Neuroscience Letters 569 (2014) 137–141

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The novel dopamine D3 receptor antagonist, SR 21502, reduces cocaine conditioned place preference in rats P. Hachimine a , N. Seepersad b , S. Ananthan c , R. Ranaldi a,b,∗ a b c

CUNY Graduate Center, Neuropsychology Doctoral Program, United States Queens College of the City University of New York, Department of Psychology, United States Organic Chemistry Department, Southern Research Institute, United States

h i g h l i g h t s • The selective D3 antagonist, SR 21502, blocks cocaine conditioned place preference. • Dopamine D3 receptors play a role in cocaine conditioned place preference. • Cocaine-seeking related behaviors depend on dopamine D3 receptors.

a r t i c l e

i n f o

Article history: Received 2 February 2014 Received in revised form 13 March 2014 Accepted 24 March 2014 Keywords: Cocaine D3 receptor antagonist Conditioned place preference Addiction

a b s t r a c t Research has shown that dopamine (DA) D3 receptors play a crucial role in cocaine addiction. Recently, there has been a strong focus on the development of DA D3 receptor antagonists as potential pharmacological treatments for cocaine addiction. We investigated the ability of a novel selective D3 receptor antagonist SR 21502 to block the expression of cocaine-induced conditioned place preference (CPP) in rats. CPP was determined using a two-chamber apparatus. All of the animals had free access to both chambers on day 1, followed by 4 alternating conditioning days of cocaine injection (paired chamber) and 4 alternating non-conditioning days with saline (non-paired chamber). On the test day, animals were systemically treated with 0, 3.75, 7.5 or 15 mg/kg of SR 21502, 10 min prior to being placed in the CPP apparatus, and the time spent in each chamber was recorded for 15 min. The amount of time spent in the cocaine-paired chamber on the test and pre-exposure days was analyzed. Vehicle-treated animals spent significantly more time in the cocaine-paired side during the test than during the pre-exposure session, indicating a cocaine CPP. SR 21502 produced a dose-related significant reduction in the time spent in the cocaine-paired side compared to vehicle. The DA D3 receptor antagonist SR 21502 blocks the rat’s preference for the cocaine-paired chamber, thereby attenuating the rewarding effect of the cocaine cues. This suggests that this compound may be an effective pharmacological treatment against cocaine addiction. © 2014 Elsevier Ireland Ltd. All rights reserved.

Cocaine addiction is a serious public health concern for which there are no strongly effective pharmacotherapeutic treatments. One of the hallmarks of cocaine addiction is compulsive drug-seeking with susceptibility to relapse [1] even after long periods of abstinence [2,3]. Drug-associated stimuli can often induce relapse. For instance, in cocaine-abstinent humans, cocaine-related cues [1,4] can

∗ Corresponding author at: Psychology Department, Queens College, 65-30 Kissena Boulevard, Flushing, NY 11367, United States. Tel.: +1 718 997 3553; fax: +1 718 997 3257. E-mail address: [email protected] (R. Ranaldi). http://dx.doi.org/10.1016/j.neulet.2014.03.055 0304-3940/© 2014 Elsevier Ireland Ltd. All rights reserved.

trigger intense craving, often leading to relapse. Thus, understanding the mechanisms underlying cocaine-seeking would facilitate the development of effective medications against relapse. Animal models have been developed that can be helpful in understanding drug seeking. These include the conditioned place preference (CPP) paradigm – utilized in the present study – which assesses the preference an animal expresses for cocaine cues over non-cocaine cues. This preference presumably reflects the “desirability” for the cocaine cues, a phenomenon that appears to be related to craving and drug-seeking [5,6]. Dopamine (DA) neurotransmission is associated with reward [7–9] and incentive motivation [10–12]. Similar to cocaine itself [13], cocaineassociated cues increase DA neurotransmission in the mesolimbic

