Pregabalin reduces cocaine self-administration and relapse to cocaine seeking in the rat

Pregabalin reduces cocaine self-administration andrelapse to cocaine seeking in the rat

Giordano de Guglielmo1, Andrea Cippitelli1, Lorenzo Somaini2, Gilberto Gerra3, Hongwu Li1,Serena Stopponi1, Massimo Ubaldi1, Marsida Kallupi1 & Roberto Ciccocioppo1

Pharmacology Unit, School of Pharmacy, University of Camerino, Via Madonna delle Carceri, Camerino, Italy1, Addiction Treatment Centre, Health Local Unit,Biella, Italy2 and Drug Prevention and Health Branch, Division for Operations, United Nations Office on Drugs and Crime, Vienna, Austria3

ABSTRACT

Pregabalin (Lyrica™) is a structural analog of g-aminobutyric acid (GABA) and is approved by the FDA for partialepilepsy, neuropathic pain and generalized anxiety disorders. Pregabalin also reduces excitatory neurotransmitterrelease and post-synaptic excitability. Recently, we demonstrated that pregabalin reduced alcohol intake and preventedrelapse to the alcohol seeking elicited by stress or environmental stimuli associated with alcohol availability. Here, wesought to extend these findings by examining the effect of pregabalin on cocaine self-administration (0.25 mg/infusion) and on cocaine seeking elicited by both conditioned stimuli and stress, as generated by administration ofyohimbine (1.25 mg/kg). The results showed that oral administration of pregabalin (0, 10 or 30 mg/kg) reducedself-administration of cocaine over an extended period (6 hours), whereas it did not modify self-administration of food.In cocaine reinstatement studies, pregabalin (10 and 30 mg/kg) abolished the cocaine seeking elicited by both thepharmacological stressor yohimbine and the cues predictive of cocaine availability. Overall, these results demonstratethat pregabalin may have potential in the treatment of some aspects of cocaine addiction.

Keywords Cocaine, GABA, pregabalin, rat, relapse, self-administration.

Correspondence to: Roberto Ciccocioppo, School of Pharmacy, Pharmacology Unit, University of Camerino, Via Madonna delle Carceri, 62032 Camerino,Italy. E-mail: [email protected]

INTRODUCTION

Cocaine addiction is a major health and social problem.Although consistent effort has been made in the develop-ment of new pharmacotherapies for cocaine addiction,no medications for its treatment have been approved. Therewarding effects of cocaine are mediated by inhibition ofdopamine (DA) reuptake in the mesolimbic DA system,which originates from the ventral tegmental area (VTA)in the midbrain and projects to the nucleus accumbens(NAc) and other forebrain regions (Wise 1996; Gardner2000). For this reason, most of the pharmacotherapeuticstrategies investigated for the treatment of cocaine addic-tion have focused on the DA system, but they have beenfound to be ineffective (Grabowski et al. 2000; Haneyet al. 2001; Nann-Vernotica et al. 2001; Gorelick,Gardner & Xi 2004).

In addition to the direct effect on DA neurotransmis-sion, cocaine also produces an inhibitory effect on theGABAergic neurons in the VTA and NAc (Cameron &

Williams 1994; Henry & White 1995; Kiyatkin & Rebec2000), which has been thought to play an important rolein cocaine reward and relapse (Carlezon & Wise 1996;Kalivas & McFarland 2003; Shaham et al. 2003).

Therefore, it has been proposed that pharmacologicalelevation of g-aminobutyric acid (GABA) levels in thebrain or augmentation of GABAergic neurotransmissionmay represent a potential approach to counteract cocainereward and seeking. Consistent with this view, it wasreported that manipulation of GABA activity caused theinhibition of various cocaine-related addictive behaviors(Roberts, Andrews & Vickers 1996; Giorgetti et al. 1998;Gasior, Ungard & Witkin 1999; Di Ciano & Everitt 2003).For example, the GABA-B positive modulator GS39783decreased psychostimulant conditioned-reinforcementand conditioned-reward (Halbout et al. 2011). Alterna-tive approaches for the treatment of cocaine addictioninclude the use of anti-epileptics, such as carbamazepine,topiramate, gapabentin and many others (Preti 2007;Somaini et al. 2011). Various rationales have prompted

