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Differential involvement of dopamine D1 receptors in morphine- and lithium-conditioned saccharin avoidance
Physiology & Behavior 96 (2009) 73–77
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Physiology & Behavior j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p h b
Differential involvement of dopamine D1 receptors in morphine- and lithium-conditioned saccharin avoidance Sandro Fenu a,b,1, Emilia Rivas a,1, Gaetano Di Chiara a,b,c,⁎ a b c
Department of Toxicology, University of Cagliari, Cagliari, Italy National Institute of Neuroscience, University of Cagliari, Cagliari, Italy CNR Institute of Neuroscience, Cagliari Section, Cagliari, Italy
a r t i c l e
i n f o
Article history: Received 13 December 2007 Received in revised form 6 August 2008 Accepted 19 August 2008 Keywords: Conditioned taste avoidance Dopamine D1 receptor D2 receptor Lithium chloride Morphine hydrochloride Raclopride Saccharin SCH 39166
a b s t r a c t Conditioned saccharin avoidance (CSA) can be produced when either lithium chloride (LiCl) or a reinforcing drug, such as morphine, is administered following exposure to the taste of saccharin. In this study we investigated the involvement of dopamine (DA) transmission in the acquisition of morphine and LiCl-CSA. CSA was evaluated in a two-bottle choice paradigm with two conditioning pairings between saccharin and morphine or LiCl as unconditioned stimulus (US). Morphine hydrochloride (7.5 mg/kg s.c.) or LiCl (40 mg/kg i.p.), administered 45 and 120′ respectively after saccharin-drinking session, induced strong CSA. The DA D1 receptor antagonist, SCH 39166 (0.1 mg/kg s.c.), impaired morphine-CSA if administered 15′ and, to a lesser extent, 30′ but not 45′ before the drug (i.e immediately after saccharin drinking). In contrast SCH 39166 reduced LiCl-CSA when administered 45′ before the drug and even more so when administered 105′ before LiCl i.e. immediately after saccharin drinking. Therefore SCH 39166 impaired morphine-CSA when given shortly before the drug, while it impaired LiCl-CSA when given shortly after saccharin. Raclopride, a specific antagonist of D2 receptors, failed to affect LiCl- and morphine-CSA. These results are consistent with the idea that DA, acting on D1 receptors, plays a differential role in morphine- and LiCl-CSA. In LiCl-CSA DA is necessary for the processing (consolidation) of the short-term memory trace of the saccharin taste to be associated with the lithium-induced aversive state, while in morphine CSA contributes to mediate the appetitive properties of the drug. © 2008 Elsevier Inc. All rights reserved.
1. Introduction Reinforcing drugs, similarly to lithium chloride (LiCl), can act as unconditioned stimuli (US) to induce avoidance of a saccharin solution (conditioned stimulus, CS) predictively paired with their systemic administration. This phenomenon, termed conditioned saccharin avoidance (CSA), has been viewed as a case of conditioned aversion and an expression of the double nature, appetitive/aversive of addictive drugs. Thus, it has been hypothesized that drugs like cocaine, morphine and nicotine have both appetitive and aversive properties and that, depending on the experimental conditions, can asymmetrically drive behavior and result in approach and positive reinforcement or in avoidance and negative reinforcement [1–3]. However, rats also learn to avoid saccharin predictively paired with a sucrose solution [4] and a less concentrated sucrose solution paired with a more concentrated one [5]. Since sucrose is devoid of aversive properties, these observations exclude that avoidance of the taste CS is the result of aversive conditioning. On this basis, this phenomenon has been interpreted as
⁎ Corresponding author. Dipartimento di Tossicologia, Via Ospedale 72, 09124 Cagliari, Italy. Tel.: +39 070 675 8666/8667; fax: +39 070 675 8665. E-mail address: [email protected] (G. Di Chiara). 1 These authors contributed equally. 0031-9384/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2008.08.017
the result of an “anticipatory suppression”, secondary to an “anticipatory contrast effect” (ACE), related to failure of saccharin to mimic the hedonic value of sucrose [5]. Indeed, comparative studies of drug- and lithium-CSA show the existence of several differences between drugand lithium-CSA. Thus, drug-CSA, in contrast to lithium-CSA, does not result in aversive reactions (gapes, chin rubs, forelimb flails, paw tread) to saccharin, as shown in a taste reactivity paradigm [2,3], in response to the taste CS, it is sensitive to the incentive value of the CS (saccharin) being modulated by food and water deprivation [6–8] and it is impaired by lesions of the gustatory thalamus and cortex [9]. On this basis, the explanatory framework of anticipatory suppression utilized for sucroseCSA has been extended to drug-CSA [10]. Accordingly, drug-CSA would be the result of the fact that the rewarding properties of saccharin do not correspond to those of the reward (reinforcing drug) it predicts. An advantage of the appetitive interpretation of the CSA properties of drugs is that it provides a paradigm for the study of the neurochemical mechanism of the appetitive properties of drugs [11,12]. A long standing issue in the field of drug reinforcement is that of the role of DA [13–17]. Wise original anhedonia hypothesis, assigning to DA a primary role in food and drug reward, has been more recently contrasted with incentive-motivational and activational theories that explicitly negate a DA role in reward and hedonia [13,15]. This paradigm shift has involved not only food reward but also drug reward
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including, paradoxically, amphetamine and cocaine reward. For example, Berridge and Robinson [13] do exclude that amphetamine and cocaine psychostimulants produce reward and hedonia (‘liking’ in their terminology) by stimulating DA transmission and rather suggest that their rewarding effects are eventually related to stimulation of NA and 5HT transmission. Recently we have reported that nicotine and morphine CSA are prevented by systemic administration of a DA D1 receptor antagonist (SCH 39166) given immediately after saccharin and 15 min before the drug. In contrast, under the same conditions, SCH 39166 failed to affect lithium-induced CSA [12]. These observations indicate that DA is involved in the motivational properties of morphine and nicotine but not of lithium. However, LiCl-CSA is impaired if the administration of LiCl is delayed by 60 min from saccharin drinking session and SCH 39166 is given immediately after saccharin (i.e. 60 min before lithium). Therefore, while not important for the motivational properties of lithium, DA D1 receptors appear essential for the processing (consolidation) of the short-term memory trace of the taste CS (saccharin) when a 60 min CS–US delay is introduced [18]. As indicated by the ineffectiveness of SCH 39166 on LiCl-CSA at 15 min CS–US delays, a DA-dependent consolidation of the saccharin taste is not operative at 15 min CS–US delays [12]. However, in the case of morphine and nicotine CSA, a 15 min CS–US delay does not allow to establish whether D1 blockade impairs drug-CSA by acting on the saccharin taste consolidation or whether by acting on the drug motivational properties. In the present study this issue has been investigated by testing the effects of DA D1 and D2 antagonists on the acquisition of morphine CSA by allowing a 45 min CS–US delay, administered at different time points after saccharin, i.e. immediately, 15 min or 30 min thereafter. For comparative purposes the delay-dependent effects of SCH 39166 and raclopride on LiCl-CSA were also investigated.