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and mesocortical systems [14,15], and result in drug-seeking in animals. Moreover, cocaine CPP studies demonstrate that placement in the cocaine-paired chamber is associated with enhanced DA levels in mesolimbic regions [16,17]. Likewise, presentation of cocaine-related stimuli to addicts results in intense drug craving and activation of DA-innervated brain regions [4,18]. Thus, antagonism of cue-induced DA neurotransmission should reduce the capacity of these cues to elicit cocaine-seeking and related behaviors, and in the CPP paradigm, reduce the expression of cocaine-induced CPP. To date, strongly effective anti-cocaine treatments do not exist [5,19]. Accumulating research data demonstrate that not only can DA D1 and D2 receptor antagonists attenuate drug-seeking elicited by cocaine-paired stimuli in reinstatement procedures [20], but they can also block the expression of cocaine-induced CPP [21–23]. Although these broader DA antagonists can reduce cocaine-seeking [19], they can – especially D2 antagonists – also cause extrapyramidal side effects. Thus, the search continues for an effective pharmacological treatment devoid of problematic side effects. Because the capacity of reward-associated stimuli to control behavior is at least partially dependent on DA D3 receptor stimulation [24,25], significant efforts have been made toward the development of DA D3 receptor agents that are selective for D3 receptors. There is an increasing body of evidence suggesting that DA D3 receptor antagonists [19] can block cocaine’s behavioral effects. These compounds have a higher selectivity for DA D3 than D2 receptors, suggesting that they might be useful in antagonizing drug reward with minimal D2 receptor-mediated extrapyramidal side effects [26]. For instance, NGB 2904 [27], a DA D3 receptor antagonist, can inhibit cocaine-cue induced reinstatement of cocaine-seeking in rats and SB-277011A, another DA D3 receptor antagonist, can attenuate the expression of cocaine-induced CPP [28,29]. As promising as DA D3 receptor antagonists may be, most of the currently available compounds possess suboptimal physicochemical properties [30], precluding them from use as effective pharmacological treatments. As such, there continues to be a strong need to develop novel DA D3 receptor antagonists. In the continuing search for novel D3 receptor selective antagonists, among a series of compounds belonging to the acylaminobutylpiperazine class, compound SR 21502, (N-(4-(4-(2-(tert-butyl)-6-(trifluoromethyl)pyrimidin-4yl)piperazin-1-yl)butyl)imidazo[1,2-a]pyridine-2-carboxamide dihydrochloride), was identified as a ligand with high DA D3 vs. D2 receptor binding selectivity (>100-fold) and favorable physicochemical properties [31,32]. This study was designed to investigate the effect of SR 21502 on cocaine cue induced behavior, as determined with the CPP paradigm. Specifically, we tested the hypothesis that SR 21502 would block the expression of cocaine-induced CPP in rats.

a reverse 12 h light: 12 h dark cycle (lights were turned on at 6 pm). All sessions were conducted during the animals’ active period (the dark cycle). 1.2. Apparatus All behavioral testing was conducted in four identical subject containment environments each measuring 40.5 cm × 20.5 cm × 24.5 cm (l × w × h) and partitioned into two distinct chambers connected by a passageway. Each chamber had a combination of a grid or rod floor with white or striped walls on each side. A removable guillotine door was used to block the passageway when necessary. Each chamber was equipped with 32 infrared transmitters and receivers positioned on two adjacent walls (16 per wall) that tracked the subject’s location and the amount of time it spent in each chamber. 1.3. Drugs Cocaine (a gift from the National Institute on Drug Abuse, Bethesda, MD) was dissolved in 0.9% saline to achieve a concentration of 10 mg/ml. SR 21502, provided by Southern Research Institute (Birmingham, AL) was dissolved in distilled water to achieve concentrations of 0, 3.75, 7.5 and 15 mg/ml. All compounds were injected intraperitoneally (IP) in volumes of 1 ml/kg. The rationale for using this dose range stems from our cocaine selfadministration studies [31], which shows that the aforementioned doses significantly reduced cocaine self-administration. 1.4. Procedure 1.4.1. Pre exposure On the pre-exposure day (day 1), each animal was placed in the passageway between the two chambers and allowed to freely explore the chambers for 15 min. The amount of time spent in each chamber was recorded. The chamber in which any one animal spent the most time was designated its “preferred” chamber. An independent samples t-test (p > .6356) indicated that the rats failed to prefer one chamber over the other.

