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Effects of GABAB receptor agents on cocaine priming, discrete contextual cue and food induced relapses
European Journal of Pharmacology 571 (2007) 166 – 173 www.elsevier.com/locate/ejphar
Effects of GABAB receptor agents on cocaine priming, discrete contextual cue and food induced relapses Małgorzata Filip ⁎, Małgorzata Frankowska Laboratory of Drug Addiction Pharmacology, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, 12 Smętna, Poland Received 16 April 2007; received in revised form 24 May 2007; accepted 24 May 2007 Available online 13 June 2007
Abstract In the present study we investigated the effects of the GABAB receptor antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), the agonists baclofen and 3-aminopropyl(methyl)phoshinic acid (SKF 97541), and the allosteric positive modulator 3,5-bis(1,1dimethylethyl)-4-hydroxy-β,β-dimethylbenzenepropanol (CGP 7930) on cocaine seeking behavior. The effects of the above drugs on the reinstatement of responding induced by natural reinforcer (food) were also studied. Male Wistar rats were trained to self-administer either cocaine (0.5 mg/kg/infusion) or food (sweet milk) and responding on the reinforcer-paired lever was extinguished. Reinstatement of responding was induced by a noncontingent presentation of the self-administered reinforcer (10 mg/kg cocaine, i.p.), a discrete contextual cue, or a contingent presentation of food. SCH 50911 (3–10 mg/kg) dose-dependently attenuated responding on the previously cocaine-paired lever during both reinstatement conditions, with slightly greater efficacy at reducing conditioned cue reinstatement. At the same time, it failed to alter reinstatement of food-seeking behavior. Baclofen (1.25–5 mg/kg) and SKF 97541 (0.03–0.3 mg/kg) attenuated cocaine- or food-seeking behavior; the effect of the drug appeared more effective for cocaine-seeking than food-seeking. CGP 7930 (10–30 mg/kg) reduced cocaine seeking without affecting food-induced reinstatement on reward seeking. Our results indicate that tonic activation of GABAB receptors is required for cocaine seeking behavior in rats. Moreover, the GABAB receptor antagonist SCH 50911 was effective in reducing relapse to cocaine at doses that failed to alter reinstatement of food-seeking behavior (present study), basal locomotor activity, cocaine and food self-administration (Filip et al., submitted for publication), suggesting its selective effects on motivated drug-seeking behavior. The potent inhibitory responses on cocaine seeking behavior were also seen following the GABAB receptor agonists or the allosteric positive modulator, however, doses of baclofen and SKF 97541 that inhibited cocaine-seeking were only threefold lower of those that inhibited food-seeking. In addition, the direct GABAB receptor agonists and the allosteric positive modulator cause decreases in cocaine or food self-administration (Filip et al., submitted for publication), indicating their nonspecific effects on relapse to drug-seeking and drug-taking behavior. In conclusion, the GABAB receptor antagonist SCH 50911 seems to be viable treatment for reducing cocaine craving and preventing relapse, while the GABAB receptor allosteric positive modulator CGP 7930 may hold the highest promise for attenuating cue-evoked relapses to cocaine as well as the direct rewarding properties of cocaine. © 2007 Elsevier B.V. All rights reserved. Keywords: GABAB receptor; Cocaine-seeking behavior; Food-seeking behavior; (Rat)
1. Introduction Drug dependence is characterized by high rates of relapse to drug-seeking and drug-taking behavior following periods of abstinence and drug detoxification (Mendelson and Mello, 1996; O'Brien, 1997). Studies in humans provide evidence that relapse to cocaine use or cocaine craving can be initiated by ⁎ Corresponding author. Tel.: +48 12 6623293; fax: +48 12 6374500. E-mail address: [email protected] (M. Filip). 0014-2999/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2007.05.069
multiple triggers including the self-administered drug (de Wit) or drug-associated environmental cues (Carter and Tiffany, 1999; Childress et al., 1993). Relapse can be modeled in preclinical studies in reinstatement procedure in which laboratory animals are trained to self-administer drugs and then subjected to extinction training during which – in an operant version of this procedure – lever presses are not reinforced with drugs. Reinstatement of extinguished lever responding (the operational measure of drug seeking) is determined after such manipulations as noncontingent priming
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injections of the drug (de Wit and Stewart, 1981), exposure to cues associated with drug intake (Meil and See, 1996) or exposure to stress (Erb et al., 1996). The reinstatement model has good face validity for modeling the activation of craving and arousal by environmental conditioned stimuli in drug dependent individuals. A large body of evidence indicates a major role of the activation of the dopaminergic and glutamatergic pathways in the nucleus accumbens, the prefrontal cortex, the ventral tegmental area, the amygdala and the ventral hippocampus in the drugpriming and cue-induced reinstatement of cocaine seeking (for review see: Kalivas and McFarland, 2003; Rebec and Sun, 2005; Schmidt et al., 2005; See, 2005). Moreover, recent behavioral findings show the cocaine seeking is also effectively reduced by the inhibitory neurotransmission of γ-aminobutyric acid (GABA). For example, indirect GABA agonist vigabatrin exerted inhibitory actions on the reinstatement of extinguished cocaine-seeking behavior induced by cocaine priming (Filip et al., 2007). The abolishment of cocaine-induced reinstatement of drug-seeking behavior was also seen after activation of both GABAA and GABAB receptors by direct infusion of a mixture of the receptor agonists, muscimol and baclofen, into the dorsal prefrontal cortex, the ventral pallidum (McFarland and Kalivas, 2001) or the ventral hippocampus (Rogers and See, 2007). The same treatment combination when microinfused into the lateral orbitofrontal cortex (Fuchs et al., 2004a), the ventral tegmental area (Di Ciano and Everitt, 2003), the accumbens core (Di Ciano and Everitt, 2003; Fuchs et al., 2004b) or the ventral hippocampus (Rogers and See, 2007) attenuated cue-induced cocaine seeking. More recently, GABAB receptor agonists given systemically reduced cocaine-seeking behavior in laboratory animals: baclofen decreased drug-associated cue-controlled cocaine-seeking behavior in rats (Di Ciano and Everitt, 2003), while both baclofen and 3-amino-2[S]-hydroxypropylmethylphosphinic acid (CGP 44532) attenuated the relapse to cocaine priming doses in baboons (Weerts et al., 2007). In the present study we investigated the effects of the GABAB receptor agonists baclofen (Froestl et al., 1995a) and 3aminopropyl(methyl)phoshinic acid (SKF 97541; Froestl et al., 1995a), the antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911; Froestl et al., 1995b) as well as the allosteric positive modulator 3,5-bis(1,1-dimethylethyl)-4-hydroxy-β,βdimethylbenzenepropanol (CGP 7930; Urwyler et al., 2001) on cocaine-primed and conditioned cue-induced reinstatement of drug-seeking behavior following chronic intravenous cocaine self-administration in an animal model of relapse. Additionally, we investigated the effects of the above GABAB receptor ligands and the allosteric positive modulator on the reinstatement of responding induced by food. 2. Materials and methods 2.1. Animals Male Wistar rats (280–300 g) delivered by a licensed breeder (T. Górzkowska, Warsaw, Poland) were housed individually in standard plastic rodent cages in a colony room maintained at 20±
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1 °C and at 40–50% humidity under a 12-h light–dark cycle (lights on at 06:00). Animals had free access to food (Labofeed pellets) and water during the 7-day habituation period. Then, rats used in the cocaine self-administration procedures were maintained on limited water during initial training sessions (see below), while animals used in the food self-administration procedures were maintained on limited food intake (see below). All experiments were conducted during the light phase of the light–dark cycle (between 08:00–15:00) and were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and with approval of the Bioethics Commission as compliant with the Polish Law (21 August 1997). The animals were experimentally naïve. 2.2. Drugs 3-Aminopropyl(methyl)phoshinic acid (SKF 97541; Tocris, UK), (R)-baclofen (Tocris, UK), cocaine hydrochloride (National Institute on Drug Abuse, RTI International, USA), (2S)-(+)-5,5dimethyl-2-morpholineacetic acid (SCH 50911; Tocris, UK) and 3,5-bis(1,1-dimethylethyl)-4-hydroxy-β,β-dimethyl-benzenepropanol (CGP 7930; Tocris, UK) were used. Baclofen, cocaine, SCH 50911 and SKF 97541 were dissolved in sterile 0.9% NaCl, while CGP 7930 was diluted in 2 drops of ethanol and then in 1% Tween (Sigma Aldrich, USA). Cocaine was given either i.v. (0.05 ml/infusion) or i.p. (1 ml/kg); other drugs were injected i.p. in a volume of 1 ml/kg. Baclofen, CGP 7930, SCH 50911 or SKF 97541 were administered at 30, 30, 45 or 30 min, respectively, before reinstatement tests. The dose-range and pretreatment intervals of the GABAB receptor ligands and the allosteric positive modulator were chosen based on their functional in vivo activity at GABAB receptors (Carai et al., 2004a,b; Colombo et al., 2001; Froestl et al., 1995a,b; Slattery et al., 2005a,b; Smith et al., 2004). 2.3. Cocaine self-administration Rats were trained to press the lever of standard operant conditioning chambers (Med-Associates, USA) under a fixed ratio 5 schedule of water reinforcement. Two days following “lever press” training and free access to water, the rats were chronically implanted with a silastic catheter in the external right jugular vein, as described previously (Filip, 2005). Catheters were flushed every day with 0.1 ml of saline solution containing heparin (70 U/ml, Biochemie, Austria) and 0.1 ml of solution of cephazolin (10 mg/ml; Biochemie GmbH, Austria). Catheter patency was tested periodically with the ultrashortacting barbiturate anesthetic methohexital (10 mg/kg, i.v.; loss of consciousness within 5 s). After a 10-day recovery period, all animals were water deprived for 18 h and trained to lever press to fixed ratio 5 schedule of water reinforcement over a 2-h session. Subjects were then given access to cocaine during 2-h daily sessions performed 6 days/week (maintenance) and from that time they were given ad libitum water. The house light was illuminated throughout each session. Each completion of five presses on the “active” lever complex (fixed ratio 5 schedule) resulted in a 5-s infusion of cocaine