3.2. Phase 2: conditioning (CSA acquisition) The conditioning phase lasted 2 days. In this phase, all subjects were given access to a novel saccharin solution (0.1% in tap water) during the scheduled 20 min fluid-access period and the amount drunk was recorded for each rat and assigned to various experimental groups, such that saccharin consumption was comparable among groups. Immediately (Experiments 1 and 2), 15 or 30′ (Experiment 1), 45 or 105′ (Experiment 2) following this exposure rats were injected with saline, D1 (SCH 39166) or D2 (raclopride) DA receptor antagonists. Animals were injected with morphine or LiCl or saline respectively, 45 min (Experiment 1) or 120 min (Experiment 2) later (see below for details). 3.2.1. Phase 3: test (CSA expression) This phase lasted 1 day without any drug treatment. All animals were given access to both 0.1% saccharin and water for 20 min in a two-bottle choice paradigm (one bottle contained 0.1% saccharin and one bottle tap water). The degree of conditioned taste aversion was determined by calculating the percentage of saccharin consumption on the test day relative to the total fluid intake (saccharin plus water). 3.3. Experiment 1: morphine hydrochloride (45′ CS–US delay) During conditioning 90 rats were given access to saccharin and divided in two main experimental groups and administered, 45′ after saccharin intake, with saline s.c. (n=33) or morphine hydrochloride 7.5 mg/kg s.c. (n=57) as US. Saline or SCH 39166 was administered immediately, 15 or 30′ after saccharin (CS) withdrawal, while raclopride was administered immediately or 30′ after CS withdrawal; see Fig. 1 for details. 3.4. Experiment 2: lithium chloride (120′ CS–US delay)
2. Materials and methods 2.1. Subjects Male Sprague–Dawley rats (n = 172)(Harlan, San Pietro al Natisone, Udine, Italy) weighing 200–225 g were housed in group of six per cage with standard food (Global Diet 2018, Harlan Italy) and water ad libitum, for at least 1 week in the central animal room, under controlled environmental conditions: constant temperature (23 °C), humidity (60%) and a 12 h light/dark cycle (light from 7 a.m. to 7 p.m.). After this period rats were housed one per cage in the behavioral test room at the same controlled environmental conditions. All experiments were performed in their home cage and carried out during daylight hours (starting 10 a.m.). In all CSA experiments rats had access to fluid (0.1% saccharin or water depending of the stage of the experiment) for 20 min each day starting the day before the beginning of the Experimental procedures and throughout its entire duration. Animals drank fluid from two special bottles (50 ml capacity), put inside the home cage by metallic support. All animal experiments were conducted in accordance with the statement revised and approved by the Society for Neuroscience in January 1995 and with the guidelines for care and use of experimental animals of the European Communities Directive (86/609; D.L.:27.01.1992, No. 116).
During conditioning 82 rats were given access to saccharin and divided in two main experimental group and administered, 120′ after saccharin intake, with saline i.p. (n = 38) or LiCl 40 mg/kg i.p. (n = 44) as US. Saline, SCH 39166 or raclopride was administered immediately, 45 or 105′ after saccharin (CS) withdrawal; see Fig. 1 for details.
3. Experimental procedures The experiments were performed for 8 days and consisted of three phases: training, conditioning and test. 3.1. Phase 1: training Following 24 h of water deprivation, all subjects were given 20min access to water daily for 5 consecutive days and the intake was recorded for each rat.
Fig. 1. Timeline of Experiments 1 and 2 showing the time of saccharin availability and of the injections (arrows). [(A, saline; B, SCH 39166 (0.1 mg/kg s.c.); C, raclopride (0.3 mg/kg s.c.)].
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3.5. Drugs SCH 39166 (0.1 mg/kg) [(−)-trans-6,7,7a,8,9,13b-hexahydro-3chloro-2-hydroxy-N-methyl-5a-benzo-(d)-naphtho-(2,1b)azepine, Schering Plough, Milano, Italy] and raclopride (0.3 mg/kg; Sigma Aldrich, Milano, Italy) were dissolved in saline and injected subcutaneously in a volume of 1 ml/kg of body weight. The pH of the solution was adjusted to 7.0. Morphine hydrochloride (7.5 mg/kg of salt, Franchini Prodotti Chimici srl, Italy) was dissolved in saline and injected subcutaneously in a volume of 1 ml/kg of body weight. LiCl (40 mg/kg of salt; Merck, Milano, Italy) was dissolved in water to make an isotonic solution 0.15 M and injected intraperitoneally in a volume of 0.64 ml/100 g of body weight. Saccharin (Original Hermesetas, Bracco, Milano, Italy) was dissolved in tap water to make a 0.1% solution. Saccharin and tap water (depending on the stage of Experimental procedures) were given to the rats in special bottles of 50 ml each one. 3.6. Statistical analysis Statistical analysis was carried out by Statistica for Windows. In all experiments data are expressed as the percentage of saccharin consumption on test day relative to the total fluid intake. Data are expressed as mean ± SEM. Analysis of data was performed using three way ANOVA (pretreatment × time × treatment). Following a significant p value, post hoc analyses (Tukey's test) were performed for assessing specific group comparison. The level of statistical significance was set at p b 0.05. 4. Results 4.1. Experiment 1: morphine-CSA (45′ CS–US delay) Fig. 2 shows the effect of saccharin pairing with morphine (7.5 mg/kg s.c.) on saccharin intake and the effect of SCH 39166 (0.1 mg/kg s.c.) and raclopride (0.3 mg/kg s.c.) administered immedi-
Fig. 3. CSA induced by LiCl (40 mg/kg i.p.) and effect of DA D1 and D2 receptor blockade. SCH 39166 (0.1 mg/kg s.c.), raclopride (0.3 mg/kg i.p.) or saline was administered immediately (0), 45 or 105′ after the 20-min saccharin (CS) drinking session. LiCl (US) was given 120′ after saccharin intake. All drugs were administered during the conditioning phase (acquisition) of CSA. Each bar represents mean ± S.E.M. of the percentage of saccharin intake on test day relative to the total fluid intake in a two bottles choice with tap water. ⁎p b 0.001 vs saline i.p. of the correspondent control group; †p b 0.05, ††p b 0.001 vs LiCl i.p. of the correspondent group.