ORIGINAL ARTICLE

bs_bs_bannerAddiction Biologydoi:10.1111/j.1369-1600.2012.00468.x

© 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction Addiction Biology

the use of these drugs. Among others, the ability of thesedrugs to reduce neuronal hyperexcitability through inhi-bition of various ion channels (Stahl 2004). The use ofthese drugs has led to mixed results. In some cases, theseanti-epileptics were effective (Hart et al. 2004; Haney et al.2005; Brodie et al. 2009; Somaini et al. 2011), while onthe other hand, clinical studies with reserpine as well asgabapentine showed ineffectiveness in reducing cocaineuse (Berger et al. 2005; Bisaga et al. 2006; Gonzalez et al.2007). Furthermore, two recent meta-analysis studiesconfirmed a general lack of efficacy of these agents forcocaine addiction (Minozzi et al. 2008; Alvarez et al.2010).

Pregabalin (Lyrica, Pfizer, Italy) is a close structuralanalog of gabapentin and thus of GABA, and it hasshown promise in the treatment of a number of patho-logical conditions associated with neuronal hyperactivity.The drug has received marketing authorization foradjunctive treatment of epilepsy, for the treatment ofperipheral neuropathic pain and more recently for gener-alized anxiety disorders. Several large randomized andplacebo-controlled clinical trials have demonstrated thatpregabalin is well-tolerated and is effective for each ofthese conditions (Dworkin et al. 2003; Pande et al. 2003,2004; Lesser et al. 2004; Rosenstock et al. 2004;Beydoun et al. 2005; Pohl et al. 2005; Richter et al. 2005;Rickels et al. 2005). Of note, clinical evidence supportingthe efficacy of pregabalin and gabapentin in the treat-ment of addiction has recently been demonstrated. Forexample, small open-label clinical studies demonstratedthat pregabalin treatment reduced the severity of alcoholwithdrawal symptoms and blunted the cravings associ-ated with early abstinence (Addolorato & Leggio 2010;Di Nicola et al. 2010). In addition, the results from arecent randomized double-blind study showed thatpregabalin facilitated alcohol abstinence with anefficacy similar to naltrexone (Martinotti et al. 2010),while gabapentin has been demonstrated to be effectivefor treating the protracted abstinence phase in alcoholdependence (Mason et al. 2009). These clinical find-ings were supported by experiments in our laboratory,in which we showed that pregabalin reduced alcohol self-administration and cue- and stress-induced re-lapse in high alcohol-drinking rats (Stopponi et al. 2012).In agreement, pregabalin was recently shown usefulfor the treatment of anxiety-like behavior and motorsymptoms associated with spontaneous cannabinoidwithdrawal (Aracil-Fernandez, Almela & Manzanares2011).

Altogether, these results point to the possibility thatpregabalin may represent a potential new therapy forcocaine addiction. To test this hypothesis, we conductedan extensive series of experiments to evaluate the efficacyof pregabalin in reducing cocaine intake and relapse

elicited by stress or environmental conditioning factorsin rats.

MATERIALS AND METHODS

Animals

Male Wistar rats (Charles River, Calco, Italy) were used inthese studies. At the time of the drug treatments, theirbody weights ranged between 350 and 400 g. They werekept in single cages in a room with a reverse 12-hourlight/12-hour dark cycle (lights off at 9:30 am), a tem-perature of 20–22°C and humidity of 45–55%. The ratswere offered free access to tap water and food pellets(4RF18; Mucedola, Settimo Milanese, Italy). All of theprocedures were conducted in adherence with the Euro-pean Community Council Directive for Care and Use ofLaboratory Animals and the National Institutes of HealthGuide for the Care and Use of Laboratory Animals.

Intravenous (i.v.) catheterization

Animals were anesthetized by intramuscular injection of100–150 ml of a solution containing tiletamine chlorid-rate (58.17 mg/ml) and zolazepam chlorohydrate(57.5 mg/ml). For i.v. surgery, incisions were made toexpose the right jugular vein. A catheter made from micro-renathane tubing (inner diameter = 0.020 in., outsidediameter = 0.037 in.) was subcutaneously positionedbetween the vein and the back. After insertion into thevein, the proximal end of the catheter was anchored to themuscles underlying the vein with surgical silk. The distalend of the catheter was attached to a stainless steelcannula bent at an angle of 90°.The cannula was insertedinto a support made by dental cement on the back of theanimals and was covered with a plastic cap. For 1e weekafter surgery, the rats were treated daily with 0.2 ml of theantibiotic sodium cefotaxime (262 mg/ml). For the dura-tion of the experiments, the catheters were flushed dailywith 0.2–0.3 ml of heparinized saline solution. Bodyweight was monitored everyday, and catheter patency wasconfirmed approximately every 3 days, with an injectionof 0.2–0.3 ml of thiopental sodium (250 mg/ml) solu-tion. Patency of the catheter was assumed if there was animmediate loss of reflexes. Self-administration experi-ments began 1 week after the post-surgery recovery.

