Bupropion and Nicotine Enhance Responding for Nondrug Reinforcers Via Dissociable Pharmacological Mechanisms in Rats

Psychopharmacology (2009) 207:381–390 DOI 10.1007/s00213-009-1666-5

ORIGINAL INVESTIGATION

Bupropion and nicotine enhance responding for nondrug reinforcers via dissociable pharmacological mechanisms in rats

Matthew I. Palmatier & Melissa E. Levin & Kara L. Mays & Eric C. Donny & Anthony R. Caggiula & Alan F. Sved

Received: 1 July 2009 /Accepted: 1 September 2009 /Published online: 17 September 2009 # Springer-Verlag 2009

Abstract not nicotine, was blocked by pretreatment with the alpha Rationale Nicotine serves as a primary reinforcer but also noradrenergic antagonist prazosin. potently enhances responding for nonnicotine stimuli with Conclusion The reinforcement enhancing effects of nico- reinforcing properties. One of the most successful pharma- tine and bupropion increased over time and repeated cotherapies for smoking cessation, bupropion, also treatments suggesting a shared mechanism of action. increases responding for nondrug reinforcers such as food However, the reinforcement enhancing effects of nicotine and brain stimulation rewards. are mediated by nicotinic acetylcholine receptors, whereas Objective The present studies investigated whether treat- the reinforcement enhancing effects of bupropion were ment with bupropion and nicotine had similar effects on mediated by alpha noradrenergic receptors. responding for a reinforcing visual stimulus (VS). They also investigated whether the effects of bupropion and Keywords Nicotine . Bupropion . Operant conditioning . nicotine depended on common pharmacological substrates. Self-administration . Dopamine . Acetylcholine . Results Nicotine (0.4 mg/kg base) enhanced responding for Norepinephrine the VS, and this enhancing effect increased across testing sessions, replicating our previous findings. Bupropion (3, 10, and 30 mg/kg salt) dose-dependently increased Introduction responding for the VS. Treatment with 10 and 30 mg/kg bupropion resulted in a profile similar to nicotine; operant Although sustained release bupropion (Zyban SR®) has responding increased over repeated drug treatments. The enjoyed clinical success as a smoking cessation aid (Hurt et reinforcement enhancing effect of nicotine, but not bupro- al. 1997; Jorenby et al. 1999), the specific reasons for this pion, was blocked by pretreatment with the nicotinic success remain elusive. Preclinical studies have demon- acetylcholine receptor antagonist mecamylamine. In con- strated that bupropion and nicotine have similar subjective trast, the reinforcement enhancing effect of bupropion, but effects (Besheer et al. 2004), both drugs are psychomotor stimulants (Bevins and Palmatier 2003; Wilkinson and M. I. Palmatier (*) Department of Psychology, Kansas State University, Bevins 2007), both serve as primary reinforcers in nonhuman 469 Bluemont Hall, subjects (Chaudhri et al. 2006a; Tella et al. 1997), and both Manhattan, KS 66502, USA compounds increase the concentration of extracellular e-mail: [email protected] catecholamines in midbrain limbic regions (see Balfour et M. E. Levin : E. C. Donny : A. R. Caggiula al. 2000; Dwoskin et al. 2006 for review). Thus, the clinical Department of Psychology, University of Pittsburgh, efficacy of bupropion may depend on its ability to “replace” Pittsburgh, PA 15260, USA some of the subjective, psychomotor, and/or reinforcement- related effects of nicotine (Warner and Shoaib 2005). K. L. Mays : A. F. Sved Department of Neuroscience, University of Pittsburgh, In addition to being primary reinforcers, nicotine and other Pittsburgh, PA 15260, USA psychomotor stimulants (i.e., cocaine and amphetamine) have 382 Psychopharmacology (2009) 207:381–390 a second spectrum of reinforcement-related effects: they was to investigate pharmacological substrates of bupropion- can increase responding for reinforcing nondrug stimuli and nicotine-enhanced reinforcements. In order to investi- (Chaudhri et al. 2006b; Palmatier et al. 2007a;Robbins gate the role of nAChRs, rats were challenged with the 1976). For example, nicotine (Donny et al. 2003; Palmatier nonselective antagonist mecamylamine. Based on previous et al. 2007b) cocaine (Chaudhri et al. 2006b) and amphet- findings (Palmatier et al. 2007a), we predicted that the amine (Glow and Russell 1973;Robbins1977) can increase reinforcement enhancing effects nicotine, but not bupro- responding for visual and auditory stimuli with