4 summarizes some of thecompounds that have been administered in controlled clinical trialsof cocaine and methamphetamine addiction categorized based ontheir mechanism of action. Here, we briefly describe results from anumber of the drugs that have been recently tested.

Studies in animals have consistently shown that enhancement ofGABA activity reduces cocaine self-administration (Filip et al., 2007c;Peng et al., 2008a). Preliminary results from clinical trials using baclofen,a GABAB receptor agonist, and topiramate, which activates GABAA

receptors, have shown some success in reducing cocaine use in human

ine (meth) seeking behavior in rats induced by meth or cue.

e Effect Reference

↓ meth Anggadiredja et al., 2004a↓ cue↓ cue, ↓ meth Anggadiredja et al., 2004a

/kg, i.v. ↔ meth Boctor et al., 2007g, i.p. ↓ cue, ↓ meth Anggadiredja et al., 2004a

↓ cue Anggadiredja et al., 2004b↔ meth

, 0.1 mg/kg, s.c. respectively ↓ meth Davidson et al., 2007i.p. ↓ cue, ↓ meth Gass et al., 2009i.v. ↔ meth Harrod et al., 2003/kg, s.c. ↓ meth, ↓ cue Hiranita et al., 2004/kg, i.p. ↓ meth, ↓ cue Hiranita et al., 2006, i.p. ↔ meth, ↔ cue Moffett and Goeders, 2007g, i.p ↓ meth, ↔ cue Moffett and Goeders, 2007

Table 4Controlled clinical trials of potential therapeutics in cocaine and/or methamphetamine addicts.

Class of drug Drug # patients Specific diagnoses Result Reference

GABA Baclofen 70 Cocaine dependent ↓ cocaine use in heavier users Shoptaw et al., 2003115 Severe cocaine dependent ↔ negative urine screen and craving Kahn et al., 2009

Tiagabine 45 Cocaine and opiate dependenton methadone maintenance

↑ negative urine screen Gonzalez et al., 2003

50 Cocaine and opiate dependenton methadone maintenance

↓ cocaine intake and↑ abstinence rate

Gonzalez et al., 2007

Topiramate 40 Cocaine dependent ↑ rate of abstinence Kampman et al., 2004Vigabatrin 20 Cocaine or methamphetamine

dependent↑ rate of abstinence Brodie et al., 2003

30 ↑ negative urine screen Brodie et al., 2005Dopamine Bupropion 106 Cocaine and opioid dependent,

on methadone maintenance↑ negative urine screen Poling et al., 2006

151 Methamphetamine dependent ↑ rate of abstinence Elkashef et al., 2008Disulfiram 122 Cocaine and alcohol dependent ↑ duration of abstinence Carroll et al., 1998

20 Cocaine and opiate dependent,on buprenorphine maintenance

↑ duration of abstinence George et al., 2000

67 Cocaine and opiate dependent,on methadone maintenance

↓ self-reported use Petrakis et al., 2000

121 Cocaine dependent ↑ negative urine screen Carroll et al., 2004Levodopa/carbidopa 161 Cocaine dependent ↑ negative urine screen in

patients treated with voucherbased reinforcement therapy

Schmitz et al., 2008

Opioid Buprenorphine 178 Cocaine and opiate dependent ↑ negative urine screen Montoya et al., 2004Serotonin/norepinephrine Desipramine 160 Cocaine and opioid dependent,

on methadone maintenance↑ negative urine screen Kosten et al., 2003

Serotonin Citalopram 76 Cocaine dependent ↑ negative urine screen Moeller et al., 2007Norepinephrine Propranolol 108 Cocaine dependent ↑ duration of abstinence and Kampman et al., 2001

199 ↓ withdrawal symptoms Kampman et al., 2006Unknown (glutamate?) Modafinil 62 Cocaine dependent ↑ negative urine screen Dackis et al., 2005