1.1. Subjects

1.4.2. Conditioning Assignment to the four SR 21502 dose groups was matched to time spent in the preferred chamber. Furthermore, cocaine was paired with the preferred chamber for half of the animals in a group, and with the non-preferred chamber for the remaining animals of that group. Following pre-exposure, each animal underwent eight (days 2–9) daily 30 min conditioning sessions over consecutive days. All of the animals, except those in a no cocaine control group (described below), received IP cocaine (10 mg/kg) injections on conditioning sessions 2, 4, 6 and 8 prior to placement in their assigned chambers, and IP saline vehicle injections on sessions 1, 3, 5 and 7 prior to placement in the alternate chamber. The animals in the no cocaine control group received IP saline vehicle injections prior to all sessions. This group, along with an additional group that received cocaine in one chamber and no cocaine in the alternate chamber, served as paradigm groups to demonstrate that this procedure produces a cocaine conditioned place preference. The guillotine door was inserted during all conditioning sessions for all animals.

Subjects were male Long Evans rats bred in our facility from males and females obtained from Charles River Laboratories (Kingston, NY, USA), and weighed between 350 and 400 g at the time of the experiment. The animals were housed individually with free access to food (Purina Rat Chow) and water and maintained on

1.4.3. Conditioned place preference test On the 10th day, all animals were placed in the passageway between the two chambers (no guillotine door) and allowed to freely explore both chambers for 15 min. Time spent in each chamber was recorded (as described above in the apparatus section). All

1. Methods The protocol used in the present experiment was in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals and was approved by the Queens College Institutional Animal Care and Use Committee.

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Fig. 1. Mean (± SEM) time spent in the cocaine-paired compartment of the CPP chamber during pre-exposure and test sessions. The paradigm groups were treated with either vehicle (vehicle) or 10 mg/ml/kg of cocaine (N = 6 in each group). A significant phase (test vs. pre-exposure) difference is indicated, p < 0.05.

animals received vehicle or a dose (3.75, 7.5 or 15 mg/kg, IP) of SR 21502 10 min prior to being placed in the testing apparatus. 1.4.4. Data analysis Conditioned-place preference was determined by comparing the amount of time spent in the cocaine-paired chamber on the test and pre-exposure days. These values were analyzed using a two-way analysis of variance (ANOVA) with phase (pre-exposure and test) as a repeated measures factor and dose of SR 21502 as a between-groups factor. A separate ANOVA was conducted on the data for the paradigm groups (saline or cocaine conditioning). Significant phase by dose interactions were followed by tests of simple effect of dose at each level of the phase (pre-exposure or test) factor. Significant simple effects were followed by post hoc Dunnett’s tests. 2. Results Rats that received cocaine on conditioning days spent more time in the cocaine-paired chamber on the test day (610 ± 44 s) than on the pre-exposure day (458 ± 46 s) as opposed to rats that did not receive cocaine on conditioning days – (449 ± 36 s) and (490 ± 44 s), respectively (see Fig. 1). A two-way ANOVA with phase as repeated measures on data from these groups revealed a significant interaction of phase by drug [F1,10 = 5.502, p < 0.05]. Tests of simple effect of drug (cocaine or saline) at each level of phase revealed a significant effect in the test level [F1,10 = 7.711, p < 0.05] but not in the preexposure level demonstrating that this procedure produces cocaine CPP. Fig. 2 shows the dose-dependent effects of SR 21502 on the expression of CPP. A two-way ANOVA with phase as a repeated measures factor and dose of SR 21502 as a betweengroups factor revealed a significant phase by group interaction [F3,42 = 9.923, p < 0.001]. Tests of simple effects of dose at each level of phase revealed a significant effect at the test level [F3,42 = 19.814, p < 0.001] but not in the pre-exposure level. Post hoc Dunnett’s tests revealed that each SR 21502 dose was significantly lower than the vehicle (ps < 0.05). 3. Discussion The purpose of the present study was to investigate whether or not the novel DA D3 receptor antagonist, SR 21502, blocks

