THE BIOCHEMICAL BASES FOR REWARD Implications for the Placebo Effect

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1 / Evaluation & the Health Professions / December 2002 de la Fuente-Fernández, Stoessl / BIOCHEMICAL BASES FOR REWARD The authors propose that the placebo effect is mediated by reward-related mechanisms. Recent evidence suggests that it is the expectation of reward (in this case, the expectation of clinical benefit) that triggers the placebo response. In Parkinson s disease, the placebo effect is mediated by the release of dopamine in the striatum. The authors argue that placeboinduced dopamine release in limbic structures, particularly in the nucleus accumbens, could also be a major biochemical substrate for the placebo effect encountered in other medical disorders. Other neuroactive substances involved in the reward circuitry (e.g., opioids) are also likely to contribute to the placebo response, and such contribution may be disorder specific (e.g., opioid release in placebo analgesia; serotonin regulation in response to placebo antidepressants). In addition, placebos may have a role in substitution programs for the treatment of drug addiction. THE BIOCHEMICAL BASES FOR REWARD Implications for the Placebo Effect RAÚL DE LA FUENTE- FERNÁNDEZ A. JON STOESSL Pacific Parkinson s Research Centre, University of British Columbia AUTHORS NOTE: This article was supported by the Canadian Institutes of Health Research, the National Parkinson Foundation (Miami, Florida), the British Columbia Health Research Foundation (Canada) (R.F.- F.), the Pacific Parkinson s Research Institute (Vancouver, BC, Canada) (R.F.-F.), and the Canada Research Chairs program (A.J.S.). EVALUATION & THE HEALTH PROFESSIONS, Vol. 25 No. 4, December DOI: / Sage Publications 387

2 388 Evaluation & the Health Professions / December 2002 The power of placebos to improve a great variety of medical conditions has long been recognized (Beecher, 1955, 1961; de la Fuente-Fernández, Schulzer, & Stoessl, 2002; de la Fuente-Fernández & Stoessl, 2002). However, little is known about the biochemical bases underlying the placebo effect. If one accepts that the placebo effect is related to the mind s healing power, it becomes clear that many different types of therapy can evoke a placebo response. Traditional placebos include pills ( sugar pills ), injections ( salt injections ), and surgical procedures ( sham or imitation operations ). But there are also unconventional placebo agents. For example, several studies have pointed out the healing power of religious experiences (Koenig et al., 1998; Koenig, Larson, & Larson, 2001; Oxman, Freeman, & Manheimer, 1995). Indeed, recent direct biochemical evidence suggests that expectation (belief or faith) seems to be at the very heart of the placebo response (de la Fuente-Fernández et al., 2001; de la Fuente-Fernández & Stoessl, 2002). Theoretical and neuropharmacological approaches have led to the same conclusion (Amanzio & Benedetti, 1999; Benedetti, Arduino, & Amanzio, 1999; Kirsch, 1997). We provide evidence here to support the notion that the placebo effect is mediated by the reward circuitry. PLACEBO EFFECT AND REWARD Some authors have suggested that the placebo effect may have evolved as a result of natural selection (Morris, 1997). Accordingly, placebo responders could have greater chances of survival. The fact that most medicines, potions, and remedies dispensed in ancient times would today be considered placebos gives support to the idea that placebo responders may be best fit for survival. Indeed, until recently, the history of medicine has simply been the history of the placebo effect. However, the ability to respond to placebos does not seem to be associated with any specific psychological profile (Brody, 1980; Shapiro & Shapiro, 1997). Also, because one individual may respond to a particular placebo at a given time does not necessarily mean that he or she will maintain a placebo effect on future exposures to the same placebo or respond to a different placebo. Most of us have experienced placebo responses at one time or another. A common experience is, for example, the calming and pain-

3 de la Fuente-Fernández, Stoessl / BIOCHEMICAL BASES FOR REWARD 389 relieving properties that a child may attribute to a candy. This observation suggests that we all have the potential to manifest placebo responses at an early age. Candy is probably the first sugar pill to which we have been exposed. However, candy can also be used as an effective reward on other occasions during childhood. With this simple example, the potential connection between a placebo and a reward becomes apparent. Therefore, one may predict that the brain mechanisms involved in handling rewarding signals should also be activated during placebo responses. THE REWARD CIRCUITRY: DOPAMINERGIC PATHWAYS Midbrain dopamine cells are activated by primary rewards and reward-predicting stimuli (Schultz, 1998), and such activation seems to be the basis of drug addiction (Di Chiara & Imperato, 1988). There are three major dopamine cell groups: retrorubral area (A8), substantia nigra (A9), and ventral tegmental area (A10). Each one projects to different brain areas (Alexander, DeLong, & Strick, 1986; Bjorklund & Lindvall, 1984). Thus, there is a projection from the substantia nigra pars compacta to the dorsal striatum (nigrostriatal pathway), a projection from the lateral regions of the ventral tegmental area to subcortical limbic structures (mesolimbic pathway) and a projection that originates in the medial regions of the ventral tegmental area and targets different frontal cortical areas (mesocortical pathway). Most of these frontal areas are heavily connected with subcortical limbic regions. In addition to the ventral tegmental area, the medial regions of the substantia nigra pars reticulata and the retrorubral area also have mesolimbic and mesocortical projections. Although the nigrostriatal pathway controls motor function, the limbic system which includes the ventral striatum, the amygdala, the hippocampus, the olfactory tubercle, and the septal region is mostly involved in emotional responses (Alexander et al., 1986). The role of the nucleus accumbens, the major structure of the ventral striatum (Holt, Graybiel, & Saper, 1997), in reward mechanisms has been studied extensively (Fibiger & Phillips, 1986; Wise & Rompre, 1989). In particular, it has been shown that the release of dopamine in the nucleus accumbens is associated with the