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(0.5 mg/kg per 0.1 ml) and a 5-s presentation of a stimulus complex (activation of the white stimulus light directly above the “active” lever and the tone generator, 2000 Hz; 15 dB above ambient noise levels). Following each injection, there was a 20-s time-out period during which responding was recorded but had no programmed consequences. Response on the “inactive” lever never resulted in cocaine delivery. Acquisition of the conditioned operant response lasted a minimum of 10 days until subjects met the following criteria: minimum requirement of 22 reinforcements with an average of 6 days and active lever presses with an average of 6 consecutive days and a standard deviation within those 6 days of b 10% of the average; this criterion was selected based on our prior experiments (Filip, 2005). Once stable rates of responding were established, the extinction procedure was carried out on the following day. During extinctions sessions subjects had 2-h daily training sessions with no delivery of cocaine or the presentation of the conditioned stimulus. Once they reached the extinction criteria (a minimum of 10 extinction days with the responding on the active lever below 10% of the level observed during maintenance during at least 3 consecutive days), the separate groups of rats (n = 7–8 rats/group) were tested for response reinstatement induced by either a noncontingent presentation of the selfadministered reinforcer (10 mg/kg cocaine, i.p.) or discrete contextual cue (tone + light previously paired with cocaine selfadministration). Before test sessions rats were pretreated with either appropriate vehicle, baclofen (1.25–5 mg/kg), CGP 7930 (10–30 mg/kg), SCH 50911 (3–10 mg/kg), or SKF 97451 (0.03– 0.3 mg/kg). During the reinstatement tests (2-h sessions), active lever presses on the fixed ratio 5 schedule resulted only in an intravenous injection of saline. Drug combinations were given in a randomized order in three-four reinstatement tests that each rat received and test sessions were separated by at least two-three extinction sessions.
presentation of food. Each completion of a fixed ratio 5 schedule on the “active” lever resulted in a delivery of the portion of sweetened milk (0.1 ml) in daily 2-h sessions. Following each reward, there was a 20-s time-out period during which responding was recorded but had no programmed consequences. Response on the “inactive” lever never resulted in food delivery. Before test sessions rats were pretreated with either appropriate vehicle, baclofen (1.25–5 mg/ kg), CGP 7930 (10–30 mg/kg), SCH 50911 (3–10 mg/kg), or SKF 97451 (0.03–0.3 mg/kg). Drug combinations were given in a randomized order in three-four reinstatement tests that each rat received and test sessions were separated by at least two-three extinction sessions. 2.5. Statistical analyses During reinstatement of cocaine- or food-seeking behavior, the number of responses on the active and inactive lever (including time out responding) for each group pretreated with a GABAB receptor ligand or the allosteric positive modulator was
2.4. Food self-administration Food self-administration was conducted in a manner parallel to cocaine self-administration. Food-restricted rats (20 g/rat/day) were trained to press the lever of a standard operant chambers (MedAssociates, USA) under a fixed ratio 5 schedule of reinforcement (each completion of a fixed ratio 5 schedule on the “active” lever resulted in a delivery of the portion of sweetened milk (0.1 ml)) in daily 2-h sessions. Following each reward, there was a 20-s timeout period during which responding was recorded but had no programmed consequences. Response on the “inactive” lever never resulted in food delivery. The house light was on throughout each session. Rats remained in maintenance training until lever pressing stabilized (the number of active lever presses varied by 10% or less over the course of 3 consecutive maintenance days). Once stable rates of responding were established, the extinction procedure was carried out on the following day. During extinctions sessions subjects had 2-h daily training sessions with no delivery of food. Once they reached the extinction criteria (a minimum of 10 extinction days with the responding on the active lever below 10% of the level observed during maintenance during at least 3 consecutive days), the separate groups of rats (n =7–8 rats/group) were tested for response reinstatement induced by a contingent
Fig. 1. Effects of the GABAB receptor agonists (baclofen and SKF 97541), the allosteric positive modulator (CGP 7930) and the antagonist (SCH 50911) on the response reinstatement induced by a noncontingent presentation of the selfadministered reinforcer (10 mg/kg cocaine, i.p.). Number of active (cross hatched bars) and inactive (white bars) lever presses following cocaine priming injections (COC) are shown for pretreatment with baclofen (BAC; 1.25–5 mg/ kg), SKF 97541 (SKF; 0.03–0.3 mg/kg), CGP 7930 (CGP; 10–30 mg/kg), SCH 50911 (SCH; 3–10 mg/kg) and the appropriate vehicle (Veh). The baseline extinction (Ext) responding is also presented. The data points represent the means of data from 7–8 rats. ⁎P b 0.01, ⁎⁎ P b 0.001 vs. Ext; +P b 0.05, ++ P b 0.01 vs. Veh-COC 10.
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inactive (F(4,30) = 0.8), lever presses. A significant decrease was observed following baclofen, 2.5 and 5 mg/kg. Pretreatment with SKF 97541 (0.03–0.3 mg/kg) significantly altered the number of active (F(4,30) = 15.6, P b 0.001), but not (F(4,30) = 2.1), inactive lever presses. A significant decrease was observed following all doses of SKF 97541. Pretreatment with CGP 7930 (10–30 mg/kg) significantly altered the number of active (F(3,24) = 5.3, P b 0.01), but not inactive (F(3,24) = 0.3), lever presses. A significant decrease was observed following CGP 7930, 30 mg/kg. Pretreatment with SCH 50911 (3–10 mg/kg) significantly altered the number of active (F(3,24) = 6.2, P b 0.01), but not inactive (F(3,24) = 0.7), lever presses. The individual dose groups of pretreatment with SCH 50911 (3–10 mg/kg) in combination with cocaine did not indicate a significant alteration, however, a higher dose of SCH 50911 attenuated cocaine-seeking behavior by 45%. 3.1.2. Cue-primed reinstatement After 10 days of extinction the rats were tested for response reinstatement induced by the discrete contextual cue. Fig. 2 shows the effects of GABAB receptor agents on cue-primed reinstatement. Fig. 2. Effects of the GABAB receptor agonists (baclofen and SKF 97541), the allosteric positive modulator (CGP 7930) and the antagonist (SCH 50911) on the response reinstatement induced by a contingent presentation of discrete contextual cues (tone +light previously paired with cocaine self-administration). Number of the active (cross hatched bars) and inactive (white bars) lever presses following the cue are shown for pretreatment with baclofen (BAC; 1.25–5 mg/kg), SKF 97541 (SKF; 0.03–0.3 mg/kg), CGP 7930 (CGP; 10–30 mg/kg), SCH 50911 (SCH; 3–10 mg/kg) and the appropriate vehicle (Veh). The baseline extinction (Ext) responding is also presented. The data points represent the means of data from 7–8 rats. ⁎P b 0.01 vs. Ext; +P b 0.05, ++P b 0.01 vs. Veh-Cue.
analyzed by separate one-way ANOVAs and where appropriate a post hoc Dunnett's test was used to analyze differences between group means. 3. Results 3.1. Cocaine seeking Rats showed stable lever responding during the last 6 selfadministration maintenance sessions with an acquisition criterion requiring that the rate of active lever presses varied by less than 10%. The animals had self-administered 22–38 injections of cocaine with the daily mean cocaine intake between 11 and 18 mg/kg. 3.1.1. Cocaine-primed reinstatement After 10 days of extinction the rats were tested for response reinstatement induced by cocaine (10 mg/kg, i.p.). Fig. 1 shows the effects of GABAB receptor agents on cocaine-primed reinstatement. Pretreatment with baclofen (1.25–5 mg/kg) significantly altered the number of active (F(4,30) = 5.6, P b 0.001), but not
Fig. 3. Effects of the GABAB receptor agonists (baclofen and SKF 97541), the allosteric positive modulator (CGP 7930) and the antagonist (SCH 50911) on the response reinstatement induced by a contingent presentation of food (sweetened milk). Number of the active (cross hatched bars) and inactive (white bars) lever presses following presentation of food are shown for pretreatment with baclofen (BAC; 1.25–5 mg/kg), SKF 97541 (SKF; 0.03–0.3 mg/kg), CGP 7930 (CGP; 10–30 mg/kg), SCH 50911 (SCH; 3–10 mg/kg) and the appropriate vehicle (Veh). The baseline extinction (Ext) responding is also presented. The data points represent the means of data from 7–8 rats. ⁎P b 0.01, ⁎⁎P b 0.001 vs. Ext; + P b 0.01, ++P b 0.001 vs. Veh-Food.