uncondi- pion, would be blocked by mecamylamine. We also tioned and conditioned reinforcing properties. investigated the role of NE receptors with prazosin and Several recent findings suggest that bupropion also propranolol. Prazosin is a nonselective competitive antag- increases responding for nondrug reinforcers. Bupropion onist at α1-NE receptors, with some affinity for postsynap- has been shown to increase responding for food on a tic α2-NE receptors (Ordway et al. 1993). Propranolol is a progressive ratio schedule of reinforcement (Bruijnzeel and competitive antagonist for β-adrenergic receptors and Markou, 2003), lower reward threshold for intracranial self- nonselective across subtypes (Nahorski 1976). We hypoth- stimulation (Cryan et al. 2003), and increase cue-induced esized that the reinforcement enhancing effects of bupro- reinstatement of nicotine-seeking behavior (Liu et al. 2008). pion would depend on noradrenergic receptors because the In addition, several studies suggest that bupropion can NE system has frequently been implicated in the rewarding increase responding for nicotine infusions (Rauhut et al. and reinforcing effects of psychomotor stimulants (Ventura 2003;Shoaibetal.2003; Stairs and Dworkin 2008), an effect et al. 2003; Zhang and Kosten 2005), and prazosin can that seems at odds with smoking cessation. Interestingly, in reduce the psychomotor stimulant effects of bupropion in each of these studies, nicotine infusions were delivered in mice (Martin et al. 1990). However, since nicotine self- conjunction with a sensory stimulus (infusion/time-out “cues”). administration is usually reduced by increasing synaptic NE Hence, the increase in nicotine self-administration may be (Coen et al. 2009; Rauhut et al. 2002), we predicted that attributable to the reinforcement-enhancing effects of bupro- blocking postsynaptic NE receptors would not reduce the pion on responding for the cues associated with nicotine. reinforcement enhancing effect of nicotine. Nicotine and bupropion share two pharmacological actions that may lead to increased responding for other primary rewards. First, both drugs directly affect nicotinic Method acetylcholine receptors (nAChRs). Although the drugs have opposing effects at these receptors (nicotine serves as an General method agonist, whereas bupropion is an antagonist, see Fryer and Lukas 1999; Slemmer et al. 2000), nicotine can desensitize Subjects Male Sprague Dawley rats (Harlan Farms, IN) nAChRs, and some of the behavioral and physiological weighing 174–200 g on arrival were housed individually in effects of nicotine have been attributed to nicotine-induced hanging wire mesh cages. Rats were housed in a temperature- decreases in nAChR function (Picciotto et al. 2008). Second, and humidity-controlled colony room on a reverse 12:12 h nicotine and bupropion also increase the postsynaptic effects light:dark cycle. Unrestricted access to food and water was of norepinephrine (NE) and dopamine (DA) in midbrain allowed for 3 days after their arrival. Food access was limbic regions (Balfour et al. 2000;Chaudhrietal.2006b; subsequently restricted to 20 g/day allowing limited growth Dwoskin et al. 2006;Fuetal.1998, 2003). Increased (approximately 20 g/week) throughout the remainder of the catecholamine activity in these regions is widely regarded as study (Donny et al. 1995). a necessary component of appetitive and goal-directed behaviors (Robinson and Berridge 1993; Ventura et al. Apparatus Experimental sessions were conducted in 30 2003). A shared or comparable ability to enhance responding operant conditioning chambers (BRS/LVE Model RTC- for nondrug reinforcement may depend on these latter effects 020, MD; see Donny et al. 1995 for further details) mea- of bupropion and nicotine. suring 25×31×28 cm (width×length×height). One wall of The first goal of the present research was to investigate each chamber was equipped with two retractable levers, and the putative reinforcement enhancing effects of bupropion stimulus lights were located above each lever. A pellet without the complication of having two or more reinforcers dispenser and food trough were located between the two associated with a single operant. A second goal was to levers, approximately 2 cm from the floor of the chamber. compare the reinforcement enhancing effects of bupropion A house light fixture was located above the food trough, to those of nicotine. Based on previous research, we approximately 1 cm from the top of the chamber. A