ately, 15 or 30′ after saccharin withdrawal, i.e. 45, 30 or 15 min before morphine. Three way ANOVA showed a main effect of morphine (F1,54 = 260.96; p b 0.001), a main effect of SCH 39166 pre-treatment (F1,54 = 21.81; p b 0.001), a significant SCH 39166 × time interaction (F2,54 = 3.79; p b 0.05), SCH 39166 × morphine interaction (F1,54 = 27.92; p b 0.001) and a significant SCH 39166 × time× morphine interaction (F2,54 = 3.14; p b 0.05). Tukey's post-hoc test revealed that morphine (7.5 mg/kg s.c.) induced CSA to saccharin (p b 0.001) and that SCH 39166 (0.1 mg/kg s.c.) prevented morphine-CSA when administered 15 or 30′ but not 45 min before morphine (p b 0.001). Moreover three way ANOVA showed that raclopride (0.3 mg/kg s.c.) pretreatment did not affect morphine-induced CSA given at any time before morphine (F1,43 = 0.015; p = 0.90). 4.2. Experiment 2: lithium chloride-CSA (120′ CS–US delay)
Fig. 2. CSA induced by morphine hydrochloride (7.5 mg/kg s.c.) and effect of DA D1 and D2 receptor blockade. SCH 39166 (0.1 mg/kg s.c.) or saline was administered immediately (0′), 15 or 30′ after the 20-min saccharin (CS) drinking session, while raclopride (0.3 mg/kg s.c.) was administered immediately (0′), or 30′ after CS drinking session. Morphine hydrochloride (US) or saline was given 45′ after saccharin intake. All drugs were administered during the conditioning phase (acquisition) of CSA. Each bar represents mean ± S.E.M. of the percentage of saccharin intake on test day relative to the total fluid intake in a two bottle choice with tap water. ⁎p b 0.001 vs saline s.c. of the correspondent control group; †p b 0.001 vs morphine of the correspondent group; # p b 0.001 vs SCH 39166 (0′) plus morphine.
Fig. 3 shows the effect of saccharin pairing with 40 mg/kg i.p. of LiCl administered 120 min after saccharin withdrawal and the effect of SCH 39166 (0.1 mg/kg s.c.) and raclopride (0.3 mg/kg s.c.) given immediately, 45 or 105′ after saccharin, i.e.,120, 75 and 15 min before lithium. Three way ANOVA showed a main effect of LiCl (F1,45 = 1387; p b 0.001), a main effect of SCH 39166 pre-treatment (F1,45 = 17.29; p b 0.001), a main effect of time (F2,45 = 8.41; p b 0.001). Furthermore, a significant SCH 39166 × time interaction (F2,45 = 6.84; p b 0.05), SCH 39166 × LiCl interaction (F1,45 = 27.23; p b 0.001), and a significant SCH 39166 × time × LiCl interaction (F2,45 = 8.35; p b 0.001). Tukey's post-hoc test revealed that LiCl pairing reduced saccharin intake (p b 0.001) and that SCH 39166 (0.1 mg/kg s.c.) reduced this effect when administered immediately (p b 0.001) and 45′ (p b 0.05) but not 105 min after saccharin, i.e. 15 min before lithium. Moreover three way ANOVA showed that raclopride (0.3 mg/kg s.c.) pretreatment did not affect LiClinduced CSA given at any time before LiCl (F1,40 = 1.43; p = 0.23). 5. Discussion The main finding of the present study is that the DA D1 receptor antagonist, SCH 39166, impaired lithium- and morphine-CSA in a time-dependent but opposite fashion in relation to CS and US
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exposure. While the effect of SCH 39166 on morphine-CSA was dependent upon its temporal proximity to the drug US, that on LiCl-CSA was related to temporal proximity to the saccharin CS. This effect was DA receptor specific as the DA D2 receptor antagonist raclopride was without effect. These results suggest that DA D1 receptors are differentially involved in morphine- and lithium-CSA. Thus, while in the case of morphine-CSA the D1 antagonist seems to interfere with the motivational properties of morphine, in the case of LiCl-CSA the antagonist would interfere with the processing (consolidation) of the saccharin taste trace to be associated with the LiCl induced malaise. We previously showed that systemic SCH 39166, given immediately after saccharin, impairs lithium-CSA if LiCl is given 60 min [18] but not 15 min after saccharin [12]. Thus, the introduction of a long delay between the taste CS (saccharin) and the US (lithium) makes lithium-CSA sensitive to disruption by D1 blockade, consistently with a role of DA D1 transmission in the consolidation of the shortterm memory trace of the taste CS. The present study confirms and extends these observations to a longer CS (saccharin)–US (lithium) delay (2 h). The reason for utilizing different CS–US delays for morphine-CSA (45 min) and for LiCl–CSA (120 min) comes from the different temporal requirements of DA-dependent mechanisms that form the substrate of morphine-CSA and lithium-CSA. Morphine-CSA is lost with a CS–US interval of 120 min (unpublished observations) and 45 min is the maximal delay allowed for efficient morphine-CSA; in the case of lithium-CSA, on the other hand, a 45 min CS–US interval is too short since with a 45 min delay from saccharin SCH 39166 is still able to impair CSA (Fig. 3). This explains the need to use a 120 min CS–US delay in the case of lithium-CSA. In our previous studies [18] a 60 min CS–US delay was utilized for lithium-CTA but in that study the use of a less sensitive single-bottle test made this interval compatible with the observation of a clear-cut time dependence. More recently a role for DA D1 receptors in LiCl CTA learning has been suggested also by Cannon et al [19]. It is notable that in this study genetic deletion of DA D1 receptors impaired acquisition of lithiumconditioned aversion to sucrose but not to salt taste, suggesting a relationship with the motivational (rewarding) properties of sucrose rather than with its purely sensory properties. Also in the case of morphine there seems to be a relationship between the D1 antagonist effect and reward, with the difference that in this case drug reward rather than taste reward is involved. Therefore we suggest that DA D1 antagonists disrupt morphine-CSA by