210 ↑ negative urine screen in patientswithout alcohol dependence

Anderson et al., 2009

Vaccine TA-CD Vaccine 18 Cocaine dependent ↑ negative urine screen Martell et al., 2005


subjects (Shoptaw et al., 2003). Moreover, a clinical laboratory studyshowed that baclofen reduced cocaine self-administration in non-opioiddependent, non-treatment-seeking cocaine addicts (Haney et al., 2006).However, baclofen did not help to initiate abstinence in heavy cocainedependent subjects in a recent clinical trial (Kahn et al., 2009).Topiramate reduced cocaine use and increased negative urine tests inan open label (Johnson, 2005), and a controlled clinical trial (Kampmanet al., 2004). In addition, vigabatrin, an inhibitor of GABA transaminase,showed promising effects in three open label studies of cocaine- and/ormethamphetamine-dependent outpatients (Brodie et al., 2003; Brodieet al., 2005; Fechtner et al., 2006). Controlled clinical trials are underwayto further evaluate the effects of vigabatrin (Brodie et al., 2005). It shouldbe noted that while visual safety for short term use in cocaine addicts isestablished (Fechtner et al., 2006), peripheral field damage with longterm use is possible (The Royal College of Ophthalmologists, 2008).While facilitation of GABA activity shows evidence for reducing cocaineuse, it is interesting to note that tiagabine, which blocks presynapticGABA release, also decreased cocaine use and increased abstinence ratesin two controlled clinical trials (Gonzalez et al., 2003; Gonzalez et al.,2007).

Several recent studies have tested various dopaminergic agents inthe treatment of psychostimulant addiction. Bupropion, a nonselec-tive DA reuptake inhibitor, showed variable effects in two differentcontrolled trials in cocaine-opiate dependent individuals (Margolinet al., 1995; Poling et al., 2006). DA precursor treatment via L-dopa/carbidopa combination failed to reduce cocaine use or craving in threerandomized, double-blind trials (Shoptaw et al., 2005; Mooney et al.,2007), but showed some promising effects in combination withbehavioral therapy (Schmitz et al., 2008). Several researchers havealso evaluated the effects of second generation antipsychotic drugs oncocaine use and craving. Although risperidone and olanzapine havebeen shown to diminish euphoria associated with cocaine intake orcraving triggered by cocaine-associated cues in human laboratorystudies (Smelson et al., 2004; Smelson et al., 2006), they failed to

reduce cocaine use in controlled clinical trials (Kampman et al., 2003;Grabowski et al., 2004; Reid et al., 2005). Aripiprazole is a novelantipsychotic drug that acts as a partial agonist at both DA D2 and5HT1A receptors. We recently showed that acute treatment witharipiprazole blocked both cocaine- and cue-induced reinstatement ofcocaine-seeking in rats (Feltenstein et al., 2007). In addition,aripiprazole has shown initial promising effects in reducing cocainecraving (Beresford et al., 2005; Vorspan et al., 2008) and clinical trialsare currently underway to further examine its effectiveness. As notedin Table 1, DA D1-like receptor agonists attenuated both cocaine- andcue-induced reinstatement in rat models (Spealman et al., 1999; Selfet al., 2000; Alleweireldt et al., 2002). One of these agonists (DAS-431,also called adrogolide) is under investigation in cocaine dependentsubjects (Heidbreder & Hagan, 2005).

Another major approach to psychostimulant addiction has beenthe evaluation of drugs with some similar pharmacological propertiesas abused psychostimulants to suppress withdrawal symptoms andprevent relapse (i.e., “agonist replacement therapy”). Methylpheni-date is an approved medication for the treatment of attention deficithyperactivity disorder that blocks catecholamine reuptake. Methyl-phenidate showed some beneficial effects in reducing cocaine useonly in cocaine dependent patients with comorbid attention deficithyperactivity disorder (Levin et al., 2007). As noted in Table 4,disulfiram, a DA metabolism inhibitor, has been reported to reducecocaine use in cocaine addicts with or without concurrent alcohol oropiate dependence (Carroll et al., 1998; George et al., 2000; Petrakiset al., 2000; Carroll et al., 2004). However, disulfiram also enhancescardiovascular responses to cocaine and thus produces cardiovascularside effects if combined with cocaine, although this risk may be lessthan originally estimated (Malcolm et al., 2008). Another recenttreatment approach involves modafinil, which possesses stimulant-like activity and a complex pharmacodynamic profile that involvesenhanced Glu activity (Dackis et al., 2005). As shown in Table 4,modafinil has been reported to reduce cocaine use in comparison with


