Serotonin-Dopamine Interactions in the Control of Conditioned Reinforcement and Motor Behavior Deanna M. Sasaki-Adams, B.S., and Ann E. Kelley, Ph.D. These studies addressed the question of serotonin (5-HT)- reinforcement test. Dopamine, but not 5-HT, selectively dopamine (DA) interactions with regard to reward-related facilitated CR responding, although 5-HT non-specifically behavior and motor activity in rats. The first experiment increased responding as well. In the third and fourth evaluated the effect of chronic treatment with fluoxetine (7 experiments, it was demonstrated that intra-accumbens mg/kg/day), a serotonin-selective reuptake inhibitor, and 5-HT causes increased motor activity, which was partially buproprion (15 mg/kg/day), a dopamine reuptake inhibitor, blocked by DA antagonists. The results suggest that on responding for conditioned reinforcement (CR). Chronic chronically increased levels of 5-HT may facilitate reward- fluoxetine, but not buproprion, enhanced CR responding, related behavior, but most likely via indirect modulatory and also potentiated cocaine-induced increases in CR mechanisms affecting general arousal and motor tone. responding. In the second experiment, animals received [Neuropsychopharmacology 25:440–452, 2001] intra-accumbens infusions of either 5-HT (0, 1, 5, and 10 © 2001 American College of Neuropsychopharmacology. ␮g) or DA (10, 20 ␮g) prior to the conditioned Published by Elsevier Science Inc. KEY WORDS: Nucleus accumbens; Fluoxetine; Buproprion; self-injurious behavior. Since both these transmitter Cocaine; Conditioned reinforcement; Serotonin; Dopamine; systems appear to play such a critical role in mental Locomotor activity functions, there has been a considerable amount of in- The dopaminergic and serotonergic neurotransmitter terest in their potential interactions. systems are thought to play a critical role in the regula- The nucleus accumbens, which has been implicated tion of emotion and mood, and have been implicated in in reward and motivation, is one brain region where a spectrum of neuropsychiatric disorders. Psychotropic such an interaction may take place. There are high lev- drugs affecting dopaminergic or serotonergic systems els of dopamine (DA), dopamine receptors, serotonin have been used to treat such disorders as depression, (5-HT), and serotonin receptors in this forebrain region bipolar disorder, schizophrenia, eating disorders, ob- (Beal and Martin 1985; Bonaventure et al. 1997; Bouyer sessive compulsive disorder, and autism and have also et al. 1984; Eberle-Wang et al. 1997; Joyce and Marshall been used to alleviate motor dysfunction associated 1987; Kilpatrick et al. 1987; Phelix and Broderick 1995; with Tourette’s syndrome, Parkinson’s disease, and Van Bockstaele et al. 1993; Van Bockstaele and Pickel 1993). The classical role of dopamine in the nucleus ac- cumbens has been attributed to regulating motivation From the Department of Psychiatry, University of Wisconsin- Madison Medical School, Madison, WI. and reward-related behavior (Robbins and Everitt 1996; Address correspondence to: Ann E. Kelley, Ph.D., Department of Schultz 1997; Wise and Rompré 1989). For example, Psychiatry, University of Wisconsin-Madison Medical School, 6001 drugs of abuse, such as cocaine and amphetamine, are Research Park Boulevard, Madison, WI 53719. Received 8 November 1999; revised 5 November 2000; accepted 4 believed to exert their euphoric effects primarily via ac- December 2000. tivating the dopamine system (Di Chiara and Imperato NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 3 © 2001 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/01/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(01)00240-8 NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 3 5-HT-DA Interactions in Reward and Motor Behavior 441 1988; Koob and Bloom 1988). In contrast to the substan- 5-HT receptors. For example, 5-HT1B and 5-HT3 ago- tial body of research on dopamine in the nucleus ac- nists tend to facilitate dopaminergic effects (De Deur- cumbens, there has been comparatively little attention waerdere et al. 1998; Parsons et al. 1996), whereas 5- given to the role of serotonin and serotonin-dopamine HT2C agonists have been reported to inhibit such effects interactions in the nucleus accumbens. (Walsh and Cunningham 1997). There are a number of reasons why further under- In the present work, we have conducted several ex- standing of dopamine-serotonin interactions would be periments examining the role of 5-HT and DA in condi- useful. Although depression undoubtedly involves a tioned reinforcement and locomotor activity in rats. The complex dysregulation of many transmitter and neu- first experiment sought to examine the effect of chronic roendocrine systems, a