Drugs

Pregabalin was prepared from Lyrica (150 mg) capsules.The powder was transferred into 20-ml test tubes andwas suspended in distilled water (30 mg/1 ml or 10 mg/1 ml, according to the drug dose used). The test tubeswere vortexed before filling a 1-ml syringe for oral injec-tion. Drug vehicle consisted of distilled water that wasgiven p.o., which is the same route of administration ofthe active principle.

2 Giordano Guglielmo et al.


Cocaine HCl (Sigma-Aldrich, Milan, Italy) was dis-solved in saline (0.25 mg/0.1 ml) and given intrave-nously. Yohimbine (Sigma-Aldrich) was dissolved indistilled water and injected i.p. in a volume of 1 ml/kg.

Operant training

The self-administration stations consisted of operantconditioning chambers (Med Associates, Inc., St. Albans,VT, USA) enclosed in lit, sound attenuating, ventilatedenvironmental cubicles. The front door and the back wallof the chambers were made of transparent plastic, andthe other walls were opaque metal. Each chamber wasequipped with two retractable levers located in the frontpanel. Cocaine was delivered by a plastic tube that wasconnected to the catheter before the beginning of thesession. An infusion pump was activated by responses onthe right or ‘active’ lever, while responses on the left or‘inactive’ lever were recorded but did not result in anyprogrammed consequences. Activation of the pumpresulted in a delivery of 0.1 ml of the fluid. An IBM com-patible computer controlled the delivery of the fluids andthe recording of the behavioral data.

For the food self-administration studies, each chamberwas equipped with a food dispenser positioned 4 cmabove the grid floor at the center of the front panel of thechamber, and two retractable levers were located 3 cm(one to the right and one to the left) away from the foodreceptacle. A food delivery system was activated byresponses on the right ‘active’ lever, while responses onthe left ‘inactive’ lever were recorded but did not result inactivation of the feeder. Active lever presses resulted inthe delivery of 45 mg of food pellets [TestDiet, 1811156(5TUM)]. An IBM compatible computer controlled thedelivery of pellets and registered the total number ofrewards and the number of right and left lever presses.

Experiment 1. Effect of pregabalin oncocaine self-administration

Rats (n = 7) were trained to self-administer cocaine undera fixed ratio 5 (FR-5) schedule of reinforcement in 6-hourdaily sessions. Every five active lever presses resulted inthe delivery of one cocaine dose (0.25 mg/0.1 ml infu-sion). Following each cocaine infusion, a 20-second timeout (TO) period occurred, during which responses at theactive lever did not lead to programmed consequences.This TO period was concurrent with illumination of a cuelight located above the active lever to signal delivery ofthe positive reinforcement. Additionally, an intermittenttone (7 kHz, 70 dB) was sounded throughout the 6-hourcocaine sessions. The rats were trained to self-administercocaine until a stable baseline (variation less than 10%over the last three sessions) of reinforcement was estab-lished. A Latin square, within-subject design was used for

the drug treatments. The rats were injected p.o. with pre-gabalin (0, 10 and 30 mg/kg) 1 hour before the begin-ning of the session. The animals were subjected tococaine self-administration at 3–4 day intervals betweenthe drug tests (Cippitelli et al. 2008).

Experiment 2. Effect of pregabalin onfood self-administration

Rats (n = 16) were trained to self-administer food pellets(45 mg) under an FR-1 schedule of reinforcement for30 minutes a day. Following each food pellet delivery, a10-second TO period occurred, during which responses atthe active lever had no programmed consequences. ThisTO period was concurrent with illumination of a cuelight located above the active lever to signal delivery ofthe positive reinforcement. The rats were trained to self-administer food for several days until a stable baseline(variation less than 10% over the last three sessions) ofreinforcement was established. At this point, the animalswere divided into two groups (n = 8) and were injectedwith pregabalin (0 and 30 mg/kg) 1 hour before thebeginning of the session.