white hypothesized that bupropion would enhance responding house light was illuminated at the beginning and extin- for a sensory reinforcer in a dose-dependent manner that guished at the end of each session. The sensory reinforcer was comparable to nicotine. A third goal of these studies (visual stimulus or VS) consisted of 1 s illumination of the Psychopharmacology (2009) 207:381–390 383 stimulus light located directly above the active lever testing sessions, and the procedures have been described in followed by 1 min extinction of the house light. We have detail elsewhere (Palmatier et al. 2006). Briefly, rats were previously established that the VS has moderate reinforcing shaped to associate individual lever extensions with a food properties which are potently enhanced by presession reward. After rats met a minimum criterion of 25 total nicotine administration (Palmatier et al. 2007c) reinforced lever press responses, an extinction test exam- ined unconditional side preferences. Lever (active vs Drugs Nicotine hydrogen tartrate salt, bupropion hydro- inactive) was then randomly assigned to each subject for chloride, and (±)-propranolol hydrochloride (Sigma, St. the subsequent stimulus reinforcement sessions, with the Louis, MO) were dissolved in 0.9% saline. Prazosin constraint that side preference was balanced in each drug hydrochloride (Sigma, St. Louis, MO) was dissolved in condition. Stimulus reinforcement tests were carried out in distilled water. Subcutaneous (s.c.) nicotine injections and 60-min sessions over 23 consecutive days. Meeting the fixed intraperitoneal (i.p.) bupropion and propranolol injections ratio (FR) schedule on the active lever resulted in presentation were delivered at a volume of 1 ml/kg. Prazosin was injected of the moderately reinforcing VS. The fixed ratio schedule at a volume of 2 ml/kg, sc. Nicotine solution pH was adjusted was increased from one to two and subsequently five to 7.0 (±0.2) with dilute NaOH, and dose (0.4 mg/kg) was responses across test sessions when rats met a stability calculated from the base form. All other drug doses were criterion under each ratio (≤10% variation in response rate calculated from the salt form. Mecamylamine doses were and reinforcers earned for three consecutive sessions). As a derived from our previous studies investigating the reinforce- result, a fixed ratio 1 (FR1) schedule was in force from ment enhancing effects of nicotine (Liu et al. 2007; Palmatier sessions one to five, an FR2 was in force from sessions six to et al. 2007a). Higher doses were not tested due to the 12, and an FR5 was in force from sessions 13–23. potential for noncholinergic action of mecamylamine at micromolar brain concentrations (O'Dell and Christensen Bupropion and nicotine pretreatment tests After stable 1988). Doses of prazosin and propranolol were derived from responding was established under the FR5 schedule, rats previous studies investigating the effects of these antagonists were randomly assigned to one of five groups according to on the behavioral effects of nicotine (Hahn and Stolerman the bupropion dose (0, 3, 10, or 30 mg/kg BUP) or nicotine 2005; Villegier et al. 2007), cocaine (Zhang and Kosten comparison condition (0.4 mg/kg NIC). BUP rats were 2005) and amphetamine (Dickinson et al. 1988; Yokel and injected i.p. with the appropriate solution 30 min before Wise 1976). each subsequent test session, and NIC rats were injected s.c. 5 min before testing. The nicotine dose was selected based on previous studies from our laboratory suggesting Procedure that this dose/route combination produces robust enhancing effects (Palmatier et al. 2007c). Bupropion doses were A schematic representation of experimental procedures, selected based on previous studies examining the effects of dose conditions, and the number of subjects in each con- bupropion on operant behavior (Bruijnzeel and Markou dition are presented in Table 1. 2003; Paterson et al. 2008). Testing occurred over seven consecutive days in order to provide acute (day 1) and Phase 1: reinforcement-enhancing effects of bupropion chronic (day 7) measures of reinforcement-enhancing and nicotine effects. Previous studies suggest that the reinforcement- enhancing effects of s.c. nicotine become asymptotic over Food shaping and acquisition of stimulus reinforcement The this test period, an effect reminiscent of psychomotor first five sessions were food autoshaping and preference- stimulant sensitization (Palmatier et al. 2007c).