blunting the appetitive properties of the drug. Our conclusion is at variance with the interpretation of the role of DA in morphine-CSA provided by Mackey and van der Kooy [20]. These authors reported that alpha-flupentixol, a D1/D2 DA receptor antagonist, and 6-OHDA lesions of the insular (visceral) cortex [21] prevent morphine-CSA but not morphine-conditioned place-preference [20,21]. On this basis Mackey and van der Kooy [20,21] suggested that morphine has both aversive and appetitive motivational properties differentially related to DA. Aversive properties, expressed by CSA, would be DA-dependent while appetitive properties, expressed by conditioned place preference, would be DA-independent. Our observations are consistent with those of Makey and van der Kooy [20,21] as far as regards the DA-dependency of CSA but, in contrast with these authors, we interpret morphine-CSA as an expression of morphine appetitive properties due to anticipatory suppression of saccharin preference following comparison between the appetitive properties of saccharin and those of morphine, as proposed by Grigson [10]. On the other hand, in contrast with Makey and van der Kooy [20] we and others [22–29] have demonstrated that DA receptors are essential for morphine-conditioned place-preference. As to the role of DA in morphine-CSA Grigson et al [9] have pointed out that the lesions performed by Makey et al [30] include the gustatory cortex. Since lesions of the gustatory thalamic nuclei, which relay taste stimuli to the gustatory cortex, impair morphine- but not
LiCl–CSA [9] it has been suggested that gustatory cortex DA plays a role in comparing the reinforcing value of the drug and that of a gustatory stimulus like saccharin [9]. The present study does not provide any indication on the area involved in the hypothetical reward comparison. In principle, impairment of DA transmission might increase the hedonic value of the gustatory saccharin stimulus or blunt the hedonic value of morphine, thus reducing CSA. Given morphine ability to increase DA transmission preferentially in the NAc shell and given the role of DA D1 receptors in that area in morphine-conditioned place preference, we favor the second interpretation, i.e. an impairement of morphine hedonic value as the mechanism of reduction of morphine CSA by D1 blockade. The present observations might contribute to shed light on the controversial issue of the role of DA in behavior [13–17]. Our results are consistent with the idea that DA plays multiple roles in motivation and reward. DA might play a role in the acquisition of motivational properties by conditioned taste stimuli through an action on the processing of the taste CS [18]. We have previously provided evidence for this role in a single-bottle lithium-conditioned taste aversion (CTA) paradigm. The present study confirms those observations with a sensitive two-bottle test. DA might also play a role in the appetitive properties of drug reinforcers. This is at variance with the appetitive properties of food taste, for which a role of DA has been excluded [13,14]. The differential role played by DA in drug and food reward might be in turn indicative of their differential nature. Accordingly, we have distinguished two kinds of hedonia, one related to food reward, mediated by taste stimuli (sensory hedonia) and independent from DA and the other related to drug reward and to an incentive arousal state (state hedonia, euphoria, high) [11]. Acknowledgments This study was supported by funds from Ministero dell'Università e della Ricerca, Progetti di Ricerca Nazionale (bando 2003) and Centre of Excellence for Studies on Dependence and from the European Commission, NIDE project. References [1] Hunt T, Amit Z. Conditioned taste aversion induced by self-administered drugs: paradox revisited. Neurosci Behav Rev 1987;11:107–30. [2] Parker LA. Taste reactivity responses elicited by reinforcing drugs: a dose response analysis. Behav Neurosci 1991;6:955–64. [3] Parker LA. Rewarding drugs produce taste avoidance, but not taste aversion. Neurosci Biobehav Rev 1995;19:143–57. [4] Flaherty CF, Checke S. Anticipation of incentive gain. Anim Learn Behav 1982;10: 177–82. [5] Flaherty CF, Turovsky J, Krauss KL. Relative hedonic value modulates anticipatory contrast. Physiol Behav 1994;55(6):1047–54. [6] Bell SM, Thiele TE, Seeley RJ, Bernstein IL, Woods Sc. Effects of food deprivation on conditioned taste aversion in rats. Pharmacol Biochem Behav 1998;60:459–66. [7] Gomez F, Grigson PS. The suppressive effects of LiCl, sucrose, and drug of abuse are modulated by sucrose concentration in food-deprived rats. Physiol Behav 1999;67 (3):351–7. [8] Grigson PS, Lyuboslavsky P, Tanase D, Wheeler RA. Water-deprivation prevents Morphine-, but not LiCl-induced, suppression of sucrose intake. Physiol Behav 1999;67(2):277–86. [9] Grigson PS, Lyuboslavsky P, Tanase D. Bilateral lesion of the gustatory thalamus disrupt morphine- but not LiCl-induced intake suppression in rats: evidence against the conditioned taste aversion hypothesis. Brain Res 2000;858:327–37. [10] Grigson PS. Conditioned taste aversion and drug of abuse: a reinterpretation. Behav Neurosci 1997;111:129–36. [11] Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, Cadoni C, et al. Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology 2004;47:227–41. [12] Fenu S, Rivas E, Di Chiara G. Differential role of dopamine in drug- and lithiumconditioned saccharin avoidance. Physiol Behav 2005;85:37–43. [13] Berridge KC, Robinson TE. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Rev 1998;28:309–69. [14] Di Chiara G. Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav Brain Res 2002;137(1–2):75–114. [15] Salamone JD, Correa M. Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine. Behav Brain Res 2002;137(1–2):3–25.