Experiment 3. Effect of pregabalin on yohimbine-inducedreinstatement of cocaine seeking

Rats (n = 9) were trained to self-administer cocaine underan FR-1 schedule of reinforcement; each active leverpressing resulted in the delivery of one cocaine dose(0.25 mg/0.1 ml infusion) for 2 hours. Following eachcocaine infusion, a 20-second TO period occurred, duringwhich pressing the active lever did not lead to pro-grammed consequences. TO was accompanied by illumi-nation of a cue light located above the active lever tosignal delivery of the positive reinforcement, while anintermittent tone was sounded throughout the 2-hoursessions. Once a stable self-administration baseline (vari-ation less than 10% over the last three sessions) wasreached (12 days), the extinction phase started. Duringextinction (session was 1-hour long), the lever presseswere no longer associated with cocaine delivery, but allcues were presented to allow for their concomitantextinction. In 13 days, operant responding decreaseduntil the mean number of reinforced responses was fivetimes lower than the training reinforced responses.

The day after the last extinction session, the rats weresubjected to the reinstatement test. To evaluate the effectof pregabalin on yohimbine-induced reinstatement, ratswere administered pregabalin or its vehicle in a counter-balanced order (Latin square) 1 hour before yohimbineinjection. Yohimbine (1.25 mg/kg) was administered30 minutes prior to the onset of the reinstatementsession. A 3-day interval occurred between drug tests,during which the animals were subjected to extinction

Effect of pregabalin on cocaine self-administration and relapse 3


sessions. The yohimbine dose, time of injection andexperimental design were as described in the previousstudies (Marinelli et al. 2007; Cippitelli et al. 2008,2010a; Stopponi et al. 2012).

Additionally, other eight rats were used to test theeffect of pregabalin on the extinction of cocaine-reinforced lever pressing. For this purpose, for 12 daysafter i.v. surgery, the rats were subjected to a 2-hourcocaine self-administration training as described earlier.This training period was followed by 13 days of extinc-tion. Starting at day 14, the effect of pregabalin on theextinction response was evaluated. Rats were tested withpregabalin (0, 10 and 30 mg/kg) using a within-subject,counterbalanced Latin square design. A 3-day intervalwas allowed between drug tests, during which theanimals were subjected to extinction sessions.

Experiment 4. Effect of pregabalin ondiscriminative-cue-induced reinstatement of cocaine seeking

This experiment consisted of the following three phases:

Training discrimination phase. The purpose of these proce-dures was to train the rats to self-administer i.v. cocainewhile simultaneously establishing discriminative stimuli(SD) associated with cocaine availability or non-availability. Once the rats (n = 8) developed stable levels ofdaily 2-hour cocaine intakes (training phase), they weresubjected to a discrimination learning regimen as follows.In three daily 1-hour sessions, either cocaine or salinewas available as the only infusion solution. Each trainingday included one saline and two cocaine sessions con-ducted in a random sequence. The sessions were initiatedby extension of the levers into the chambers and concur-rent onset of the respective SD, which remained presentuntil termination of the session by retraction of thelevers. The SD associated with cocaine availability (S+)consisted of an intermittent tone (7 kHz, 70 dB), whereasthe SD predictive of the saline vehicle solution (S- or noreward) consisted of continuous illumination of the self-administration chamber’s house light. To prevent acci-dental overdosing, drug infusions were followed by a20-second TO period, which was signaled by illuminationof a white cue light while the lever remained inactive.Saline infusions produced by lever presses during the S-sessions were followed by a 20-second TO period and sig-naled by a white noise (70 dB). In both the S+ and the S-conditions, two levers were present. Only the right leverwas active and produced an i.v. infusion of the respectivesolution when pressed. The left lever was inactive, andresponses at this lever were recorded as a measure ofnon-specific activation.

Extinction phase. Responses at the previously active leveractivated the syringe pump motor only but had no other

programmed consequences (neither cocaine nor salinewas administered, and no cues were presented). Thesesessions lasted 1 hour and were conducted once dailyuntil extinction of response was reached (less than 10total responses over the last three sessions).