Table 1 Schematic representation of groups, number of subjects, and treatments from each experiment

Group Number Experiment 1 Experiment 2

Acquisition (sessions 1–23) Drug pretreatment nAChR (sessions 31–35) NE-R (sessions 41–52) (sessions 24–30)

SAL 8 Active lever: VS SAL (i.p./s.c.) 0, 0.05, and 0.1 mg/kg 0, 0.1, 0.3, and 1 mg/kg prazosin 0.4 NIC 8(FR1, FR2, and FR5) 0.4 NIC mecamylamine 3 BUP 9 3 BUP 0, 2.5, 5, and 10 mg/kg 10 BUP 9 10 BUP propranolol 30 BUP 8 30 BUP 384 Psychopharmacology (2009) 207:381–390

Phase 2: pharmacological substrates of enhanced group (NIC, 0, 3, 10, and 30 BUP) as the between subjects reinforcement factor. Significant effects involving more than two groups were explored using pairwise comparisons. For phase 1, nACh receptor antagonist tests All rats/groups from exper- pairwise ANOVAs were used to assess main effects of iment 1 were pretreated with mecamylamine (0, 0.5, or group, the linear effect of session and group by session 1 mg/kg) to determine if nonspecific blockade of nAChRs interactions. Additional t tests (with Bonferroni correction) altered the reinforcement enhancing effects of bupropion were conducted to specify the group differences at the start and to confirm our previous finding that pretreatment with and end of the study (i.e., days 1 and 7 of treatment), as mecamylamine (1 mg/kg) abolishes the reinforcement illustrated graphically in Fig. 2c. During phase 2, mixed enhancing effect of nicotine (Palmatier et al. 2007a). factors ANOVAs included dose (antagonist treatment dose) Testing took place over five consecutive sessions in which as a within subjects factor, and group was the between mecamylamine or vehicle was injected 45 min before subjects factor. For phase 2, which did not assess change in testing; the appropriate dose of BUP or NIC was injected responding over time, pairwise comparisons were made 15 or 40 min after mecamylamine pretreatment, respec- with t tests using Bonferroni correction. All t tests are tively. Sessions 31, 33, and 35 were vehicle tests, and reported as ts(df) and include corrected p values (calculated responses and reinforcers earned were monitored for any p multiplied by the number of comparisons). long-term or progressive effects of mecamylamine. No progressive effects of mecamylamine treatment were observed (ps≥0.37), so data from these tests were averaged for analyses (0 mg/kg mecamylamine). Sessions 32 and 34 Results were mecamylamine tests, dose (0.5 or 1 mg/kg) was randomized and balanced within each group. Phase 1: reinforcement enhancing effects of bupropion and nicotine NE receptor antagonist tests To further characterize the reinforcement-enhancing effects of bupropion and nicotine, Acquisition of stimulus reinforcement (sessions 1–23) Despite additional pretreatment tests included prazosin (0.1, 0.3, or equal training on both levers, responding on the active lever 1 mg/kg) and propranolol (2.5, 5, or 10 mg/kg). Before NE was higher than responding on the inactive lever across the antagonist testing began, all rats received five sessions (36– acquisition phase (main effect of lever for FR1, FR2, and 40) with only presession injections of their assigned BUP or FR5 schedules, p<0.01), demonstrating that the VS served NIC test solution in order to re-establish the 3-day perfor- as a primary reinforcer (Fig. 1). mance criteria (≤10% variation in responses/reinforcers earned) and prevent any carryover effect of mecamylamine Bupropion and nicotine pretreatment tests (sessions 24–30) treatment. NE receptor antagonist tests were conducted over Both nicotine and bupropion increased responding at the 12 consecutive sessions. Prazosin or propranolol was admin- active lever preferentially, and the enhancing effect of istered on “even” test days (Sessions 42, 44, 46, etc.) 45 min bupropion was systematically related to bupropion dose. before testing sessions; compound and dose were assigned by The two-way ANOVA confirmed that active lever respond- Latin square. Intervening saline tests (Sessions 41, 43, 45, ing was high than inactive lever responding during this etc.) were monitored for carryover or progressive effects of phase (p<0.01), but the rate of active lever responding the antagonists. Since no carryover or progressive effect of increased linearly with session (p<0.01) and depended on antagonist treatment was found on the vehicle test sessions group (p<0.01); there was also a significant interaction (ps≥0.46), the dependent measures were averaged across between group and the linear change over sessions (p<0.05; sessions and served as the 0 mg/kg control for both Fig. 2a, b). For inactive lever responding, the effects of compounds. Doses of each drug were chosen from previous session (p=0.275, group (p=0.367), and the group×session studies and were not expected to have nonspecific effects on interaction (p=0.379) all failed to reach significance. motor activity or operant performance (e.g., Zhang and t tests were used to illustrate the effects of nicotine and Kosten 2005). bupropion relative to saline on active lever responding on sessions 24 and 30 (day 1 and day 7 of drug pretreatment), Data analyses Responding on the active lever served as the and additional pairwise ANOVAs with linear contrasts were main dependent variable. Where appropriate, inactive lever conducted to assess the pattern of change in active lever responses were included or analyzed separately. Analyses responding over sessions relative to saline. Active lever of variance (ANOVAs) were the primary significance tests. responding in both the NIC and BUP groups failed to During phase 1, mixed factors ANOVAs included the linear significantly differ from saline on session 24, although BUP effect of session and lever as within subject factors and pretreatment revealed a nonsignificant trend for increased Psychopharmacology (2009) 207:381–390 385