placebo (Dackis et al., 2005). However, a recently completed multi-site, controlled clinical trial revealed that this effect is only significantin patients without alcohol dependence (Anderson et al., 2009). Onthe other hand, in one human laboratory study, pre-treatment withmodafinil decreased cocaine discrimination (Malcolm et al., 2006).Another study found a reduction in cocaine self-administration innontreatment-seeking cocaine-dependent individuals after modafiniltreatment (Hart et al., 2008). In addition, dextroamphetaminetreatment decreased cocaine intake in cocaine- or cocaine/heroin-dependent subjects (Shearer et al., 2003; Grabowski et al., 2004).Finally, oral formulations of cocaine have been shown to decrease thesubjective and physiological responses to cocaine (Walsh et al., 2000).

In addition to primarily targeting psychostimulant addiction, a fewcompounds have been tested in patients with codependency to bothcocaine and opiates. The opioid partial agonist, buprenorphine, hasbeen found to reduce cocaine self-administration in monkeys (Mello& Negus, 2007) and decreased the use of opiates and cocaine inopiate-cocaine dependent individuals (Montoya et al., 2004). Anotherexample is desipramine, a tricyclic antidepressant that reducedcocaine use in opiate-cocaine co-dependent patients maintained onbuprenorphine (Kosten et al., 2003).

A somewhat different approach has been the development ofvaccines that target cocaine, methamphetamine, nicotine, phencycli-dine, or morphine (Orson et al., 2008). Vaccines act by producingantibodies that bind to the drug during subsequent exposures andthereby block or reduce the rate of drug entry into the CNS. Animalstudies have shown that conjugate vaccines can produce an adequateamount of antibody and can inhibit both reinstatement and locomotoractivity after drug re-exposure (Carrera et al., 2000; Norman et al.,2009). In human studies, TA-CD vaccine (cholera toxin B conjugatedcocaine preparation) significantly reduced cocaine effects duringhuman laboratory trials and decreased cocaine use in outpatienttreatment programs, while concurrently exhibiting good immunoge-nicity, safety, and efficacy (Orson et al., 2008). Moreover, earlypreclinical studies of methamphetamine are underway and havedemonstrated various effects onmethamphetamine self-administrationin rats (McMillan et al., 2004; Orson et al., 2008; Duryee et al., 2009).

In summary, although none of the drugs mentioned above has yetbeen approved for the treatment of psychostimulant addiction,several compounds have shown initial promising results in controlledclinical trials. Some of these drugs ameliorate withdrawal symptomsand reduce cocaine reinforcement, thus appearing to be bettercandidates for abstinence initiation (e.g., modafinil and bupropion).Other drugs (particularly GABA enhancing agents such as topiramateand vigabatrin) may increase unpleasant side effects and/or reducecocaine reinforcement and craving. Such compounds may act moreeffectively for relapse prevention. Given the relatively limited data onall of these compounds, and significant side effects for some, morethorough assessments will be required to identify the best possiblecandidates for wider application in treatment.

In addition to drugs with published preliminary data on clinicalefficacy, several classes of compounds identified in reinstatement studiescould provide promising clinical leads. As noted in Tables 1 and 2, primeexamples includeDAD3 antagonists, CRF1 receptor antagonists,mGluR2/3 receptor agonists, mGluR5 antagonists, N-acetylcysteine, and dualdopamine/serotonin releasers such as PAL-278 (Rothman et al., 2008).