Reinstatement test. Reinstatement tests began the dayafter the last extinction day. To evaluate the effect of pre-gabalin on cue-induced cocaine seeking, the rats weretreated with pregabalin or its vehicle in a Latin squarecounterbalanced order 1 hour before the reinstatementtest. This test lasted 1 hour under conditions identical tothose in the discrimination phase, except that cocainewas not available. Pregabalin was given in the S+ condi-tion, and an interval of 3–4 days was allowed betweentests.

Statistical analysis

The effects of pregabalin on cocaine self-administrationand the difference among responses during the extinctionand reinstatement of the vehicle-treated group were ana-lyzed by a one-way within-subject analysis of variance(ANOVA). Food self-administration was evaluated by aone-way ANOVA. Discrimination was analyzed by a two-factor ANOVA, with one within factor (time) and onebetween factor (self-administration). The effects of prega-balin on discriminative-cue- and stress-induced reinstate-ment were analyzed separately by a two-way ANOVA,where the two within factors were treatment and leverpresses. ANOVA was followed by the Newman–Keuls test,when appropriate. Statistical significance was set atP < 0.05.

RESULTS

Experiment 1. Effect of pregabalin oncocaine self-administration

Over the course of the study, the rats acquired stableself-administration of cocaine (101.8 � 3.6 reinforcedresponses). Treatment with pregabalin significantlydecreased the operant response for cocaine [F(2,6) = 23.2,P < 0.001]. As shown in Fig. 1a, post hoc analysis demon-strated a significant reduction in reinforced responses atconcentrations of 10 (P < 0.01) and 30 (P < 0.001)mg/kg of pregabalin. Inter-TO and inactive lever re-sponses were very low and not affected by pregabalin treat-ment [F(2,6) = 0.7, NS]. Figure 1b shows the hourly timecourse of infusions following pregabalin treatment.

Experiment 2. Effect of pregabalin onfood self-administration

Food-reinforced lever pressing was 97.0 � 8.7 and94.9 � 9.2 with 0 (vehicle) and 30 mg/kg of pregabalin,



respectively. A one-way ANOVA showed that food self-administration was not significantly modified by pregaba-lin treatment [F(1,14) = 0.0, NS]. Responses at the inactivecontrol lever were almost absent and not altered bypregabalin treatment [F(1,14) = 0.0, NS].

Experiment 3. Effect of pregabalin onyohimbine-induced reinstatement of cocaine seeking

A stable baseline of response to cocaine was establishedin 12 days. During this training period, the reinforcedresponse for cocaine reached a value of 27.4 � 3.8. Fol-lowing cocaine self-administration, the extinction phasestarted. Responses to the active lever progressivelydecreased from 35.2 � 6.2 at the first day to 5.9 � 1.8at the last day. As shown in Fig. 2, administration of

yohimbine significantly reinstated the operant responsefor the active (cocaine) lever [F(1,8) = 18.9, P < 0.01]. Incontrast, inactive lever responding was not modified byyohimbine [F(1,8) = 0.6, NS].

The two-way ANOVA demonstrated a main effect ofpregabalin treatment on the reduction of the effects ofyohimbine [F(2,16) = 6.2, P < 0.01]. There was also amain effect of the lever [F(1,8) = 61.5, P < 0.001] as wellas significance in the interaction treatment ¥ lever[F(2,16) = 21.7, P < 0.001]. Post hoc analysis demonstrateda significant inhibition of reinstatement following admin-istration of both 10 and 30 mg/kg of pregabalin(P < 0.001). However, inactive lever responding, a poten-tial measure of non-directed behavior and/or responsegeneralization (Shalev, Grimm & Shaham 2002; Cippitelliet al. 2010b), was modified by drug treatment at thehigher dose examined (P < 0.001). Difference score analy-sis (active minus inactive lever pressing [values �

standard error of the mean (SEM) were as follows:16.8 � 1.7, 6.7 � 1.5 and 5.2 � 1.7 for pregabalin 0, 10and 30 mg/kg, respectively) produced essentially thesame results [F(2,16) = 21.7, P < 0.001]. By a post hoc test,both doses of 10 and 30 mg/kg of pregabalin blockedyohimbine-induced reinstatement (P < 0.001).