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Pretreatment with baclofen (1.25–5 mg/kg) significantly altered the number of active (F(4,34) = 3.8, P b 0.01), but not inactive (F(4,30) = 2.1), lever presses. A significant decrease was observed following baclofen, 5 mg/kg. Pretreatment with SKF 97541 (0.03–0.3 mg/kg) significantly altered the number of active (F(4,34) = 4.5, P b 0.01), but not inactive (F(4,34) = 0.8), lever presses. A significant decrease was observed following SKF 97541, 0.1 and 0.3 mg/kg. Pretreatment with CGP 7930 (10–30 mg/kg) significantly altered the number of active (F(3,24)= 5.3, P b 0.01), but not inactive (F(3,24) = 1.46), lever presses. A significant decrease was observed following both doses of CGP 7930, 10 and 30 mg/kg. Pretreatment with SCH 50911 (3–10 mg/kg) significantly altered the number of active (F(3,24) = 3.74, P b 0.05), but not inactive (F(3,24) = 2.39), lever presses. A significant decrease was observed following SCH 50911, 10 mg/kg. 3.2. Food seeking Rats showed stable responding on levers during the last 3 self-administration maintenance sessions with an acquisition criterion requiring that the rate of active lever presses varied by less than 10%. Rats responded significantly more frequently on the active lever than on the inactive lever (P b 0.05), independently of food self-administration test day. After 10 days of extinction the rats were tested for response reinstatement induced by the contingent presentation of food. Fig. 3 shows the effects of GABAB receptor agents on food seeking. Pretreatment with baclofen (1.25–5 mg/kg) significantly altered the number of active (F(4,30) = 59.8, P b 0.001), but not inactive (F(4,30) = 1.8), lever presses. A significant decrease was observed following baclofen, 5 mg/kg. Pretreatment with SKF 97541 (0.03–0.3 mg/kg) significantly altered the number of active (F(4,25) = 16.53, P b 0.001), but not inactive (F(4,34) = 0.8), lever presses. A significant decrease was observed following SKF 97541, 0.3 mg/kg. Pretreatment with CGP 7930 (10–30 mg/kg) significantly altered the number of active (F(3,24) = 111.9, P b 0.001), but not inactive (F(3,24) = 0.29), lever presses. However, the individual dose groups of pretreatment with CGP 7930 (10–30 mg/kg) in combination with food did not indicate a significant alteration in the response reinstatement. Pretreatment with SCH 50911 (3–10 mg/kg) significantly altered the number of active (F(3,24) = 35.29, P b 0.005), but not inactive (F(3,24) = 0.31), lever presses. However, the individual dose groups of pretreatment with SCH 50911 (3–10 mg/kg) in combination with food did not indicate a significant alteration in the response reinstatement. 4. Discussion The present findings indicate for the first time that that SCH 50911, the selective GABAB receptor antagonist, significantly reduced cocaine-associated cue-induced and attenuated cocaine-induced reinstatement of cocaine seeking, but failed to alter food-induced reinstatement. We also report that pharma-
cological direct stimulation of GABAB receptors by agonists baclofen or SKF 97541 attenuated cocaine- or food-seeking behavior; the effect of SKF 97541 appeared somewhat more effective for cocaine-seeking than food-seeking. Finally, we demonstrate that the GABAB receptor modulator CGP 7930 can block cocaine seeking without affecting food-induced reinstatement on reward seeking. The ability of SCH 50911 (10 mg/kg), the selective and potent GABAB receptor antagonist (Bolser et al., 1995; Froestl et al., 1995b), to reduce discrete contextual cues (tone + light) indicates that tonic activation of GABAB receptors is required for the cocaine seeking behavior in rats. When used at the same dose SCH 50911 attenuated – although non-significantly – reinstatement of responding induced by a noncontingent presentation of the selfadministered reinforcer (10 mg/kg cocaine, i.p.). Since conditioned-cued reinstatement models are more analogous relapse in humans than cocaine-primed reinstatement (Childress et al., 1993; Jaffe et al., 1989), the stronger inhibitory efficacy of SCH 50911 to reduce cocaine-associated cue-induced reinstatement indicates that this antagonist could may be used as an effective therapeutic drug for preventing relapse. Interestingly, the potent inhibitory responses on cocaine seeking behavior were also seen following pretreatment with the direct GABAB receptor agonists (baclofen and SKF 97541) or the allosteric positive modulator (CGP 7930). The results with baclofen are consistent with the study by Di Ciano and Everitt (2003) who observed that the agonist, when tested at similar dose ranges, decreased responding maintained by the responsecontingent presentations of cocaine-associated conditioned reinforcers in rats. Hotsenpiller and Wolf (2003) found that baclofen attenuated cocaine-conditioned locomotion in rats and more recently, Weerts et al. (2007) found that baclofen and another GABAB receptor agonist CGP 44532 attenuated the relapse to cocaine (i.v.) priming doses in baboons. Partly supporting preclinical studies, baclofen dose-dependently decreased ratings of cocaine craving in a methadone group (Haney et al., 2006), but not in heavy cocaine users (Shoptaw et al., 2003). The inhibitory effects of the GABAB receptor agonists used in the present study seem to be more potent toward cocainethan cue-induced reinstatement since the minimum effective doses of baclofen and SKF 97541 in the cocaine relapse model were 2 or 3 times lower, respectively, than the minimum effective doses of these drugs in the cue relapse model. It should be underlined that differences in responses of direct GABAB receptor antagonist, agonists and the allosteric positive modulator on the incentive motivational effects of cocaine. Thus, an effective dose of SCH 50911 (10 mg/kg) that reduced/ attenuated cocaine seeking behavior failed to alter reinstatement of food seeking (present study), cocaine and food self-administration, inactive lever responding or locomotor activity (Filip et al., submitted for publication). This suggests that decreases in cocaine seeking were related to specific motivational decreases for the artificial reinforcer (cocaine), but not to change of the natural reward or motor artifacts, per se. On the other hand, the inhibitory effects of the GABAB receptor agonists baclofen and SKF 97541 do not appear specific to drug-seeking behavior since they at the moderate doses impacted on cocaine seeking while at
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the higher doses they produced inhibitory effects on reinstatement of natural reward (present study). Moreover, baclofen in a similar dose range (2.5–5 mg/kg) reduced the primary reinforcement of cocaine during intravenous self-administration, food self-administration, and basal locomotor activity in rats (Filip et al., submitted for publication). SKF 97541 (0.1–0.3 mg/ kg) reduced the maintenance of cocaine and food selfadministration, but, in contrast to baclofen, does not alter basal locomotor activity in rats (Filip et al., submitted for publication). The GABAB allosteric positive modulator CGP 7930 inhibited cocaine-seeking behavior, but not food-seeking behavior (present study), food self-administration or basal locomotor activity (Filip et al., submitted for publication). Taking into account such effects of CGP 7930 (30 mg/kg) it seems that this modulator displays more selective action on motivated cocaine-seeking behavior than direct GABAB receptor agonists. On the other hand, it also effectively diminished cocaine's rewarding effects as assessed by self-administration (Smith et al., 2004; Filip et al., submitted for publication) suggesting that decreases in cocaine-triggered reinstatement of cocaine-seeking behavior might be due to its direct antagonistic interaction with cocaine per se. The mechanism through which GABAB receptor antagonist, agonist and allosteric positive modulator act to inhibit responding to cocaine-seeking remains largely unexplained. Thus, activation of both the dopaminergic and/or glutamatergic systems appears to have significance in altering the drug-priming and cue-induced reinstatement of cocaine seeking (for review see: Kalivas and McFarland, 2003; Rebec and Sun, 2005; Schmidt et al., 2005; See, 2005) and GABAB receptors are widely distributed in several brain areas related to cocaine seeking where they modulate both the excitatory and the inhibitory components of pre- and postsynaptic mechanisms (Thompson and Gahwiler, 1992). For example, in the ventral