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Fig. 2. Mean (± SEM) time spent in the cocaine-paired compartment of the CPP chamber during pre-exposure and test sessions. These experimental groups were treated with either vehicle (Veh, N = 10) or one of the SR 21502 doses of 3.75 mg/kg (N = 11), 7.5 mg/kg (N = 14) or 15 mg/kg (N = 11). * Represents a significant difference from the vehicle group.

the expression of cocaine-induced CPP. We found that SR 21502 caused a dose-related reduction in preference for the cocainepaired chamber. In another study conducted in our lab [31], the effects of SR 21502 on spontaneous locomotor activity were tested and results showed that the 15 mg/kg dose of SR 21502 failed to significantly reduce locomotor activity. Thus, it is unlikely that the observed reduction in preference for the cocaine-paired chamber in the current experiment was due to non-specific motoric decrements. Rather, the observed reduction in preference for the cocaine-paired chamber in the present study suggests reduced rewarding effects of cocaine cues. These results are consistent with our recent findings that SR 21502 reduced cue-induced reinstatement of cocaine-seeking [31]. Exposure to cocaine cues appears to be one of the most powerful triggers of cocaine-seeking, often leading to relapse [4,33,34]. In the present investigation, we used the CPP paradigm, in which a previously neutral environment, through conditioning, acquires rewarding properties similar to those of cocaine. The preference for the cocaine-paired chamber suggests that the cocaine cues elicit approach-like behavior, similar to those behaviors elicited by cocaine cues in animals, or addicts, that are seeking cocaine. Thus, the expression of cocaine CPP is thought to be relevant to human drug-seeking and relapse following exposure to cues previously associated with drug use [35,36]. Furthermore, the finding that SR 21502, an antagonist selective for dopamine D3 receptors, effectively reduced the rewarding effects of cocaine cues suggests that D3 receptors may also play a critical role in cocaine-seeking. Our data are in accord with previous studies showing a reduction in cocaine CPP by other D3 receptor antagonists. For instance, SB 277011A and SB-414796, both dopamine D3 receptor antagonists, have been tested in cocaine CPP and have been shown to decrease preference for the cocaine-paired chamber [29,37,38]. In addition, the capacity of dopamine D3 receptor antagonists to reduce “desirability” for cocaine-cues has also been assessed using reinstatement procedures. SB 277011A, NGB 2904 and SR 21502 have been tested in cocaine self-administration and demonstrated to inhibit cocainecue induced reinstatement, suggesting a reduction in the rewarding effects evoked by cocaine cues [27,31,39]. A growing body of evidence indicates that the aforementioned D3 receptor antagonists not only reduce the rewarding effects of cocaine-cues but also suppress the effects of cocaine priming on cocaine seeking. For example, both SB 277011A and NGB-2904 reduce the reinstatement of cocaine seeking triggered by cocaine injection [29,39,40]