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Figure 1 Effect of pregabalin on cocaine self-administration. (a)Values represent the mean [�standard error of the mean (SEM)]number of infusions at the active lever and responses at the inactivelever (n = 7). (b) The hourly time course of infusions is described.Significantly different from vehicle-treated rats (0), **P < 0.01,***P < 0.001

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Figure 2 Effect of pregabalin on yohimbine-induced reinstatementof cocaine-seeking. During the training phase, the animals reached astable baseline of cocaine responding, while during the extinctionsessions, the number of responses progressively decreased. Com-pared to extinction (Ext), yohimbine (1.25 mg/kg, i.p.) elicited asignificant reinstatement of response that was significantly reducedfollowing treatment with pregabalin (0, 10 and 30 mg/kg.). Valuesrepresent the mean [�standard error of the mean (SEM)] numberof responses at the cocaine active lever and the inactive lever (n = 9).Significantly different from Ext, ��P < 0.001. Significantly differentfrom vehicle (0), ***P < 0.001



Additional rats were used to test the effect of prega-balin on the extinction of cocaine self-administration.The results demonstrated that at doses that reducedyohimbine-induced reinstatement to cocaine seeking,pregabalin did not produce reinstatement per se and it didnot decrease responses below the extinction baseline. Thevalues � SEM were 13.0 � 2.4 and 2.4 � 0.6 (pregaba-lin vehicle), 14.0 � 2.6 and 5.8 � 0.9 (pregabalin10 mg/kg), and 15.9 � 2.1 and 7.8 � 2.4 (pregabalin30 mg/kg) for the active and inactive lever, respectively.The ANOVA demonstrated a main effect of the lever[F(1,7) = 21.2, P < 0.01], which was not accompanied by amain effect of treatment [F(2,14) = 2.0, NS] nor an interac-tion between treatment and lever [F(2,14) = 0.6, NS].

Experiment 4. Effect of pregabalin ondiscriminative-cue-induced reinstatement ofcocaine seeking

Throughout the conditioning phase, during which theanimals discriminated between cocaine and saline, therats exhibited a strong preference for cocaine. On the lastday of the discrimination period (day 7), the animalsreached a reinforced response for cocaine of 21.7 � 1.6(first session) and of 17.7 � 0.7 (second session), whilethe response for saline was 3.1 � 1.0. During extinction,lever pressing decreased from 25.5 � 8.8 at the firstsession to 5.3 � 1.7 at the last extinction day. As shownin Fig. 3, reintroduction of the cocaine- (S+) but notsaline-associated cues (S-) significantly increased activelever responding [F(2,7) = 18.9, P < 0.001] in the rein-statement test. Inactive lever presses were not modified bypresentation of the cues [F(2,7) = 0.2, NS]. A two-wayANOVA demonstrated a lack of a main effect of treatment[F(2,14) = 2.5, NS], while a significant effect of the lever[F(1,7) = 90.9, P < 0.001] was observed. A significanttreatment ¥ lever interaction [F(2,14) = 5.2, P < 0.05]demonstrated a differential effect of pregabalin on theprevious cocaine-paired lever compared with the inactivelever. Post hoc analysis demonstrated a significant reduc-tion of reinstatement following administration of bothdoses of pregabalin (P < 0.01), while responses at theinactive lever were not altered.

DISCUSSION

Our results demonstrate that pregabalin significantlyreduced cocaine self-administration in rats.This effect wasselective for cocaine because food self-administration wasnot modified under the same treatment conditions. To ruleout drug-induced non-specific motor effects, inactive leverresponding was tested and was also unchanged by thetreatment. A critical problem in addiction treatment ispreventing the occurrence of relapse. Environmental

stimuli associated with the use of cocaine are majorfactors that precipitate cocaine relapse and can occur byclassical conditioning. Stimuli predictive of the availabil-ity of cocaine reliably elicit strong recurrence of drugseeking that can persist even after several months of absti-nence (Ciccocioppo, Sanna & Weiss 2001; Grimm et al.2001; Ciccocioppo, Martin-Fardon & Weiss 2004). In thepresent study, to evaluate the effect of pregabalin ondiscriminative-cue-induced relapse of cocaine seeking,rats were trained with an extinction/reinstatement proce-dure where re-exposure to stimuli previously paired withcocaine availability elicited a robust resumption of leverresponses. At both doses examined (10 and 30 mg/kg),pregabalin significantly reduced discriminative-cue-induced reinstatement of cocaine seeking. This effect wasselective because the drug treatment did not modify theoperant response on the inactive control lever. Anothermajor factor in cocaine addiction and relapse is stress(Zorrilla et al. 2012). Pre-clinical studies have demon-strated that yohimbine, an a-2 adrenoreceptor antagonistthat functions as a pharmacological stressor by increasingcell firing and release of noradrenaline (Holmberg,Gershon & Beck 1962; Aghajanian & VanderMaelen1982; Abercrombie, Keller & Zigmond 1988), induces