Fig. 1 Operant responding over testing sessions during the stimulus reinforcement phase. Closed symbols represent active lever responses (responses leading to the visual stimulus or VS), and open symbols represent responses on the inactive lever (responses with no programmed consequences). As illustrated in the figure, responses producing the VS remained high, while inactive lever presses decreased over testing sessions responding (Fig. 2a). However, group differences emerged over repeated sessions. With the exception of 3 mg/kg BUP, there was a significant linear increase in the active lever drug conditions (0.4 mg/kg NIC, p<0.01; 10 mg/kg BUP, p<0.01; 30 mg/kg BUP, p<0.01). This increase contributed to significant differences in active lever responding between the saline group and the 0.4 mg/kg NIC (t(13)=2.843, p= 0.014), 3 mg/kg BUP (t(10.913)=2.297, p=0.042), 10 mg/kg BUP (t(7.477)=2.786, p=0.025), and 30 mg/kg BUP (t(13)= 5.159, p<0.001) groups on day 30 as illustrated by a leftward/upward shift in the dose–response curve in Fig. 2c. These findings indicate that the acute effects of nicotine and bupropion were marginal, but a significant reinforcement-enhancing effect of both drugs emerged after repeated testing.

Phase 2: pharmacological substrates of enhanced reinforcement nACh receptor antagonist challenge (sessions 31–35) Mecamylamine (0.5 and 1.0 mg/kg) reduced the reinforcement-enhancing effects of nicotine but did not alter the reinforcement enhancing effects of bupropion. The Fig. 2 Operant responding during the bupropion and nicotine pretreatment phase. a Active lever responses over testing sessions two-way ANOVA revealed that active lever responding for rats in the five treatment groups. b Inactive lever responses over decreased as a function of group (p<0.001); there was also testing sessions for each group. c The effects of acute (first drug a group×dose interaction (p<0.001). Paired t tests investi- pretreatment test) and chronic (seventh drug pretreatment test) drug gating the interaction revealed a significant decrease in administration on active lever responding in each drug/dose condition. *p<0.05 (responding in chronic test differs significantly from active lever responding when rats in the NIC group were responding on the acute test) pretreated with both 0.5 (t(6)=2.537, p<0.05) and 1.0 mg/kg mecamylamine (MEC; t(6)=3.255, p<0.05, (Fig. 3)). There were no significant effects of MEC on active lever responding for the 0, 3, 10, or 30 mg/kg BUP groups (ps≥0.45). 386 Psychopharmacology (2009) 207:381–390

subjects' history of reinforcement on both levers during shaping suggests that the sensory reinforcement that we observed (Fig. 1) was not the result of habitual performance. Despite a history in which both levers had previously been reinforced, the effect of bupropion was specific to lever response producing the VS, suggesting that it was not the result of simple motor activation. The initial trend for increased responses on the inactive lever decreased over the first three testing sessions (Fig. 1a). Finally, the present studies demonstrate an apparent contrast between the reinforcement-enhancing effects of bupropion and nicotine. The enhancing effects of nicotine, but not bupropion, depended exclusively on nAChRs. Instead, the enhancing effects of bupropion were completely abolished by prazosin Fig. 3 Active lever responding in each drug/dose condition during the pretreatment, suggesting that they are critically dependent on nACh receptor antagonist challenge tests. *ps<0.05 (0.5 and 1 mg/kg α β mecamylamine pretreatment significantly reduced responding for the -NE receptors. Notably, the blockade of -NE receptors NIC group) did not alter the enhancing effects of either drug. Several of the present findings bear further discussion. Furthermore, in each case, the decrease in VS responding First, the parallel observations of increased responding over associated with MEC (0.5 or 1.0 mg/kg) was greater in NIC than BUP pretreated animals (ps<0.05).