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Physiology & Behavior j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p h b
Differential involvement of dopamine D1 receptors in morphine- and lithium-conditioned saccharin avoidance Sandro Fenu a,b,1, Emilia Rivas a,1, Gaetano Di Chiara a,b,c,⁎ a b c
Department of Toxicology, University of Cagliari, Cagliari, Italy National Institute of Neuroscience, University of Cagliari, Cagliari, Italy CNR Institute of Neuroscience, Cagliari Section, Cagliari, Italy
a r t i c l e
i n f o
Article history: Received 13 December 2007 Received in revised form 6 August 2008 Accepted 19 August 2008 Keywords: Conditioned taste avoidance Dopamine D1 receptor D2 receptor Lithium chloride Morphine hydrochloride Raclopride Saccharin SCH 39166
a b s t r a c t Conditioned saccharin avoidance (CSA) can be produced when either lithium chloride (LiCl) or a reinforcing drug, such as morphine, is administered following exposure to the taste of saccharin. In this study we investigated the involvement of dopamine (DA) transmission in the acquisition of morphine and LiCl-CSA. CSA was evaluated in a two-bottle choice paradigm with two conditioning pairings between saccharin and morphine or LiCl as unconditioned stimulus (US). Morphine hydrochloride (7.5 mg/kg s.c.) or LiCl (40 mg/kg i.p.), administered 45 and 120′ respectively after saccharin-drinking session, induced strong CSA. The DA D1 receptor antagonist, SCH 39166 (0.1 mg/kg s.c.), impaired morphine-CSA if administered 15′ and, to a lesser extent, 30′ but not 45′ before the drug (i.e immediately after saccharin drinking). In contrast SCH 39166 reduced LiCl-CSA when administered 45′ before the drug and even more so when administered 105′ before LiCl i.e. immediately after saccharin drinking. Therefore SCH 39166 impaired morphine-CSA when given shortly before the drug, while it impaired LiCl-CSA when given shortly after saccharin. Raclopride, a specific antagonist of D2 receptors, failed to affect LiCl- and morphine-CSA. These results are consistent with the idea that DA, acting on D1 receptors, plays a differential role in morphine- and LiCl-CSA. In LiCl-CSA DA is necessary for the processing (consolidation) of the short-term memory trace of the saccharin taste to be associated with the lithium-induced aversive state, while in morphine CSA contributes to mediate the appetitive properties of the drug. © 2008 Elsevier Inc. All rights reserved.
1. Introduction Reinforcing drugs, similarly to lithium chloride (LiCl), can act as unconditioned stimuli (US) to induce avoidance of a saccharin solution (conditioned stimulus, CS) predictively paired with their systemic administration. This phenomenon, termed conditioned saccharin avoidance (CSA), has been viewed as a case of conditioned aversion and an expression of the double nature, appetitive/aversive of addictive drugs. Thus, it has been hypothesized that drugs like cocaine, morphine and nicotine have both appetitive and aversive properties and that, depending on the experimental conditions, can asymmetrically drive behavior and result in approach and positive reinforcement or in avoidance and negative reinforcement [1–3]. However, rats also learn to avoid saccharin predictively paired with a sucrose solution [4] and a less concentrated sucrose solution paired with a more concentrated one [5]. Since sucrose is devoid of aversive properties, these observations exclude that avoidance of the taste CS is the result of aversive conditioning. On this basis, this phenomenon has been interpreted as
⁎ Corresponding author. Dipartimento di Tossicologia, Via Ospedale 72, 09124 Cagliari, Italy. Tel.: +39 070 675 8666/8667; fax: +39 070 675 8665. E-mail address: [email protected] (G. Di Chiara). 1 These authors contributed equally. 0031-9384/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2008.08.017
the result of an “anticipatory suppression”, secondary to an “anticipatory contrast effect” (ACE), related to failure of saccharin to mimic the hedonic value of sucrose [5]. Indeed, comparative studies of drug- and lithium-CSA show the existence of several differences between drugand lithium-CSA. Thus, drug-CSA, in contrast to lithium-CSA, does not result in aversive reactions (gapes, chin rubs, forelimb flails, paw tread) to saccharin, as shown in a taste reactivity paradigm [2,3], in response to the taste CS, it is sensitive to the incentive value of the CS (saccharin) being modulated by food and water deprivation [6–8] and it is impaired by lesions of the gustatory thalamus and cortex [9]. On this basis, the explanatory framework of anticipatory suppression utilized for sucroseCSA has been extended to drug-CSA [10]. Accordingly, drug-CSA would be the result of the fact that the rewarding properties of saccharin do not correspond to those of the reward (reinforcing drug) it predicts. An advantage of the appetitive interpretation of the CSA properties of drugs is that it provides a paradigm for the study of the neurochemical mechanism of the appetitive properties of drugs [11,12]. A long standing issue in the field of drug reinforcement is that of the role of DA [13–17]. Wise original anhedonia hypothesis, assigning to DA a primary role in food and drug reward, has been more recently contrasted with incentive-motivational and activational theories that explicitly negate a DA role in reward and hedonia [13,15]. This paradigm shift has involved not only food reward but also drug reward
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including, paradoxically, amphetamine and cocaine reward. For example, Berridge and Robinson [13] do exclude that amphetamine and cocaine psychostimulants produce reward and hedonia (‘liking’ in their terminology) by stimulating DA transmission and rather suggest that their rewarding effects are eventually related to stimulation of NA and 5HT transmission. Recently we have reported that nicotine and morphine CSA are prevented by systemic administration of a DA D1 receptor antagonist (SCH 39166) given immediately after saccharin and 15 min before the drug. In contrast, under the same conditions, SCH 39166 failed to affect lithium-induced CSA [12]. These observations indicate that DA is involved in the motivational properties of morphine and nicotine but not of lithium. However, LiCl-CSA is impaired if the administration of LiCl is delayed by 60 min from saccharin drinking session and SCH 39166 is given immediately after saccharin (i.e. 60 min before lithium). Therefore, while not important for the motivational properties of lithium, DA D1 receptors appear essential for the processing (consolidation) of the short-term memory trace of the taste CS (saccharin) when a 60 min CS–US delay is introduced [18]. As indicated by the ineffectiveness of SCH 39166 on LiCl-CSA at 15 min CS–US delays, a DA-dependent consolidation of the saccharin taste is not operative at 15 min CS–US delays [12]. However, in the case of morphine and nicotine CSA, a 15 min CS–US delay does not allow to establish whether D1 blockade impairs drug-CSA by acting on the saccharin taste consolidation or whether by acting on the drug motivational properties. In the present study this issue has been investigated by testing the effects of DA D1 and D2 antagonists on the acquisition of morphine CSA by allowing a 45 min CS–US delay, administered at different time points after saccharin, i.e. immediately, 15 min or 30 min thereafter. For comparative purposes the delay-dependent effects of SCH 39166 and raclopride on LiCl-CSA were also investigated.