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Figure 3 Effect of pregabalin on cue-induced reinstatement ofcocaine seeking. During the discrimination training phase, ratslearned to press the lever for cocaine in the presence of S+ and forsaline (non-reward) in the presence of S-. During extinction (Ext),lever responding progressively decreased. In the reinstatement test,responses at the cocaine-paired cues were increased in the presenceof S+ but not S-. Pregabalin (0, 10 and 30 mg/kg) significantlyreduced relapse elicited by presentation of S+.Values represent themean [�standard error of the mean (SEM)] number of responses atthe cocaine active lever and the inactive lever (n = 8). Significantlydifferent from extinction, ��P < 0.001. Significantly different fromvehicle-treated rats (0), **P < 0.01



robust cocaine seeking in rats (Lee et al. 2004; Feltenstein& See 2006; Bongiovanni & See 2008). Therefore, wealso investigated the effect of pregabalin on yohimbine-induced reinstatement of cocaine seeking. The resultsshowed that pregabalin significantly reduced the rein-statement of cocaine seeking induced by the a-2adrenoreceptor antagonist. This effect was clearly dose-dependent and was pronounced even at a very low doseof pregabalin.

Effect of pregabalin on cocaine self-administrationand relapse

In a recent series of studies, it was found that the prega-balin analog, gabapentin, did not reduce cocaine self-administration in the rat nor prevent relapse evoked bycocaine priming (Filip et al. 2007; Peng, Wijeysundera &Li 2007). Consistent with these behavioral findings, itwas reported that gabapentin did not affect cocaine-induced DA release in the NAc (Peng et al. 2008). Thesefindings are in line with two recent meta-analysis studiesin which the clinical efficacy of anti-epileptics, includinggabapentin, on cocaine addiction was not observed(Minozzi et al. 2008; Alvarez et al. 2010). Overall, thesereports are in contrast with our results obtained usingpregabalin. Several factors may account for these discrep-ancies. First, in previous works published by Peng et al.(2008) and Filip et al. (2007), cocaine was self-administered for 2–3 hours a day, while in the presentexperiment, drug self-administration was maintained for6 hours/day. As it has been recently documented, pro-tracted (6 hours/day) exposure to cocaine led to an esca-lation of drug use and is responsible for the transitiontoward a more severe dependence state (Koob & Kreek2007). Therefore, it is possible that the efficacy of agentssuch as pregabalin and gabapentin may depend on theseverity of dependence. This possibility is further sup-ported by studies on alcohol, where it was shown thatonly rats with a history of dependence were sensitive tothe inhibitory effect of gabapentin on drinking (Robertoet al. 2008). In this respect, it is also intriguing that insome clinical trials, gabapentin showed efficacy, while inother studies, the drug was ineffective (Raby 2000;Myrick et al. 2001; Hart et al. 2004, 2007; Raby &Coomaraswamy 2004; Berger et al. 2005; Haney et al.2005; Bisaga et al. 2006). It is tempting to speculate thatthe differing results achieved in these studies were influ-enced by the selection of patients with various severitiesof cocaine dependence. Alternatively, it can be speculatedthat the different outcomes observed in the present studywith pregabalin and in previous work with gabapentinmay be related to the slightly different pharmacologicalprofiles of these two drugs. In fact, even though these twomolecules share several pharmacological features, it hasalso been shown that pregabalin has increased potency in

animal models, a more linear oral bioavailability and alonger half-life in both animals and humans (Bockbraderet al. 2010).