NE receptor antagonist challenge (sessions 41–52) Prazosin (PRAZ; 0.1, 0.3, and 1.0 mg/kg) dose-dependently decreased the reinforcement enhancing effects of bupropion, but did not alter the reinforcement enhancing effects of nicotine. The two-way ANOVA revealed a main effect of main effect of dose (p<0.001) on active lever responding, but this effect was highly dependent on group (dose×group interaction, p<0.001). Pairwise comparisons revealed a significant decrease in active lever responding in the 10 [t(7)=3.613, p<0.01] and 30 mg/kg (t(6)=5.693, p=0.001) BUP groups for the highest dose of PRAZ (1.0 mg/kg). There were no significant effects of PRAZ on active lever responding for the 0.4 mg/kg NIC or 0 or 3 mg/kg BUP groups. Direct comparison of the NIC and the 30 mg/kg BUP group confirmed the greater PRAZ-induced decrease in VS responding in the BUP compared to NIC group (Fig. 4a). There were no detectable effects on active lever responding across all groups that were pretreated with propanolol (Fig. 4b).

Discussion

The present studies confirmed previous findings that bupropion enhances responding for a nondrug reinforcer (Bruijnzeel and Markou 2003; Liu et al. 2008; Paterson et al. 2008). We also extended these findings by demonstrat- Fig. 4 Active lever responding in each drug/dose condition during the ing that the reinforcement-enhancing effects of bupropion NE receptor antagonist challenge tests. a 1 mg/kg prazosin pretreatment reduced responding (asterisks) for the 10 and 30 mg/kg BUP (10 and 30 mg/kg) were comparable in profile to those of groups. b Active lever responses from the propranolol pretreatment nicotine (increasing over time/repeated treatments). The tests Psychopharmacology (2009) 207:381–390 387 repeated treatments for both bupropion and nicotine amphetamine-induced hyperlocomotion (Blanc et al. 1994) suggests that convergent pharmacological systems mediate and also attenuates NAc dopamine release induced by the reinforcement enhancing effects of both drugs. The systemic amphetamine injections (Darracq et al. 1998). In dependence on catecholaminergic receptors for bupropion fact, these latter studies and others (Nichols and Selken is also consistent with the enhancing effects of other 2007;Tassinetal.2006) implicating the α-NE system in psychomotor stimulants such as cocaine and amphetamine the motivational and psychomotor stimulant effects of (Chu and Kelley 1992; Ranaldi and Beninger 1993; amphetamines converge with our present findings with Wolterink et al. 1993). Although bupropion is an antagonist bupropion. Further studies are required to determine at nAChRs (Slemmer et al. 2000), we did not find evidence whether bupropion also increases NE release in the PFC for an additive effect between bupropion and mecamyl- and the role of this putative effect in enhanced reinforce- amine over the dose range tested. In addition, a previous ment; however, bupropion and amphetamine have similar study from our laboratory found that repeated daily chemical structures (Mehta 1983), act on similar targets treatment with mecamylamine alone does not enhance (Li et al. 2002; Rothman et al. 2001), and share an ability responding for the VS (Palmatier et al. 2007a). Combined, to increase responding for sensory reinforcers (present these findings suggest that reduced activity of nAChRs studies; Glow and Russell 1973). does not produce enhanced reinforcement. Although we have previously hypothesized that the DA The pharmacological dissociation between the system may be critical to the reinforcement enhancing reinforcement-enhancing effects of nicotine and bupropion effects of nicotine (Chaudhri et al. 2006b) and by extension are probably best explained by different primary targets of bupropion, we chose not to investigate that hypothesis in the drugs with comparable or convergent downstream the present studies. Midbrain DA function is critical to the effects. For example, nicotine is relatively selective for primary reinforcing effects of food (Thanos et al. 2008), nAChRs, both increasing and decreasing their activity abused drugs (Yokel and Wise 1976), and sensory stimuli (Picciotto et al. 2008; Wooltorton et al. 2003); but down- (Liu et al. 2006). Accordingly, antagonizing this system stream effects include increased release of DA (Benwell and might directly reduce the reinforcement enhancing effects