tegmental area GABAB receptors act as heteroreceptors present on dopamine and glutamatergic neurons (Bowery et al., 1987; Liang et al., 2000; Wirtshafter and Sheppard, 2001) as well as presynaptic autoreceptors on GABA interneurons (Rahman and McBride, 2002). Activation of these receptors by local injection of baclofen suppresses extracellular dopamine levels in the nucleus accumbens (Fadda et al., 2003) and prefrontal cortex (Yoshida et al., 1994; Westerink et al., 1997; Xi and Stein, 1999) or the cocaine-induced elevation in extracellular dopamine in the nucleus accumbens (Fadda et al., 2003). In the prefrontal cortex GABAB receptors are localized on presynaptic terminals of glutamatergic nerve endings and/or cell bodies (Margeta-Mitrovic et al., 1999), and on GABA neurons where they act as autoreceptors (Calver et al., 2002). It was also shown that in animals treated repeatedly with cocaine intraprefrontal cortex injection with baclofen increased glutamate levels in the nucleus accumbens and the ventral tegmental area (Jayaram and Steketee, 2004). The GABAB receptor allosteric positive modulator CGP 7930 synergistically interacts with endogenously released GABA and enhances the GABAB receptor-mediated inhibition of dopamine neuronal activity in the ventral tegmental area (Chen et al., 2005). It should be noted that, however, in the hippocampal CA1 area CGP 7930 selectively enhances the baclofen-induced modulation of synaptic inhibition resulting
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from activation of presynaptic autoreceptors located on the inhibitory GABA terminals, without having any significant effects on the presynaptic heterosynaptic receptors on the excitatory glutamate terminals (Chen et al., 2006). Since the ventral CA subfields of the hippocampus play an important role in the relapse to cue-induced and cocaine-primed reinstatement (Rogers and See, 2007), it may be speculated that the inhibitory effects of CGP 7930 toward cocaine-seeking behavior (the present study) may be related with stimulation of GABAB presynaptic autoreceptors in this brain structure This might be further supported by the fact that responding for food reinforcement was not altered either by CGP 7930 (Filip et al., submitted for publication) or by local inactivation of the ventral hippocampus (Rogers and See, 2007). In direct contrast to GABAB receptor stimulation, the blockade of these receptors was proposed to enhance dopamine release, since SCH 50911, given systemically or locally, resulted in activation of nigral dopamine neurons in rats (Erhardt et al., 1999) while another GABAB receptor antagonist phaclofen, perfused locally into the ventral pallidum increased extracellular dopamine level in this brain structure (Gong et al., 1998). In line with biochemical studies, SCH 50911 enhanced locomotor stimulation in mice; the effect being blocked by haloperidol (Colombo et al., 2001). Interestingly, Ashby et al. (1999) reported that SCH 50911 (3 mg/kg) did not alter dopamine efflux in the nucleus accumbens, which might suggest that activation of dopamine neurotransmission following GABAB receptor blockade is limited to striatonigral and/or mesopallidal pathways. Increases in extracellular dopamine were observed in the dorsal striatum in rodents (Ito et al., 2002; Vanderschuren et al., 2005) and cocaine addicts (Volkow et al., 2006) responding to cocaine cues. Since SCH 50911 neither produces relapse to cocaine seeking (Frankowska and Filip, unpublished results) nor substitutes for cocaine (Filip et al., submitted for publication), the local increases of basal dopamine level in brain areas related to seeking (e.g. the dorsal striatum; Erhardt et al., 1999; Ito et al., 2002; Vanderschuren et al., 2005) but not reward (the nucleus accumbens; Ashby et al., 1999) may lead to normalization of the dopamine levels in the areas related to seeking behavior since withdrawal from cocaine self-administration reduces basal extracellular levels of dopamine in those areas (Dworkin et al., 1995; Parsons et al., 1995). Additionally, it is worth to add that GABAB receptor labelling was found on the presynaptic membranes of GABA-ergic synapses in the rat substantia nigra (Boyes and Bolam, 2003) and the striatum (Lacey et al., 2005). SCH 50911 acting on presynaptic GABAB receptors located on GABA terminals may release GABA which subsequently activate postsynaptic GABAB receptor sites. The inhibitory effect of SCH 50911 on the cue-induced cocaine seeking might be also related with its partial agonistic properties at GABAB receptors seen in that experimental condition. To conclude, our present findings suggest that the GABAB receptor antagonist SCH 50911 and the allosteric positive modulator CGP 7930 have unique relevance for different aspects of human cocaine addiction. Thus, SCH 50911 may be used as anti-addiction pharmacotherapeutic agent for reducing cocaine craving and preventing relapse in abstinent cocaine addicts.
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Additionally, its antidepressant-like actions (Frankowska et al., 2007) together with selective GABAB receptor antagonists (Slattery et al., 2005a) may also offer novel approach for the treatment of cocaine withdrawal-evoked depression. CGP 7930 may hold the highest promise for attenuating cue-evoked relapses to cocaine as well as to reduce the direct rewarding properties of cocaine that model the cocaine-induced subjective “high”. It should be added that beyond simply reducing the primary rewarding effects of cocaine (Slattery et al., 2005a,b; Filip et al., submitted for publication), GABAB receptor allosteric positive modulators reduce anxiety in preclinical paradigms (Cryan et al., 2004) that could also help in the treatment of addiction. Acknowledgements We are grateful to Dr. Andrew C. McCreary for the comments and language editing of the manuscript. Expert technical assistance was provided by Ewa Nowak and Karolina Wydra. The authors would like to kindly acknowledge donation of cocaine hydrochloride from the National Institute on Drug Abuse (RTI International, NC, USA). This study was supported by grants no. 2 PO5A 007 26 and N401 119 32/2421 from the Ministry of Science and Higher Education (Warszawa, Poland). Conflict of interest: None. References Ashby Jr., C.R., Rohatgi, R., Ngosuwan, J., Borda, T., Gerasimov, M.R., Morgan, A.E., Kushner, S., Brodie, J.D., Dewey, S.L., 1999. Implication of the GABA(B) receptor in gamma vinyl-GABA's inhibition of cocaineinduced increases in nucleus accumbens dopamine. Synapse 31, 151–153. Bolser, D.C., Blythin, D.J., Chapman, R.W., Egan, R.W., Hey, J.A., Rizzo, C., Kuo, S.C., Kreutner, W., 1995. The pharmacology of SCH 50911: a novel, orally-active GABA-beta receptor antagonist. J. Pharmacol. Exp. Ther. 274, 1393–1398. Bowery, N.G., Hudson, A.L., Price, G.W., 1987. GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience 20, 365–383. Boyes, J., Bolam, J.P., 2003. The subcelllar locoalization of GABAB receptor subunits in the rat substantia nigra. Eur. J. Neurosci. 18, 3279–3293. Carai, M.A., Colombo, G., Gessa, G.L., 2004a. Protection by the GABAB receptor antagonist, SCH 50911, of gamma-hydroxybutyric acid-induced mortality in mice. Eur. J. Pharmacol. 503, 77–80. Carai, M.A., Colombo, G., Froestl, W., Gessa, G.L., 2004b. In vivo effectiveness of CGP7930, a positive allosteric modulator of the GABAB receptor. Eur. J. Pharmacol. 504, 213–216. Calver, A.R., Davies, C.H., Pangalos, M., 2002. GABA(B) receptors: from monogamy to promiscuity. Neurosignals 11, 299–314. Carter, B.L., Tiffany, S.T., 1999. Meta-analysis of cue-reactivity in addiction research. Addiction 94, 327–340. Chen, Y., Phillips, K., Minton, G., Sher, E., 2005. GABA(B) receptor modulators potentiate baclofen-induced depression of dopamine neuron activity in the rat ventral tegmental area. Br. J. Pharmacol. 144, 926–932. Chen, Y., Menendez-Roche, N., Sher, E., 2006. Differential modulation by the GABAB receptor allosteric potentiator 2,6-di-tert-butyl-4-(3-hydroxy-2,2dimethylpropyl)-phenol (CGP7930) of synaptic transmission in the rat hippocampal CA1 area. J. Pharmacol. Exp. Ther. 317, 1170–1177. Childress, A.R., Ehrman, R.N., Robbins, S.J., McLelan, A.T., O'Brien, C.P., 1993. Cue reactivity and cue reactivity interventions in drug dependence. NIDA Res. Monogr. 137, 73–95. Colombo, G., Melis, S., Brunetti, G., Serra, S., Vacca, G., Carai, M.A., Gessa, G.L., 2001. GABA(B) receptor inhibition causes locomotor stimulation in mice. Eur. J. Pharmacol. 433, 101–104.