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and cocaine cues [27,39], suggesting that D3 receptor antagonists effectively reduce cocaine-seeking. Of particular interest would be to know the site(s) of action where SR 21502 reduces cocaine-induced CPP. Dopamine D3 receptors have been localized to the nucleus accumbens and ventral putamen [41,42], globus pallidus [41], ventral pallidum [41,43,44], islands of Calleja [45–47], central nucleus of the amygdala [41,48], and the ventral tegmental area (VTA) [49–51]. Thus, it appears plausible that SR 21502 may produce its effects on cocaine cues in one or more of these neuroanatomical areas. Of these sites, the VTA and nucleus accumbens in particular may be most likely involved since they are heavily implicated in approach behaviors [52–54], behaviors that are analogous to cocaine-seeking in rats. In conclusion, the present findings demonstrate that SR 21502, a novel selective D3 receptor antagonist, reduces the effects of cocaine cues on behavior. Together with previous findings that it blocks cue-induced reinstatement of cocaine-seeking [31], this finding suggests that SR 21502 has potential as a psychotherapeutic agent for cocaine addiction, specifically for treating cue-induced relapse, and deserves further investigation. Conflict of interest The authors state that there are no conflicts of interest in this work. Acknowledgements This research was supported in part by NIH Grant R01DA024675 (S.A.) from the National Institute on Drug Abuse (NIDA). References [1] B.C. Wallace, Psychological and environmental determinants of relapse in crack cocaine smokers, J. Subst. Abuse Treat. 6 (1989) 95–106. [2] J.H. Jaffe, Drug addiction and drug abuse, in: A.G. Gilman, et al. (Eds.), Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, Pergamon Press, New York, 1990, pp. 522–573. [3] F.H. Gawin, R. Byck, H.D. Kleber, Desipramine augmentation of cocaine abstinence: initial results, Clin. Neuropharmacol. 9 (Suppl. 4) (1986) 202–204. [4] R.N. Ehrman, S.J. Robbins, A.R. Childress, C.P. O’Brien, Conditioned responses to cocaine-related stimuli in cocaine abuse patients, Psychopharmacology 107 (4) (1992) 523–529. [5] M. Solinas, C. Chauvet, N. Thiriet, R. El Rawas, M. Jaber, Reversal of cocaine addiction by environmental enrichment, Proc. Natl. Acad. Sci. U. S. A. 105 (44) (2008) 17145–17150. [6] C. Chauvet, V. Lardeux, S.R. Goldberg, M. Jaber, M. Solinasm, Environmental enrichment reduces cocaine seeking and reinstatement induced by cues and stress but not by cocaine, Neuropsychopharmacology 34 (13) (2009) 2767–2778. [7] R.A. Wise, P.P. Rompre, Brain dopamine and reward, Annu. Rev. Psychol. 40 (1989) 191–225. [8] M.T. Bardo, Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens, Crit. Rev. Neurobiol. 12 (1998) 37–67. [9] R.A. Wise, The dopamine synapse and the notion of “pleasure” centers in the brain, Trends Neurosci. 3 (1980) 200. [10] K.C. Berridge, Food reward: brain substrates of wanting and liking, Neurosci. Biobehav. Rev. 20 (1) (1995) 1–25. [11] R.A. Depue, P.F. Collins, Neurobiology of the structure of personality: dopamine,facilitation of incentive motivation, and extraversion, Behav. Brain Sci. 22 (1999) 491–569. [12] R.A. Wise, Neuroleptics and operant behavior: the anhedonia hypothesis, Behav. Brain Sci. 5 (1982) 39–87. [13] G. Di Chiara, A. Imperato, Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats, Proc. Natl. Acad. Sci. U. S. A. 85 (1988) 5274–5278. [14] E.A. Kiyatkin, E.A. Stein, Conditioned changes in nucleus accumbens dopamine signal established by intravenous cocaine in rats, Neurosci. Lett. 211 (2) (1996) 73–76. [15] M.A. Morency, R.J. Beninger, Dopaminergic substrates of cocaine-induced place conditioning, Brain Res. 399 (1986) 33–41. [16] C.L. Duvauchelle, A. Ikegami, E. Castaneda, Conditioned increases in behavioral activity and accumbens dopamine levels produced by intravenous cocaine, Behav. Neurosci. 114 (6) (2000) 1156–1166.

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The novel dopamine D3 receptor antagonist, SR 21502, reduces cocaine conditioned place preference in rats.

Research has shown that dopamine (DA) D3 receptors play a crucial role in cocaine addiction. Recently, there has been a strong focus on the developmen...
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