majority of drugs used to treat treatment with fluoxetine and buproprion in the condi- depression affects the serotonin system. Serotonin- tioned reinforcement paradigm. This paradigm mea- selective re-uptake inhibitors (SSRIs) such as fluoxetine sures an animal’s operant responding for a stimulus enhance synaptic levels of serotonin (5-HT), and are that has secondary reinforcing properties by virtue of generally quite effective in ameliorating the symptoms having been previously associated with food reward of depression. Thus, one widely held hypothesis is that (Robbins 1978). Clinical depression often manifests it- dysfunction in serotonergic neurons and their targets self as anhedonia, in which interest and motivation for may underlie depressive symptomatology (van Praag normally pleasurable stimuli is compromised. Although et al. 1987). Although serotonergic systems are most of- the conditioned reinforcement paradigm is not an animal ten implicated in mood, dopaminergic systems are tra- model of depression, it is a valid test of an animal’s re- ditionally associated with reward and appetitive moti- sponsivity to a rewarding stimulus. Further, this experi- vation. Since a hallmark of depression is diminished ment examined the effects of chronic antidepressant ability to experience pleasure, it is logical to propose treatment on the potentiating effect of cocaine in this that dopaminergic effects may be involved in the anti- paradigm. The second experiment evaluated the effect depressant effects of SSRIs. Such a putative effect of direct intra-accumbens infusion of 5-HT and dopa- would likely involve serotonin-dopamine interactions. mine in the conditioned reinforcement paradigm. The Moreover, although less commonly prescribed, drugs third experiment explored the role of 5-HT in the nu- enhancing dopaminergic function such as buproprion cleus accumbens with regard to locomotor activity. The also are effective antidepressants (Ascher et al. 1995). final experiment investigated the influence of dopamine There is ample evidence for serotonergic influences D1 and D2 antagonists on the motor activation elicited on dopamine function. Although several early studies by infusion of 5-HT into the nucleus accumbens. indicated an inhibitory role of 5-HT on dopaminergic activity (Korsgaard et al. 1985; Pycock et al. 1978; War- britton et al. 1978), much recent evidence suggests a fa- METHODS cilitatory effect on DA. For example, a number of in vivo Subjects microdialysis studies have clearly shown that exposure of the striatum or nucleus accumbens to serotonin re- The animals used in these experiments were treated in sults in increased release of dopamine (Benloucif and accordance with the Guide for the Care and Use of Lab- Galloway 1991; De Deurwaerdere et al. 1996; Hallbus et oratory Animals as adopted and promulgated by the al. 1997; Parsons and Justice 1993; Yadid et al. 1994; National Institutes of Health. A total of 51 male Spra- Yoshimoto et al. 1996), although the mechanism under- gue-Dawley rats weighing 250–300 g were housed two lying such an enhancement is unclear. Other method- per clear, plastic cage. They were maintained on a 12 ological approaches have also shown such a relation- hour light/dark schedule with lights on at 0700 h. The ship (Blandina et al. 1988; Jacocks and Cox 1992; Nurse animals were handled upon arrival and consistently et al. 1988; Yi et al. 1991). during the experiment in order to minimize the effects There has also been much interest in these interac- of stress induced by handling. In Experiments 1 and 2, tions with regard to the role of serotonin function in co- animals were maintained on a restricted feeding sched- caine’s psychomotor stimulating and reinforcing effects ule; in Experiments 3 and 4, they were maintained ad li- (Broderick and Phelix 1997; Cunningham et al. 1996; bitum. In Experiment 1, when it became apparent that Parsons et al. 1995; Walsh and Cunningham 1997). For fluoxetine-treated rats were losing weight more than example, although SSRIs do not substitute for cocaine the other groups, the rats were given extra food in an in drug discrimination tests, they do potentiate the attempt to maintain their weight. stimulus effects of cocaine (Cunningham and Callahan 1991; Kleven and Koek 1998). Although many of these Surgery studies tend to suggest a potentiating influence of sero- tonergic drugs on dopaminergic tone, the picture is For Experiments 2–4, rats were subjected to stereotaxic complicated by the existence of multiple subtypes of implantation of bilateral chronic indwelling cannulae 442 D.M. Sasaki-Adams and A.E. Kelley NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 3 (23 gauge; 0.063 cm). They were anesthetized using 0.6 soaked for 24 hours