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Slattery, D.A., Markou, A., Froestl, W., Cryan, J.F., 2005b. The GABAB receptor-positive modulator GS39783 and the GABAB receptor agonist baclofen attenuate the reward-facilitating effects of cocaine: intracranial selfstimulation studies in the rat. Neuropsychopharmacology 30, 2065–2072. Smith, M.A., Yancey, D.L., Morgan, D., Liu, Y., Froestl, W., Roberts, D.C., 2004. Effects of positive allosteric modulators of the GABAB receptor on cocaine self-administration in rats. Psychopharmacology 173, 105–111. Thompson, S.M., Gahwiler, B.H., 1992. Comparison of the actions of baclofen at pre- and postsynaptic receptors in the rat hippocampus in vitro. J. Physiol. 451, 329–345. Urwyler, S., Mosbacher, J., Lingenhoehl, K., Heid, J., Hofstetter, K., Froestl, W., Bettler, B., Kaupmann, K., 2001. Positive allosteric modulation of native and recombinant gamma-aminobutyric acid(B) receptors by 2,6-Di-tertbutyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501. Mol. Pharmacol. 60, 963–971. Vanderschuren, L.J., Di Ciano, P., Everitt, B.J., 2005. Involvement of the dorsal striatum in cue-controlled cocaine seeking. J. Neurosci. 25, 8665–8670. Volkow, N.D., Wang, G.J., Telang, F., Fowler, J.S., Logan, J., et al., 2006. Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J. Neurosci. 26, 6583–6588. Weerts, E.M., Froestl, W., Kaminski, B.J., Griffiths, R.R., 2007. Attenuation of cocaine- seeking by GABA(B) receptor agonists baclofen and CGP44532 but not the GABA reuptake inhibitor tiagabine in baboons. Drug Alcohol Depend. 89, 206–213. Westerink, B.H., Kwint, H.F., de Vries, J.B., 1997. Eating-induced dopamine release from mesolimbic neurons is mediated by NMDA receptors in the ventral tegmental area: a dual-probe microdialysis study. J. Neurochem. 69, 662–668. Wirtshafter, D., Sheppard, A.C., 2001. Localization of GABA(B) receptors in midbrain monoamine containing neurons in the rat. Brain Res. Bull. 56, 1–5. Yoshida, M., Yokoo, H., Tanaka, T., Emoto, H., Tanaka, M., 1994. Opposite changes in the mesolimbic dopamine metabolism in the nerve terminal and cell body sites induced by locally infused baclofen in the rat. Brain Res. 636, 111–114. Xi, Z.X., Stein, E.A., 1999. Baclofen inhibits heroin self-administration behavior and mesolimbic dopamine release. J. Pharmacol. Exp. Ther. 290, 1369–1374.
Effects of GABAB receptor agents on cocaine priming, discrete contextual cue and food induced relapses Małgorzata Filip ⁎, Małgorzata Frankowska Laboratory of Drug Addiction Pharmacology, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, 12 Smętna, Poland Received 16 April 2007; received in revised form 24 May 2007; accepted 24 May 2007 Available online 13 June 2007
Abstract In the present study we investigated the effects of the GABAB receptor antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), the agonists baclofen and 3-aminopropyl(methyl)phoshinic acid (SKF 97541), and the allosteric positive modulator 3,5-bis(1,1dimethylethyl)-4-hydroxy-β,β-dimethylbenzenepropanol (CGP 7930) on cocaine seeking behavior. The effects of the above drugs on the reinstatement of responding induced by natural reinforcer (food) were also studied. Male Wistar rats were trained to self-administer either cocaine (0.5 mg/kg/infusion) or food (sweet milk) and responding on the reinforcer-paired lever was extinguished. Reinstatement of responding was induced by a noncontingent presentation of the self-administered reinforcer (10 mg/kg cocaine, i.p.), a discrete contextual cue, or a contingent presentation of food. SCH 50911 (3–10 mg/kg) dose-dependently attenuated responding on the previously cocaine-paired lever during both reinstatement conditions, with slightly greater efficacy at reducing conditioned cue reinstatement. At the same time, it failed to alter reinstatement of food-seeking behavior. Baclofen (1.25–5 mg/kg) and SKF 97541 (0.03–0.3 mg/kg) attenuated cocaine- or food-seeking behavior; the effect of the drug appeared more effective for cocaine-seeking than food-seeking. CGP 7930 (10–30 mg/kg) reduced cocaine seeking without affecting food-induced reinstatement on reward seeking. Our results indicate that tonic activation of GABAB receptors is required for cocaine seeking behavior in rats. Moreover, the GABAB receptor antagonist SCH 50911 was effective in reducing relapse to cocaine at doses that failed to alter reinstatement of food-seeking behavior (present study), basal locomotor activity, cocaine and food self-administration (Filip et al., submitted for publication), suggesting its selective effects on motivated drug-seeking behavior. The potent inhibitory responses on cocaine seeking behavior were also seen following the GABAB receptor agonists or the allosteric positive modulator, however, doses of baclofen and SKF 97541 that inhibited cocaine-seeking were only threefold lower of those that inhibited food-seeking. In addition, the direct GABAB receptor agonists and the allosteric positive modulator cause decreases in cocaine or food self-administration (Filip et al., submitted for publication), indicating their nonspecific effects on relapse to drug-seeking and drug-taking behavior. In conclusion, the GABAB receptor antagonist SCH 50911 seems to be viable treatment for reducing cocaine craving and preventing relapse, while the GABAB receptor allosteric positive modulator CGP 7930 may hold the highest promise for attenuating cue-evoked relapses to cocaine as well as the direct rewarding properties of cocaine. © 2007 Elsevier B.V. All rights reserved. Keywords: GABAB receptor; Cocaine-seeking behavior; Food-seeking behavior; (Rat)
1. Introduction Drug dependence is characterized by high rates of relapse to drug-seeking and drug-taking behavior following periods of abstinence and drug detoxification (Mendelson and Mello, 1996; O'Brien, 1997). Studies in humans provide evidence that relapse to cocaine use or cocaine craving can be initiated by ⁎ Corresponding author. Tel.: +48 12 6623293; fax: +48 12 6374500. E-mail address: [email protected] (M. Filip). 0014-2999/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2007.05.069
multiple triggers including the self-administered drug (de Wit) or drug-associated environmental cues (Carter and Tiffany, 1999; Childress et al., 1993). Relapse can be modeled in preclinical studies in reinstatement procedure in which laboratory animals are trained to self-administer drugs and then subjected to extinction training during which – in an operant version of this procedure – lever presses are not reinforced with drugs. Reinstatement of extinguished lever responding (the operational measure of drug seeking) is determined after such manipulations as noncontingent priming
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injections of the drug (de Wit and Stewart, 1981), exposure to cues associated with drug intake (Meil and See, 1996) or exposure to stress (Erb et al., 1996). The reinstatement model has good face validity for modeling the activation of craving and arousal by environmental conditioned stimuli in drug dependent individuals. A large body of evidence indicates a major role of the activation of the dopaminergic and glutamatergic pathways in the nucleus accumbens, the prefrontal cortex, the ventral tegmental area, the amygdala and the ventral hippocampus in the drugpriming and cue-induced reinstatement of cocaine seeking (for review see: Kalivas and McFarland, 2003; Rebec and Sun, 2005; Schmidt et al., 2005; See, 2005). Moreover, recent behavioral findings show the cocaine seeking is also effectively reduced by the inhibitory neurotransmission of γ-aminobutyric acid (GABA). For example, indirect GABA agonist vigabatrin exerted inhibitory actions on the reinstatement of extinguished cocaine-seeking behavior induced by cocaine priming (Filip et al., 2007). The abolishment of cocaine-induced reinstatement of drug-seeking behavior was also seen after activation of both GABAA and GABAB receptors by direct infusion of a mixture of the receptor agonists, muscimol and baclofen, into the dorsal prefrontal cortex, the ventral pallidum (McFarland and Kalivas, 2001) or the ventral hippocampus (Rogers and See, 2007). The same treatment combination when microinfused into the lateral orbitofrontal cortex (Fuchs et al., 2004a), the ventral tegmental area (Di Ciano and Everitt, 2003), the accumbens core (Di Ciano and Everitt, 2003; Fuchs et al., 2004b) or the ventral hippocampus (Rogers and See, 2007) attenuated cue-induced cocaine seeking. More recently, GABAB receptor agonists given systemically reduced cocaine-seeking behavior in laboratory animals: baclofen decreased drug-associated cue-controlled cocaine-seeking behavior in rats (Di Ciano and Everitt, 2003), while both baclofen and 3-amino-2[S]-hydroxypropylmethylphosphinic acid (CGP 44532) attenuated the relapse to cocaine priming doses in baboons (Weerts et al., 2007). In the present study we investigated the effects of the GABAB receptor agonists baclofen (Froestl et al., 1995a) and 3aminopropyl(methyl)phoshinic acid (SKF 97541; Froestl et al., 1995a), the antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911; Froestl et al., 1995b) as well as the allosteric positive modulator 3,5-bis(1,1-dimethylethyl)-4-hydroxy-β,βdimethylbenzenepropanol (CGP 7930; Urwyler et al., 2001) on cocaine-primed and conditioned cue-induced reinstatement of drug-seeking behavior following chronic intravenous cocaine self-administration in an animal model of relapse. Additionally, we investigated the effects of the above GABAB receptor ligands and the allosteric positive modulator on the reinstatement of responding induced by food. 2. Materials and methods 2.1. Animals Male Wistar rats (280–300 g) delivered by a licensed breeder (T. Górzkowska, Warsaw, Poland) were housed individually in standard plastic rodent cages in a colony room maintained at 20±