3.2. Phase 2: conditioning (CSA acquisition) The conditioning phase lasted 2 days. In this phase, all subjects were given access to a novel saccharin solution (0.1% in tap water) during the scheduled 20 min fluid-access period and the amount drunk was recorded for each rat and assigned to various experimental groups, such that saccharin consumption was comparable among groups. Immediately (Experiments 1 and 2), 15 or 30′ (Experiment 1), 45 or 105′ (Experiment 2) following this exposure rats were injected with saline, D1 (SCH 39166) or D2 (raclopride) DA receptor antagonists. Animals were injected with morphine or LiCl or saline respectively, 45 min (Experiment 1) or 120 min (Experiment 2) later (see below for details). 3.2.1. Phase 3: test (CSA expression) This phase lasted 1 day without any drug treatment. All animals were given access to both 0.1% saccharin and water for 20 min in a two-bottle choice paradigm (one bottle contained 0.1% saccharin and one bottle tap water). The degree of conditioned taste aversion was determined by calculating the percentage of saccharin consumption on the test day relative to the total fluid intake (saccharin plus water). 3.3. Experiment 1: morphine hydrochloride (45′ CS–US delay) During conditioning 90 rats were given access to saccharin and divided in two main experimental groups and administered, 45′ after saccharin intake, with saline s.c. (n=33) or morphine hydrochloride 7.5 mg/kg s.c. (n=57) as US. Saline or SCH 39166 was administered immediately, 15 or 30′ after saccharin (CS) withdrawal, while raclopride was administered immediately or 30′ after CS withdrawal; see Fig. 1 for details. 3.4. Experiment 2: lithium chloride (120′ CS–US delay)
2. Materials and methods 2.1. Subjects Male Sprague–Dawley rats (n = 172)(Harlan, San Pietro al Natisone, Udine, Italy) weighing 200–225 g were housed in group of six per cage with standard food (Global Diet 2018, Harlan Italy) and water ad libitum, for at least 1 week in the central animal room, under controlled environmental conditions: constant temperature (23 °C), humidity (60%) and a 12 h light/dark cycle (light from 7 a.m. to 7 p.m.). After this period rats were housed one per cage in the behavioral test room at the same controlled environmental conditions. All experiments were performed in their home cage and carried out during daylight hours (starting 10 a.m.). In all CSA experiments rats had access to fluid (0.1% saccharin or water depending of the stage of the experiment) for 20 min each day starting the day before the beginning of the Experimental procedures and throughout its entire duration. Animals drank fluid from two special bottles (50 ml capacity), put inside the home cage by metallic support. All animal experiments were conducted in accordance with the statement revised and approved by the Society for Neuroscience in January 1995 and with the guidelines for care and use of experimental animals of the European Communities Directive (86/609; D.L.:27.01.1992, No. 116).
During conditioning 82 rats were given access to saccharin and divided in two main experimental group and administered, 120′ after saccharin intake, with saline i.p. (n = 38) or LiCl 40 mg/kg i.p. (n = 44) as US. Saline, SCH 39166 or raclopride was administered immediately, 45 or 105′ after saccharin (CS) withdrawal; see Fig. 1 for details.
3. Experimental procedures The experiments were performed for 8 days and consisted of three phases: training, conditioning and test. 3.1. Phase 1: training Following 24 h of water deprivation, all subjects were given 20min access to water daily for 5 consecutive days and the intake was recorded for each rat.
Fig. 1. Timeline of Experiments 1 and 2 showing the time of saccharin availability and of the injections (arrows). [(A, saline; B, SCH 39166 (0.1 mg/kg s.c.); C, raclopride (0.3 mg/kg s.c.)].
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3.5. Drugs SCH 39166 (0.1 mg/kg) [(−)-trans-6,7,7a,8,9,13b-hexahydro-3chloro-2-hydroxy-N-methyl-5a-benzo-(d)-naphtho-(2,1b)azepine, Schering Plough, Milano, Italy] and raclopride (0.3 mg/kg; Sigma Aldrich, Milano, Italy) were dissolved in saline and injected subcutaneously in a volume of 1 ml/kg of body weight. The pH of the solution was adjusted to 7.0. Morphine hydrochloride (7.5 mg/kg of salt, Franchini Prodotti Chimici srl, Italy) was dissolved in saline and injected subcutaneously in a volume of 1 ml/kg of body weight. LiCl (40 mg/kg of salt; Merck, Milano, Italy) was dissolved in water to make an isotonic solution 0.15 M and injected intraperitoneally in a volume of 0.64 ml/100 g of body weight. Saccharin (Original Hermesetas, Bracco, Milano, Italy) was dissolved in tap water to make a 0.1% solution. Saccharin and tap water (depending on the stage of Experimental procedures) were given to the rats in special bottles of 50 ml each one. 3.6. Statistical analysis Statistical analysis was carried out by Statistica for Windows. In all experiments data are expressed as the percentage of saccharin consumption on test day relative to the total fluid intake. Data are expressed as mean ± SEM. Analysis of data was performed using three way ANOVA (pretreatment × time × treatment). Following a significant p value, post hoc analyses (Tukey's test) were performed for assessing specific group comparison. The level of statistical significance was set at p b 0.05. 4. Results 4.1. Experiment 1: morphine-CSA (45′ CS–US delay) Fig. 2 shows the effect of saccharin pairing with morphine (7.5 mg/kg s.c.) on saccharin intake and the effect of SCH 39166 (0.1 mg/kg s.c.) and raclopride (0.3 mg/kg s.c.) administered immedi-
Fig. 3. CSA induced by LiCl (40 mg/kg i.p.) and effect of DA D1 and D2 receptor blockade. SCH 39166 (0.1 mg/kg s.c.), raclopride (0.3 mg/kg i.p.) or saline was administered immediately (0), 45 or 105′ after the 20-min saccharin (CS) drinking session. LiCl (US) was given 120′ after saccharin intake. All drugs were administered during the conditioning phase (acquisition) of CSA. Each bar represents mean ± S.E.M. of the percentage of saccharin intake on test day relative to the total fluid intake in a two bottles choice with tap water. ⁎p b 0.001 vs saline i.p. of the correspondent control group; †p b 0.05, ††p b 0.001 vs LiCl i.p. of the correspondent group.