5. Summary and conclusions

Despite the large direct and indirect costs of drug addiction onsociety, the development of adequate pharmacotherapies for addic-tion has not yet been successful. In fact, from a pharmacotherapydevelopment perspective, addiction has been largely neglected by thepharmaceutical industry. Treatment of relapse to drug-seeking anddrug-taking is considered the most difficult and critical part oftreating addictive behaviors. In this review, we focused on animal

models of relapse that may be applied for the testing of novel anti-relapse medications and we summarized the growing body ofpharmacological interventions that have shown some promise intreating relapse in psychostimulant addiction. In assessing thesummated literature on the overlap of available preclinical andclinical data, it is apparent that while a scientific framework has beenestablished, a great deal of careful preclinical and clinical studies willneed to be conducted to further assess potential medications.

As mentioned earlier, notable gaps exist between the approachesused in animal models of relapse and clinical research on relapseprevention. Although there has been a rapid increase in the number ofrecent reinstatement studies that focused on identifying potentialpharmacological treatments for relapseprevention, preclinical scientistsneed to systematically direct new efforts toward medication screening.Several procedural issues must be considered in future studies. Asalluded to earlier in this review, most preclinical investigations haveonly tested acute drug administration. However, in almost all clinicalpsychiatric conditions, medications are chronically administered.Therefore, future animal studies should strive to assess the effects ofboth acute and repeated administration of the test drug. Greaterconsideration of pharmacokinetic issues is also warranted, given theimportance of pharmacokinetics in clinical pharmacology. Continuedrefinement of reinstatement procedureswill also improve the relevanceof animal model studies for application in the clinical arena. Forexample, prior studies on stress-induced reinstatement in animals havemostly used intermittent footshock (Erb et al., 1996; Piazza & Le Moal,1998; McFarland et al., 2004) as a stressor, while human studies haveused image-guided scripts or social stress tests (Li et al., 2005; Sinhaet al., 2005).Weandothers have found that stress-inducing compounds,notably yohimbine, can readily reinstate drug-seeking in rats andmonkeys (Lee et al., 2004; Shepard et al., 2004; Feltenstein & See, 2006).This same experimental technique can be used to pharmacologicallyprovokecraving states in humandrug addicts (Stineet al., 2001), andweare currently using this “cross-species” approach in parallel studies totest anti-relapsemedications for stress-activated relapse and craving inboth rats and humans.

For the development of clinical studies, clinicians could makebetter use of the preclinical data as a guide for future drug targets.Clinical trials could also be designed with greater homology to pre-clinical experiments in terms of study design, specificity of outcomemeasures, and inclusion of abstinent former users. Despite resourcelimitations, more clinical trials of stimulant addiction treatmentshould start with baseline abstinence. Medications could be selectedbased on promising findings in preclinical screening studies and thepropensity to relapse should be measured in real-time. Theseapproaches will also help to elucidate predictive validity of thismodel. Since different medications may block only a specific form ofreinstatement of drug-seeking in animalmodels, clinicians should alsoconsider polypharmacy as a viable approach.

In conclusion, numerous drugs have shown promise in preclinicalmodels of relapse that warrant further clinical evaluations as suchcompounds become available. New advances in our understanding ofthe neurobiology of addiction and relapse will continue to guide themost promising areas for future drug development. Furthermore, itseems that the gap between basic and clinical research in terms ofanti-relapse medication development could be narrowed by anincrease in translational research and increased crosstalk betweenpreclinical and clinical investigators. The fruit of such endeavorswould be the identification and application of truly successfulpharmacotherapies for addictive disorders.

Acknowledgments

Research by the authors has been supported by NIH grantsDA10462, DA15369, DA16511, DA21690, and DA22658. The authorsalso would like to thank Robert Malcolm, Carmela Reichel, and Pouya


Tahsili-Fahadan for their invaluable comments on earlier versions ofthis review.

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