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1 °C and at 40–50% humidity under a 12-h light–dark cycle (lights on at 06:00). Animals had free access to food (Labofeed pellets) and water during the 7-day habituation period. Then, rats used in the cocaine self-administration procedures were maintained on limited water during initial training sessions (see below), while animals used in the food self-administration procedures were maintained on limited food intake (see below). All experiments were conducted during the light phase of the light–dark cycle (between 08:00–15:00) and were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and with approval of the Bioethics Commission as compliant with the Polish Law (21 August 1997). The animals were experimentally naïve. 2.2. Drugs 3-Aminopropyl(methyl)phoshinic acid (SKF 97541; Tocris, UK), (R)-baclofen (Tocris, UK), cocaine hydrochloride (National Institute on Drug Abuse, RTI International, USA), (2S)-(+)-5,5dimethyl-2-morpholineacetic acid (SCH 50911; Tocris, UK) and 3,5-bis(1,1-dimethylethyl)-4-hydroxy-β,β-dimethyl-benzenepropanol (CGP 7930; Tocris, UK) were used. Baclofen, cocaine, SCH 50911 and SKF 97541 were dissolved in sterile 0.9% NaCl, while CGP 7930 was diluted in 2 drops of ethanol and then in 1% Tween (Sigma Aldrich, USA). Cocaine was given either i.v. (0.05 ml/infusion) or i.p. (1 ml/kg); other drugs were injected i.p. in a volume of 1 ml/kg. Baclofen, CGP 7930, SCH 50911 or SKF 97541 were administered at 30, 30, 45 or 30 min, respectively, before reinstatement tests. The dose-range and pretreatment intervals of the GABAB receptor ligands and the allosteric positive modulator were chosen based on their functional in vivo activity at GABAB receptors (Carai et al., 2004a,b; Colombo et al., 2001; Froestl et al., 1995a,b; Slattery et al., 2005a,b; Smith et al., 2004). 2.3. Cocaine self-administration Rats were trained to press the lever of standard operant conditioning chambers (Med-Associates, USA) under a fixed ratio 5 schedule of water reinforcement. Two days following “lever press” training and free access to water, the rats were chronically implanted with a silastic catheter in the external right jugular vein, as described previously (Filip, 2005). Catheters were flushed every day with 0.1 ml of saline solution containing heparin (70 U/ml, Biochemie, Austria) and 0.1 ml of solution of cephazolin (10 mg/ml; Biochemie GmbH, Austria). Catheter patency was tested periodically with the ultrashortacting barbiturate anesthetic methohexital (10 mg/kg, i.v.; loss of consciousness within 5 s). After a 10-day recovery period, all animals were water deprived for 18 h and trained to lever press to fixed ratio 5 schedule of water reinforcement over a 2-h session. Subjects were then given access to cocaine during 2-h daily sessions performed 6 days/week (maintenance) and from that time they were given ad libitum water. The house light was illuminated throughout each session. Each completion of five presses on the “active” lever complex (fixed ratio 5 schedule) resulted in a 5-s infusion of cocaine
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(0.5 mg/kg per 0.1 ml) and a 5-s presentation of a stimulus complex (activation of the white stimulus light directly above the “active” lever and the tone generator, 2000 Hz; 15 dB above ambient noise levels). Following each injection, there was a 20-s time-out period during which responding was recorded but had no programmed consequences. Response on the “inactive” lever never resulted in cocaine delivery. Acquisition of the conditioned operant response lasted a minimum of 10 days until subjects met the following criteria: minimum requirement of 22 reinforcements with an average of 6 days and active lever presses with an average of 6 consecutive days and a standard deviation within those 6 days of b 10% of the average; this criterion was selected based on our prior experiments (Filip, 2005). Once stable rates of responding were established, the extinction procedure was carried out on the following day. During extinctions sessions subjects had 2-h daily training sessions with no delivery of cocaine or the presentation of the conditioned stimulus. Once they reached the extinction criteria (a minimum of 10 extinction days with the responding on the active lever below 10% of the level observed during maintenance during at least 3 consecutive days), the separate groups of rats (n = 7–8 rats/group) were tested for response reinstatement induced by either a noncontingent presentation of the selfadministered reinforcer (10 mg/kg cocaine, i.p.) or discrete contextual cue (tone + light previously paired with cocaine selfadministration). Before test sessions rats were pretreated with either appropriate vehicle, baclofen (1.25–5 mg/kg), CGP 7930 (10–30 mg/kg), SCH 50911 (3–10 mg/kg), or SKF 97451 (0.03– 0.3 mg/kg). During the reinstatement tests (2-h sessions), active lever presses on the fixed ratio 5 schedule resulted only in an intravenous injection of saline. Drug combinations were given in a randomized order in three-four reinstatement tests that each rat received and test sessions were separated by at least two-three extinction sessions.
presentation of food. Each completion of a fixed ratio 5 schedule on the “active” lever resulted in a delivery of the portion of sweetened milk (0.1 ml) in daily 2-h sessions. Following each reward, there was a 20-s time-out period during which responding was recorded but had no programmed consequences. Response on the “inactive” lever never resulted in food delivery. Before test sessions rats were pretreated with either appropriate vehicle, baclofen (1.25–5 mg/ kg), CGP 7930 (10–30 mg/kg), SCH 50911 (3–10 mg/kg), or SKF 97451 (0.03–0.3 mg/kg). Drug combinations were given in a randomized order in three-four reinstatement tests that each rat received and test sessions were separated by at least two-three extinction sessions. 2.5. Statistical analyses During reinstatement of cocaine- or food-seeking behavior, the number of responses on the active and inactive lever (including time out responding) for each group pretreated with a GABAB receptor ligand or the allosteric positive modulator was
2.4. Food self-administration Food self-administration was conducted in a manner parallel to cocaine self-administration. Food-restricted rats (20 g/rat/day) were trained to press the lever of a standard operant chambers (MedAssociates, USA) under a fixed ratio 5 schedule of reinforcement (each completion of a fixed ratio 5 schedule on the “active” lever resulted in a delivery of the portion of sweetened milk (0.1 ml)) in daily 2-h sessions. Following each reward, there was a 20-s timeout period during which responding was recorded but had no programmed consequences. Response on the “inactive” lever never resulted in food delivery. The house light was on throughout each session. Rats remained in maintenance training until lever pressing stabilized (the number of active lever presses varied by 10% or less over the course of 3 consecutive maintenance days). Once stable rates of responding were established, the extinction procedure was carried out on the following day. During extinctions sessions subjects had 2-h daily training sessions with no delivery of food. Once they reached the extinction criteria (a minimum of 10 extinction days with the responding on the active lever below 10% of the level observed during maintenance during at least 3 consecutive days), the separate groups of rats (n =7–8 rats/group) were tested for response reinstatement induced by a contingent
Fig. 1. Effects of the GABAB receptor agonists (baclofen and SKF 97541), the allosteric positive modulator (CGP 7930) and the antagonist (SCH 50911) on the response reinstatement induced by a noncontingent presentation of the selfadministered reinforcer (10 mg/kg cocaine, i.p.). Number of active (cross hatched bars) and inactive (white bars) lever presses following cocaine priming injections (COC) are shown for pretreatment with baclofen (BAC; 1.25–5 mg/ kg), SKF 97541 (SKF; 0.03–0.3 mg/kg), CGP 7930 (CGP; 10–30 mg/kg), SCH 50911 (SCH; 3–10 mg/kg) and the appropriate vehicle (Veh). The baseline extinction (Ext) responding is also presented. The data points represent the means of data from 7–8 rats. ⁎P b 0.01, ⁎⁎ P b 0.001 vs. Ext; +P b 0.05, ++ P b 0.01 vs. Veh-COC 10.
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inactive (F(4,30) = 0.8), lever presses. A significant decrease was observed following baclofen, 2.5 and 5 mg/kg. Pretreatment with SKF 97541 (0.03–0.3 mg/kg) significantly altered the number of active (F(4,30) = 15.6, P b 0.001), but not (F(4,30) = 2.1), inactive lever presses. A significant decrease was observed following all doses of SKF 97541. Pretreatment with CGP 7930 (10–30 mg/kg) significantly altered the number of active (F(3,24) = 5.3, P b 0.01), but not inactive (F(3,24) = 0.3), lever presses. A significant decrease was observed following CGP 7930, 30 mg/kg. Pretreatment with SCH 50911 (3–10 mg/kg) significantly altered the number of active (F(3,24) = 6.2, P b 0.01), but not inactive (F(3,24) = 0.7), lever presses. The individual dose groups of pretreatment with SCH 50911 (3–10 mg/kg) in combination with cocaine did not indicate a significant alteration, however, a higher dose of SCH 50911 attenuated cocaine-seeking behavior by 45%. 3.1.2. Cue-primed reinstatement After 10 days of extinction the rats were tested for response reinstatement induced by the discrete contextual cue. Fig. 2 shows the effects of GABAB receptor agents on cue-primed reinstatement. Fig. 2. Effects of the GABAB receptor agonists (baclofen and SKF 97541), the allosteric positive modulator (CGP 7930) and the antagonist (SCH 50911) on the response reinstatement induced by a contingent presentation of discrete contextual cues (tone +light previously paired with cocaine self-administration). Number of the active (cross hatched bars) and inactive (white bars) lever presses following the cue are shown for pretreatment with baclofen (BAC; 1.25–5 mg/kg), SKF 97541 (SKF; 0.03–0.3 mg/kg), CGP 7930 (CGP; 10–30 mg/kg), SCH 50911 (SCH; 3–10 mg/kg) and the appropriate vehicle (Veh). The baseline extinction (Ext) responding is also presented. The data points represent the means of data from 7–8 rats. ⁎P b 0.01 vs. Ext; +P b 0.05, ++P b 0.01 vs. Veh-Cue.