ately, 15 or 30′ after saccharin withdrawal, i.e. 45, 30 or 15 min before morphine. Three way ANOVA showed a main effect of morphine (F1,54 = 260.96; p b 0.001), a main effect of SCH 39166 pre-treatment (F1,54 = 21.81; p b 0.001), a significant SCH 39166 × time interaction (F2,54 = 3.79; p b 0.05), SCH 39166 × morphine interaction (F1,54 = 27.92; p b 0.001) and a significant SCH 39166 × time× morphine interaction (F2,54 = 3.14; p b 0.05). Tukey's post-hoc test revealed that morphine (7.5 mg/kg s.c.) induced CSA to saccharin (p b 0.001) and that SCH 39166 (0.1 mg/kg s.c.) prevented morphine-CSA when administered 15 or 30′ but not 45 min before morphine (p b 0.001). Moreover three way ANOVA showed that raclopride (0.3 mg/kg s.c.) pretreatment did not affect morphine-induced CSA given at any time before morphine (F1,43 = 0.015; p = 0.90). 4.2. Experiment 2: lithium chloride-CSA (120′ CS–US delay)
Fig. 2. CSA induced by morphine hydrochloride (7.5 mg/kg s.c.) and effect of DA D1 and D2 receptor blockade. SCH 39166 (0.1 mg/kg s.c.) or saline was administered immediately (0′), 15 or 30′ after the 20-min saccharin (CS) drinking session, while raclopride (0.3 mg/kg s.c.) was administered immediately (0′), or 30′ after CS drinking session. Morphine hydrochloride (US) or saline was given 45′ after saccharin intake. All drugs were administered during the conditioning phase (acquisition) of CSA. Each bar represents mean ± S.E.M. of the percentage of saccharin intake on test day relative to the total fluid intake in a two bottle choice with tap water. ⁎p b 0.001 vs saline s.c. of the correspondent control group; †p b 0.001 vs morphine of the correspondent group; # p b 0.001 vs SCH 39166 (0′) plus morphine.
Fig. 3 shows the effect of saccharin pairing with 40 mg/kg i.p. of LiCl administered 120 min after saccharin withdrawal and the effect of SCH 39166 (0.1 mg/kg s.c.) and raclopride (0.3 mg/kg s.c.) given immediately, 45 or 105′ after saccharin, i.e.,120, 75 and 15 min before lithium. Three way ANOVA showed a main effect of LiCl (F1,45 = 1387; p b 0.001), a main effect of SCH 39166 pre-treatment (F1,45 = 17.29; p b 0.001), a main effect of time (F2,45 = 8.41; p b 0.001). Furthermore, a significant SCH 39166 × time interaction (F2,45 = 6.84; p b 0.05), SCH 39166 × LiCl interaction (F1,45 = 27.23; p b 0.001), and a significant SCH 39166 × time × LiCl interaction (F2,45 = 8.35; p b 0.001). Tukey's post-hoc test revealed that LiCl pairing reduced saccharin intake (p b 0.001) and that SCH 39166 (0.1 mg/kg s.c.) reduced this effect when administered immediately (p b 0.001) and 45′ (p b 0.05) but not 105 min after saccharin, i.e. 15 min before lithium. Moreover three way ANOVA showed that raclopride (0.3 mg/kg s.c.) pretreatment did not affect LiClinduced CSA given at any time before LiCl (F1,40 = 1.43; p = 0.23). 5. Discussion The main finding of the present study is that the DA D1 receptor antagonist, SCH 39166, impaired lithium- and morphine-CSA in a time-dependent but opposite fashion in relation to CS and US
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exposure. While the effect of SCH 39166 on morphine-CSA was dependent upon its temporal proximity to the drug US, that on LiCl-CSA was related to temporal proximity to the saccharin CS. This effect was DA receptor specific as the DA D2 receptor antagonist raclopride was without effect. These results suggest that DA D1 receptors are differentially involved in morphine- and lithium-CSA. Thus, while in the case of morphine-CSA the D1 antagonist seems to interfere with the motivational properties of morphine, in the case of LiCl-CSA the antagonist would interfere with the processing (consolidation) of the saccharin taste trace to be associated with the LiCl induced malaise. We previously showed that systemic SCH 39166, given immediately after saccharin, impairs lithium-CSA if LiCl is given 60 min [18] but not 15 min after saccharin [12]. Thus, the introduction of a long delay between the taste CS (saccharin) and the US (lithium) makes lithium-CSA sensitive to disruption by D1 blockade, consistently with a role of DA D1 transmission in the consolidation of the shortterm memory trace of the taste CS. The present study confirms and extends these observations to a longer CS (saccharin)–US (lithium) delay (2 h). The reason for utilizing different CS–US delays for morphine-CSA (45 min) and for LiCl–CSA (120 min) comes from the different temporal requirements of DA-dependent mechanisms that form the substrate of morphine-CSA and lithium-CSA. Morphine-CSA is lost with a CS–US interval of 120 min (unpublished observations) and 45 min is the maximal delay allowed for efficient morphine-CSA; in the case of lithium-CSA, on the other hand, a 45 min CS–US interval is too short since with a 45 min delay from saccharin SCH 39166 is still able to impair CSA (Fig. 3). This explains the need to use a 120 min CS–US delay in the case of lithium-CSA. In our previous studies [18] a 60 min CS–US delay was utilized for lithium-CTA but in that study the use of a less sensitive single-bottle test made this interval compatible with the observation of a clear-cut time dependence. More recently a role for DA D1 receptors in LiCl CTA learning has been suggested also by Cannon et al [19]. It is notable that in this study genetic deletion of DA D1 receptors impaired acquisition of lithiumconditioned aversion to sucrose but not to salt taste, suggesting a relationship with the motivational (rewarding) properties of sucrose rather than with its purely sensory properties. Also in the case of morphine there seems to be a relationship between the D1 antagonist effect and reward, with the difference that in this case drug reward rather than taste reward is involved. Therefore we suggest that DA D1 antagonists disrupt morphine-CSA by blunting the appetitive