Balfour 1992), NE (Fu et al. 1998, 2003), and endogenous of bupropion and nicotine, but could also indirectly affect opioids (Dhatt et al. 1995; Wewers et al. 1999)inbrain drug-enhanced responding by changing the status of (or regions that may be critical to appetitive or goal-directed motivation to obtain) the primary reinforcer. To understand operant behaviors. These effects of nicotine are normally the precise role of DA in enhanced reinforcement, it may attributed to ascending projections from the ventral tegmen- necessary to investigate the points of convergence and tal area to the nucleus accumbens (NAc; Balfour et al. 2000; divergence with other neurological systems (e.g., Burns et Dani 2003;Danietal.2001; Picciotto et al. 2008), but may al. 1994; Phillips et al. 1994) or to dissociate the roles of also depend on descending projections to the pontine tonic and phasic dopamine responses (Exley et al. 2008; tegmentum (Laviolette and van der Kooy 2004), local Rice and Cragg 2004). cholinergic signaling in the NAc (McGehee 2006), or The final question prompted by the present findings, as descending projections from the prefrontal cortex (PFC; well as previous studies (Bruijnzeel and Markou 2003; Liu McGehee 2007). et al. 2008; Paterson et al. 2008) is whether the reinforce- Bupropion affects multiple neurotransmitter systems with- ment enhancing effects of bupropion have clinical rele- in the central nervous system, including, but not limited to, vance in smoking cessation. One recent study in human antagonism of nAChRs (Fryer and Lukas 1999), reduction of smokers demonstrated that bupropion and amphetamine NE, DA, and serotonin reuptake, and increasing the activity increased ad-lib smoking (Cousins et al. 2001). Both drugs of vesicular monoamine transporters (see Dwoskin et al. also increased measures of positive mood and euphoria, 2006 for review). The reinforcement-enhancing effects of replicating previous findings for amphetamine (Henningfield bupropion in this study may be dependent on the drugs and Griffiths 1981;Schusteretal.1979). Although they ability to directly reduce DA uptake in the NAc (Paterson et seem counterintuitive, the results are easily explained by al. 2007). However, this does not explain the effect of reinforcement-enhancing effects of bupropion and amphet- prazosin in the present studies and suggests that the amine. As reinforcement enhancers, bupropion and amphet- reinforcement enhancing effect of bupropion may be depend, amine could increase the valence of smoking-related at least partially, on an interaction between noradrenergic conditioned reinforcers (Rose et al. 2003), increasing the function in the PFC and dopaminergic function in the NAc. number of cigarettes smoked and the satisfaction derived For example, both amphetamine and bupropion increase from smoking. extracellular concentrations of DA and NE in the nucleus An important facet of bupropion-potentiated smoking in accumbens and PFC of rats (Li et al. 2002; Rothman et al. humans was that the participants were smokers who were 2001). Prazosin administration in the PFC can block not intending to quit (Cousins et al. 2001). For individuals 388 Psychopharmacology (2009) 207:381–390 attempting to quit smoking, the role that reinforcement- activity and responding with conditioned reinforcement. Psycho- – enhancing effects of bupropion might play in smoking pharmacology (Berl) 115:516 528 Chaudhri N, Caggiula AR, Donny EC, Booth S, Gharib M, Craven L, cessation is less clear. One hypothesis is that the enhancing Palmatier MI, Liu X, Sved AF (2006a) Operant responding for effects of bupropion functionally replace the enhancing conditioned and unconditioned reinforcers in rats is differentially effects of nicotine, allowing smokers to retain the degree of enhanced by the primary reinforcing and reinforcement- – reinforcement normally experienced in the presence of enhancing effects of nicotine. Psychopharmacology 189:27 36 Chaudhri N, Caggiula AR, Donny EC, Palmatier MI, Liu X, Sved AF nicotine (Warner and Shoaib 2005). This replacement (2006b) Complex interactions between nicotine and nonpharma- hypothesis prompts further questions about bupropion and cological stimuli reveal multiple roles for nicotine in reinforce- nicotine self-administration in humans and nonhuman ment. 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