analyzed by separate one-way ANOVAs and where appropriate a post hoc Dunnett's test was used to analyze differences between group means. 3. Results 3.1. Cocaine seeking Rats showed stable lever responding during the last 6 selfadministration maintenance sessions with an acquisition criterion requiring that the rate of active lever presses varied by less than 10%. The animals had self-administered 22–38 injections of cocaine with the daily mean cocaine intake between 11 and 18 mg/kg. 3.1.1. Cocaine-primed reinstatement After 10 days of extinction the rats were tested for response reinstatement induced by cocaine (10 mg/kg, i.p.). Fig. 1 shows the effects of GABAB receptor agents on cocaine-primed reinstatement. Pretreatment with baclofen (1.25–5 mg/kg) significantly altered the number of active (F(4,30) = 5.6, P b 0.001), but not
Fig. 3. Effects of the GABAB receptor agonists (baclofen and SKF 97541), the allosteric positive modulator (CGP 7930) and the antagonist (SCH 50911) on the response reinstatement induced by a contingent presentation of food (sweetened milk). Number of the active (cross hatched bars) and inactive (white bars) lever presses following presentation of food are shown for pretreatment with baclofen (BAC; 1.25–5 mg/kg), SKF 97541 (SKF; 0.03–0.3 mg/kg), CGP 7930 (CGP; 10–30 mg/kg), SCH 50911 (SCH; 3–10 mg/kg) and the appropriate vehicle (Veh). The baseline extinction (Ext) responding is also presented. The data points represent the means of data from 7–8 rats. ⁎P b 0.01, ⁎⁎P b 0.001 vs. Ext; + P b 0.01, ++P b 0.001 vs. Veh-Food.
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Pretreatment with baclofen (1.25–5 mg/kg) significantly altered the number of active (F(4,34) = 3.8, P b 0.01), but not inactive (F(4,30) = 2.1), lever presses. A significant decrease was observed following baclofen, 5 mg/kg. Pretreatment with SKF 97541 (0.03–0.3 mg/kg) significantly altered the number of active (F(4,34) = 4.5, P b 0.01), but not inactive (F(4,34) = 0.8), lever presses. A significant decrease was observed following SKF 97541, 0.1 and 0.3 mg/kg. Pretreatment with CGP 7930 (10–30 mg/kg) significantly altered the number of active (F(3,24)= 5.3, P b 0.01), but not inactive (F(3,24) = 1.46), lever presses. A significant decrease was observed following both doses of CGP 7930, 10 and 30 mg/kg. Pretreatment with SCH 50911 (3–10 mg/kg) significantly altered the number of active (F(3,24) = 3.74, P b 0.05), but not inactive (F(3,24) = 2.39), lever presses. A significant decrease was observed following SCH 50911, 10 mg/kg. 3.2. Food seeking Rats showed stable responding on levers during the last 3 self-administration maintenance sessions with an acquisition criterion requiring that the rate of active lever presses varied by less than 10%. Rats responded significantly more frequently on the active lever than on the inactive lever (P b 0.05), independently of food self-administration test day. After 10 days of extinction the rats were tested for response reinstatement induced by the contingent presentation of food. Fig. 3 shows the effects of GABAB receptor agents on food seeking. Pretreatment with baclofen (1.25–5 mg/kg) significantly altered the number of active (F(4,30) = 59.8, P b 0.001), but not inactive (F(4,30) = 1.8), lever presses. A significant decrease was observed following baclofen, 5 mg/kg. Pretreatment with SKF 97541 (0.03–0.3 mg/kg) significantly altered the number of active (F(4,25) = 16.53, P b 0.001), but not inactive (F(4,34) = 0.8), lever presses. A significant decrease was observed following SKF 97541, 0.3 mg/kg. Pretreatment with CGP 7930 (10–30 mg/kg) significantly altered the number of active (F(3,24) = 111.9, P b 0.001), but not inactive (F(3,24) = 0.29), lever presses. However, the individual dose groups of pretreatment with CGP 7930 (10–30 mg/kg) in combination with food did not indicate a significant alteration in the response reinstatement. Pretreatment with SCH 50911 (3–10 mg/kg) significantly altered the number of active (F(3,24) = 35.29, P b 0.005), but not inactive (F(3,24) = 0.31), lever presses. However, the individual dose groups of pretreatment with SCH 50911 (3–10 mg/kg) in combination with food did not indicate a significant alteration in the response reinstatement. 4. Discussion The present findings indicate for the first time that that SCH 50911, the selective GABAB receptor antagonist, significantly reduced cocaine-associated cue-induced and attenuated cocaine-induced reinstatement of cocaine seeking, but failed to alter food-induced reinstatement. We also report that pharma-
cological direct stimulation of GABAB receptors by agonists baclofen or SKF 97541 attenuated cocaine- or food-seeking behavior; the effect of SKF 97541 appeared somewhat more effective for cocaine-seeking than food-seeking. Finally, we demonstrate that the GABAB receptor modulator CGP 7930 can block cocaine seeking without affecting food-induced reinstatement on reward seeking. The ability of SCH 50911 (10 mg/kg), the selective and potent GABAB receptor antagonist (Bolser et al., 1995; Froestl et al., 1995b), to reduce discrete contextual cues (tone + light) indicates that tonic activation of GABAB receptors is required for the cocaine seeking behavior in rats. When used at the same dose SCH 50911 attenuated – although non-significantly – reinstatement of responding induced by a noncontingent presentation of the selfadministered reinforcer (10 mg/kg cocaine, i.p.). Since conditioned-cued reinstatement models are more analogous relapse in humans than cocaine-primed reinstatement (Childress et al., 1993; Jaffe et al., 1989), the stronger inhibitory efficacy of SCH 50911 to reduce cocaine-associated cue-induced reinstatement indicates that this antagonist could may be used as an effective therapeutic drug for preventing relapse. Interestingly, the potent inhibitory responses on cocaine seeking behavior were also seen following pretreatment with the direct GABAB receptor agonists (baclofen and SKF 97541) or the allosteric positive modulator (CGP 7930). The results with baclofen are consistent with the study by Di Ciano and Everitt (2003) who observed that the agonist, when tested at similar dose ranges, decreased responding maintained by the responsecontingent presentations of cocaine-associated conditioned reinforcers in rats. Hotsenpiller and Wolf (2003) found that baclofen attenuated cocaine-conditioned locomotion in rats and more recently, Weerts et al. (2007) found that baclofen and another GABAB receptor agonist CGP 44532 attenuated the relapse to cocaine (i.v.) priming doses in baboons. Partly supporting preclinical studies, baclofen dose-dependently decreased ratings of cocaine craving in a methadone group (Haney et al., 2006), but not in heavy cocaine users (Shoptaw et al., 2003). The inhibitory effects of the GABAB receptor agonists used in the present study seem to be more potent toward cocainethan cue-induced reinstatement since the minimum effective doses of baclofen and SKF 97541 in the cocaine relapse model were 2 or 3 times lower, respectively, than the minimum effective doses of these drugs in the cue relapse model. It should be underlined that differences in responses of direct GABAB receptor antagonist, agonists and the allosteric positive modulator on the incentive motivational effects of cocaine. Thus, an effective dose of SCH 50911 (10 mg/kg) that reduced/ attenuated cocaine seeking behavior failed to alter reinstatement of food seeking (present study), cocaine and food self-administration, inactive lever responding or locomotor activity (Filip et al., submitted for publication). This suggests that decreases in cocaine seeking were related to specific motivational decreases for the artificial reinforcer (cocaine), but not to change of the natural reward or motor artifacts, per se. On the other hand, the inhibitory effects of the GABAB receptor agonists baclofen and SKF 97541 do not appear specific to drug-seeking behavior since they at the moderate doses impacted on cocaine seeking while at