properties of the drug. Our conclusion is at variance with the interpretation of the role of DA in morphine-CSA provided by Mackey and van der Kooy [20]. These authors reported that alpha-flupentixol, a D1/D2 DA receptor antagonist, and 6-OHDA lesions of the insular (visceral) cortex [21] prevent morphine-CSA but not morphine-conditioned place-preference [20,21]. On this basis Mackey and van der Kooy [20,21] suggested that morphine has both aversive and appetitive motivational properties differentially related to DA. Aversive properties, expressed by CSA, would be DA-dependent while appetitive properties, expressed by conditioned place preference, would be DA-independent. Our observations are consistent with those of Makey and van der Kooy [20,21] as far as regards the DA-dependency of CSA but, in contrast with these authors, we interpret morphine-CSA as an expression of morphine appetitive properties due to anticipatory suppression of saccharin preference following comparison between the appetitive properties of saccharin and those of morphine, as proposed by Grigson [10]. On the other hand, in contrast with Makey and van der Kooy [20] we and others [22–29] have demonstrated that DA receptors are essential for morphine-conditioned place-preference. As to the role of DA in morphine-CSA Grigson et al [9] have pointed out that the lesions performed by Makey et al [30] include the gustatory cortex. Since lesions of the gustatory thalamic nuclei, which relay taste stimuli to the gustatory cortex, impair morphine- but not
LiCl–CSA [9] it has been suggested that gustatory cortex DA plays a role in comparing the reinforcing value of the drug and that of a gustatory stimulus like saccharin [9]. The present study does not provide any indication on the area involved in the hypothetical reward comparison. In principle, impairment of DA transmission might increase the hedonic value of the gustatory saccharin stimulus or blunt the hedonic value of morphine, thus reducing CSA. Given morphine ability to increase DA transmission preferentially in the NAc shell and given the role of DA D1 receptors in that area in morphine-conditioned place preference, we favor the second interpretation, i.e. an impairement of morphine hedonic value as the mechanism of reduction of morphine CSA by D1 blockade. The present observations might contribute to shed light on the controversial issue of the role of DA in behavior [13–17]. Our results are consistent with the idea that DA plays multiple roles in motivation and reward. DA might play a role in the acquisition of motivational properties by conditioned taste stimuli through an action on the processing of the taste CS [18]. We have previously provided evidence for this role in a single-bottle lithium-conditioned taste aversion (CTA) paradigm. The present study confirms those observations with a sensitive two-bottle test. DA might also play a role in the appetitive properties of drug reinforcers. This is at variance with the appetitive properties of food taste, for which a role of DA has been excluded [13,14]. The differential role played by DA in drug and food reward might be in turn indicative of their differential nature. Accordingly, we have distinguished two kinds of hedonia, one related to food reward, mediated by taste stimuli (sensory hedonia) and independent from DA and the other related to drug reward and to an incentive arousal state (state hedonia, euphoria, high) [11]. Acknowledgments This study was supported by funds from Ministero dell'Università e della Ricerca, Progetti di Ricerca Nazionale (bando 2003) and Centre of Excellence for Studies on Dependence and from the European Commission, NIDE project. References [1] Hunt T, Amit Z. Conditioned taste aversion induced by self-administered drugs: paradox revisited. Neurosci Behav Rev 1987;11:107–30. [2] Parker LA. Taste reactivity responses elicited by reinforcing drugs: a dose response analysis. Behav Neurosci 1991;6:955–64. [3] Parker LA. Rewarding drugs produce taste avoidance, but not taste aversion. Neurosci Biobehav Rev 1995;19:143–57. [4] Flaherty CF, Checke S. Anticipation of incentive gain. Anim Learn Behav 1982;10: 177–82. [5] Flaherty CF, Turovsky J, Krauss KL. Relative hedonic value modulates anticipatory contrast. Physiol Behav 1994;55(6):1047–54. [6] Bell SM, Thiele TE, Seeley RJ, Bernstein IL, Woods Sc. Effects of food deprivation on conditioned taste aversion in rats. Pharmacol Biochem Behav 1998;60:459–66. [7] Gomez F, Grigson PS. The suppressive effects of LiCl, sucrose, and drug of abuse are modulated by sucrose concentration in food-deprived rats. Physiol Behav 1999;67 (3):351–7. [8] Grigson PS, Lyuboslavsky P, Tanase D, Wheeler RA. Water-deprivation prevents Morphine-, but not LiCl-induced, suppression of sucrose intake. Physiol Behav 1999;67(2):277–86. [9] Grigson PS, Lyuboslavsky P, Tanase D. Bilateral lesion of the gustatory thalamus disrupt morphine- but not LiCl-induced intake suppression in rats: evidence against the conditioned taste aversion hypothesis. Brain Res 2000;858:327–37. [10] Grigson PS. Conditioned taste aversion and drug of abuse: a reinterpretation. Behav Neurosci 1997;111:129–36. [11] Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, Cadoni C, et al. Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology 2004;47:227–41. [12] Fenu S, Rivas E, Di Chiara G. Differential role of dopamine in drug- and lithiumconditioned saccharin avoidance. Physiol Behav 2005;85:37–43. [13] Berridge KC, Robinson TE. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Rev 1998;28:309–69. [14] Di Chiara G. Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav Brain Res 2002;137(1–2):75–114. [15] Salamone JD, Correa M. Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine. Behav Brain Res 2002;137(1–2):3–25.
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