Finally, it should be addressed that in our study, pre-gabalin was particularly potent in preventing cue- andstress-induced cocaine relapse, while its effect on cocaineself-administration was less evident. For gabapentin, lackof an effect on cocaine self-administration was observed,while, at least to our knowledge, this drug has never beentested against cue- and stress-induced relapse. Therefore,it is difficult to make a complete comparison of these twoanalogs. Overall, these results may suggest that the effectof these agents on cocaine taking is limited comparedwith their effect on cocaine seeking. The exact mecha-nism of action of pregabalin is unknown, and varioushypotheses can be proposed. For example, it has beenshown that cocaine inhibits GABA-mediated inhibitoryactivity in VTA DA neurons and alters sensitivity toGABA microinjections into the NAc (Cameron & Wil-liams 1994; Henry & White 1995), whereas both theinhibition of GABAA or the activation of GABAB recep-tor function were shown to block motivation for cocaineresponding (Backes & Hemby 2008; Halbout et al. 2011).These findings suggest that, at least in part, the effects ofpregabalin on cocaine could depend on its GABA-mimeticproperties. An alternative interpretation is that thereduction of cocaine intake by pregabalin depends on apotentiation of cocaine reward, resulting in an increasein the inter-infusion interval, which is a mechanism pre-viously suggested for DA agonists (Di Pietro et al. 2008).

Evidence from in vitro studies suggests that both pre-gabalin and gabapentin reduce excitatory neurotransmit-ter release and neuronal hyperexcitability (Schlicker,Reimann & Gothert 1985; Cunningham et al. 2004). It isalso known that they bind with high affinity to thealpha2-delta (a2-d) auxiliary subunit of voltage-gatedcalcium channels (VGCCs), which are cell membraneglycoproteins selectively permeable to calcium ions(Wang et al. 1999; Field, Oles & Singh 2001; Fink et al.2002). The entry of calcium ions into neurons via theVGCCs triggers the release of neurotransmitters by per-mitting vesicles to fuse with the cell membrane and therelease of neurotransmitters into the synaptic cleft.Certain pathologic states (i.e. epilepsy, neuropathic painand addiction) are associated with neuronal hyperexcit-ability where an excess influx of calcium ions results in alarge and sustained release of neurotransmitters, includ-ing norepinephrine, glutamate and substance P. Potentbinding of pregabalin at the a2-d subunit of the calciumchannel of hyperexcited neurons reduces the influxof calcium ions by changing the conformation of thechannel, which results in a reduction in the release ofexcitatory neurotransmitters (Stahl 2004). This, in turn,causes a decreased stimulation of the post-synaptic



receptors and restores the neurons to a normal physi-ologic state. Therefore, we speculate that this decreasedstimulation may be responsible for the observed effects ofpregabalin on cocaine-related behaviors. In fact, cocainedependence is known to lead to neuroadaptive changesassociated with overactivation of excitatory neurotrans-mission. Pregabalin, via modulation of VGCCs, maycontrol neuronal activity, resulting in a selective reduc-tion of cellular function in hyperexcited neurons in astate-dependent manner (Dooley, Donovan & Pugsley2000; Fehrenbacher, Taylor & Vasko 2003; Li et al.2006). This finding may explain why we observed thatpregabalin reduced cocaine consumption by the animalsthat were exposed to prolonged (6 hours/day) self-administration of cocaine, while gabapentin was noteffective in animals taking cocaine for shorter intervals(2–3 hours/day) where the dependence state was likelyless pronounced.

CONCLUSIONS

The present study provides pre-clinical evidence ofthe efficacy of pregabalin to reduce cocaine self-administration and the vulnerability to relapse to cocaineseeking. Based on these findings, we hypothesize that pre-gabalin may represent a new therapeutic approach forthe treatment of various aspects of cocaine addiction.Appropriate clinical investigation should be encouragedto thoroughly evaluate the potential of this drug.

Acknowledgements

This study was supported by the DPA (Grant IMPACT toR.C.). The authors thank Alfredo Fiorelli, Rina Righi andMarino Cucculelli for expert technical assistance.

Disclosure/Conflict of Interest

The authors declare no biomedical financial interests orpotential conflicts of interest.

Authors Contribution

GdG and RC were responsible for the study concept anddesign. GdG, HL, SS and MK contributed to the acquisi-tion of animal data. GdG, AC and RC assisted with thedata analysis, interpretation of findings and drafted themanuscript. LS, GG and MU provided critical revision ofthe manuscript for important intellectual content. Allauthors critically reviewed the content and approved thefinal version for publication.

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Pregabalin reduces cocaine self-administration and relapse to cocaine seeking in the rat