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the higher doses they produced inhibitory effects on reinstatement of natural reward (present study). Moreover, baclofen in a similar dose range (2.5–5 mg/kg) reduced the primary reinforcement of cocaine during intravenous self-administration, food self-administration, and basal locomotor activity in rats (Filip et al., submitted for publication). SKF 97541 (0.1–0.3 mg/ kg) reduced the maintenance of cocaine and food selfadministration, but, in contrast to baclofen, does not alter basal locomotor activity in rats (Filip et al., submitted for publication). The GABAB allosteric positive modulator CGP 7930 inhibited cocaine-seeking behavior, but not food-seeking behavior (present study), food self-administration or basal locomotor activity (Filip et al., submitted for publication). Taking into account such effects of CGP 7930 (30 mg/kg) it seems that this modulator displays more selective action on motivated cocaine-seeking behavior than direct GABAB receptor agonists. On the other hand, it also effectively diminished cocaine's rewarding effects as assessed by self-administration (Smith et al., 2004; Filip et al., submitted for publication) suggesting that decreases in cocaine-triggered reinstatement of cocaine-seeking behavior might be due to its direct antagonistic interaction with cocaine per se. The mechanism through which GABAB receptor antagonist, agonist and allosteric positive modulator act to inhibit responding to cocaine-seeking remains largely unexplained. Thus, activation of both the dopaminergic and/or glutamatergic systems appears to have significance in altering the drug-priming and cue-induced reinstatement of cocaine seeking (for review see: Kalivas and McFarland, 2003; Rebec and Sun, 2005; Schmidt et al., 2005; See, 2005) and GABAB receptors are widely distributed in several brain areas related to cocaine seeking where they modulate both the excitatory and the inhibitory components of pre- and postsynaptic mechanisms (Thompson and Gahwiler, 1992). For example, in the ventral tegmental area GABAB receptors act as heteroreceptors present on dopamine and glutamatergic neurons (Bowery et al., 1987; Liang et al., 2000; Wirtshafter and Sheppard, 2001) as well as presynaptic autoreceptors on GABA interneurons (Rahman and McBride, 2002). Activation of these receptors by local injection of baclofen suppresses extracellular dopamine levels in the nucleus accumbens (Fadda et al., 2003) and prefrontal cortex (Yoshida et al., 1994; Westerink et al., 1997; Xi and Stein, 1999) or the cocaine-induced elevation in extracellular dopamine in the nucleus accumbens (Fadda et al., 2003). In the prefrontal cortex GABAB receptors are localized on presynaptic terminals of glutamatergic nerve endings and/or cell bodies (Margeta-Mitrovic et al., 1999), and on GABA neurons where they act as autoreceptors (Calver et al., 2002). It was also shown that in animals treated repeatedly with cocaine intraprefrontal cortex injection with baclofen increased glutamate levels in the nucleus accumbens and the ventral tegmental area (Jayaram and Steketee, 2004). The GABAB receptor allosteric positive modulator CGP 7930 synergistically interacts with endogenously released GABA and enhances the GABAB receptor-mediated inhibition of dopamine neuronal activity in the ventral tegmental area (Chen et al., 2005). It should be noted that, however, in the hippocampal CA1 area CGP 7930 selectively enhances the baclofen-induced modulation of synaptic inhibition resulting
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from activation of presynaptic autoreceptors located on the inhibitory GABA terminals, without having any significant effects on the presynaptic heterosynaptic receptors on the excitatory glutamate terminals (Chen et al., 2006). Since the ventral CA subfields of the hippocampus play an important role in the relapse to cue-induced and cocaine-primed reinstatement (Rogers and See, 2007), it may be speculated that the inhibitory effects of CGP 7930 toward cocaine-seeking behavior (the present study) may be related with stimulation of GABAB presynaptic autoreceptors in this brain structure This might be further supported by the fact that responding for food reinforcement was not altered either by CGP 7930 (Filip et al., submitted for publication) or by local inactivation of the ventral hippocampus (Rogers and See, 2007). In direct contrast to GABAB receptor stimulation, the blockade of these receptors was proposed to enhance dopamine release, since SCH 50911, given systemically or locally, resulted in activation of nigral dopamine neurons in rats (Erhardt et al., 1999) while another GABAB receptor antagonist phaclofen, perfused locally into the ventral pallidum increased extracellular dopamine level in this brain structure (Gong et al., 1998). In line with biochemical studies, SCH 50911 enhanced locomotor stimulation in mice; the effect being blocked by haloperidol (Colombo et al., 2001). Interestingly, Ashby et al. (1999) reported that SCH 50911 (3 mg/kg) did not alter dopamine efflux in the nucleus accumbens, which might suggest that activation of dopamine neurotransmission following GABAB receptor blockade is limited to striatonigral and/or mesopallidal pathways. Increases in extracellular dopamine were observed in the dorsal striatum in rodents (Ito et al., 2002; Vanderschuren et al., 2005) and cocaine addicts (Volkow et al., 2006) responding to cocaine cues. Since SCH 50911 neither produces relapse to cocaine seeking (Frankowska and Filip, unpublished results) nor substitutes for cocaine (Filip et al., submitted for publication), the local increases of basal dopamine level in brain areas related to seeking (e.g. the dorsal striatum; Erhardt et al., 1999; Ito et al., 2002; Vanderschuren et al., 2005) but not reward (the nucleus accumbens; Ashby et al., 1999) may lead to normalization of the dopamine levels in the areas related to seeking behavior since withdrawal from cocaine self-administration reduces basal extracellular levels of dopamine in those areas (Dworkin et al., 1995; Parsons et al., 1995). Additionally, it is worth to add that GABAB receptor labelling was found on the presynaptic membranes of GABA-ergic synapses in the rat substantia nigra (Boyes and Bolam, 2003) and the striatum (Lacey et al., 2005). SCH 50911 acting on presynaptic GABAB receptors located on GABA terminals may release GABA which subsequently activate postsynaptic GABAB receptor sites. The inhibitory effect of SCH 50911 on the cue-induced cocaine seeking might be also related with its partial agonistic properties at GABAB receptors seen in that experimental condition. To conclude, our present findings suggest that the GABAB receptor antagonist SCH 50911 and the allosteric positive modulator CGP 7930 have unique relevance for different aspects of human cocaine addiction. Thus, SCH 50911 may be used as anti-addiction pharmacotherapeutic agent for reducing cocaine craving and preventing relapse in abstinent cocaine addicts.
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Additionally, its antidepressant-like actions (Frankowska et al., 2007) together with selective GABAB receptor antagonists (Slattery et al., 2005a) may also offer novel approach for the treatment of cocaine withdrawal-evoked depression. CGP 7930 may hold the highest promise for attenuating cue-evoked relapses to cocaine as well as to reduce the direct rewarding properties of cocaine that model the cocaine-induced subjective “high”. It should be added that beyond simply reducing the primary rewarding effects of cocaine (Slattery et al., 2005a,b; Filip et al., submitted for publication), GABAB receptor allosteric positive modulators reduce anxiety in preclinical paradigms (Cryan et al., 2004) that could also help in the treatment of addiction. Acknowledgements We are grateful to Dr. Andrew C. McCreary for the comments and language editing of the manuscript. Expert technical assistance was provided by Ewa Nowak and Karolina Wydra. The authors would like to kindly acknowledge donation of cocaine hydrochloride from the National Institute on Drug Abuse (RTI International, NC, USA). This study was supported by grants no. 2 PO5A 007 26 and N401 119 32/2421 from the Ministry of Science and Higher Education (Warszawa, Poland). Conflict of interest: None. References Ashby Jr., C.R., Rohatgi, R., Ngosuwan, J., Borda, T., Gerasimov, M.R., Morgan, A.E., Kushner, S., Brodie, J.D., Dewey, S.L., 1999. Implication of the GABA(B) receptor in gamma vinyl-GABA's inhibition of cocaineinduced increases in nucleus accumbens dopamine. Synapse 31, 151–153. Bolser, D.C., Blythin, D.J., Chapman, R.W., Egan, R.W., Hey, J.A., Rizzo, C., Kuo, S.C., Kreutner, W., 1995. The pharmacology of SCH 50911: a novel, orally-active GABA-beta receptor antagonist. J. Pharmacol. Exp. Ther. 274, 1393–1398. Bowery, N.G., Hudson, A.L., Price, G.W., 1987. GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience 20, 365–383. Boyes, J., Bolam, J.P., 2003. The subcelllar locoalization of GABAB receptor subunits in the rat substantia nigra. Eur. J. Neurosci. 18, 3279–3293. Carai, M.A., Colombo, G., Gessa, G.L., 2004a. Protection by the GABAB receptor antagonist, SCH 50911, of gamma-hydroxybutyric acid-induced mortality in mice. Eur. J. Pharmacol. 503, 77–80. Carai, M.A., Colombo, G., Froestl, W., Gessa, G.L., 2004b. In vivo effectiveness of CGP7930, a positive allosteric modulator of the GABAB receptor. Eur. J. Pharmacol. 504, 213–216. Calver, A.R., Davies, C.H., Pangalos, M., 2002. GABA(B) receptors: from monogamy to promiscuity. Neurosignals 11, 299–314. Carter, B.L., Tiffany, S.T., 1999. Meta-analysis of cue-reactivity in addiction research. Addiction 94, 327–340. Chen, Y., Phillips, K., Minton, G., Sher, E., 2005. GABA(B) receptor modulators potentiate baclofen-induced depression of dopamine neuron activity in the rat ventral tegmental area. Br. J. Pharmacol. 144, 926–932. Chen, Y., Menendez-Roche, N., Sher, E., 2006. Differential modulation by the GABAB receptor allosteric potentiator 2,6-di-tert-butyl-4-(3-hydroxy-2,2dimethylpropyl)-phenol (CGP7930) of synaptic transmission in the rat hippocampal CA1 area. J. Pharmacol. Exp. Ther. 317, 1170–1177. Childress, A.R., Ehrman, R.N., Robbins, S.J., McLelan, A.T., O'Brien, C.P., 1993. Cue reactivity and cue reactivity interventions in drug dependence. NIDA Res. Monogr. 137, 73–95. Colombo, G., Melis, S., Brunetti, G., Serra, S., Vacca, G., Carai, M.A., Gessa, G.L., 2001. GABA(B) receptor inhibition causes locomotor stimulation in mice. Eur. J. Pharmacol. 433, 101–104.
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