4 390 Evaluation & the Health Professions / December 2002 LIMBIC CORTEX / HIPPOCAMPUS THALAMUS (MD) NAC PALLIDUM (ventral) Amygdala VTA PAG Hypothalamus inhibition of pain transmission (spinal cord, thalamus) inhibition of pain perception (limbic system/cortex) NAC = nucleus accumbens VTA = ventral tegmental area PAG = periaqueductal gray MD = mediodorsal nucleus (thalamus) Figure 1: The Reward Circuitry The nucleus accumbens (NAC), which occupies a central position in the dopamine-opioid connection of the reward circuitry, is likely to play a major role in mediating the placebo effect. Other structures, including the ventral tegmental area (VTA), amygdala, limbic cortex, and periaqueductal gray (PAG), may be also involved in the placebo response. SOURCE: de la Fuente-Fernández, Schulzer, and Stoessl (2002). Reprinted with permission. dependence liability of drugs such as cocaine, opioids, and alcohol (Robinson & Berridge, 1993). Interestingly, such reward-related dopamine release appears to be more related to the expectation of the reward than to the reward itself. Thus, although electrical intracranial stimulation in animals will only occur when the electrodes are positioned to stimulate dopamine release in response to experimenterderived stimulation, self-stimulation itself does not result in the release of dopamine (Garris et al., 1999). THE DOPAMINE-OPIOID CONNECTION There is substantial neuroanatomical and neurochemical evidence for dopamine-opioid interconnections (see Figure 1). We have already seen that the nucleus accumbens receives a major dopaminergic projection from the ventral tegmental area. The nucleus accumbens in

5 de la Fuente-Fernández, Stoessl / BIOCHEMICAL BASES FOR REWARD 391 turn sends projections to the ventral pallidum and from there to the mediodorsal nucleus of the thalamus, thereby closing a loop to the limbic cortex (Alexander et al., 1986). The limbic and prefrontal cortex (and amygdala), all of which are under dopaminergic control, can in turn influence opioid release directly in the periaqueductal gray, a major center for pain regulation in the brain stem (Christie, James, & Beart, 1986; Mantyh, 1982; Wyss & Sripanidkulchai, 1984). However, it should be noted that the ventral tegmental area also projects directly to the periaqueductal gray (Beitz, 1982). The nucleus accumbens itself sends projections to the periaqueductal gray through the hypothalamus (Yu & Han, 1989) and perhaps through the amygdala as well (Ma & Han, 1991). Thus, we can see that the activation of dopamine cells in the ventral tegmental area could play a substantial role in the control of opioid release both directly and indirectly via accumbens-ventral pallidal-thalamocortical-periaqueductal gray and accumbens-hypothalamic/amygdalo-periaqueductal gray loops. The release of dopamine in the nucleus accumbens or in other limbic structures could therefore play a role in the transmission and perception of pain (Altier & Stewart, 1999) (see Figure 1). Conversely, the periaqueductal gray sends projections to limbic structures, including the ventral tegmental area, the nucleus accumbens, the amygdala, and limbic frontal areas (Cameron, Khan, Westlund, Cliffer, & Willis, 1995; Eberhart, Morrell, Krieger, & Pfaff, 1985; Herrero, Insausti, & Gonzalo, 1991). Particularly well characterized are projections to the nucleus accumbens from neurons of the periaqueductal gray that contain substance P- or leucine-enkephalin-like immunoreactivity (Li, Rao, & Shi, 1990). Hence, there is also an anatomical substrate to support the notion that the release of opioids may influence dopamine release in the nucleus accumbens (Di Chiara & Imperato, 1988; Pontieri, Tanda, & Di Chiara, 1995; Spanagel, Herz, & Shippenberg, 1990). In other words, the dopamine-opioid connection is likely to be bidirectional. Perhaps the most familiar example of the significance of this interaction is the observation that activation of brain opioid systems can lead to reward via stimulation of dopamine release. Indeed, whereas normal animals can readily be trained to selfadminister opioid drugs of abuse, this will not occur if the dopamine projections are destroyed (Spyraki, Fibiger, & Phillips, 1983). However, the other implication of this bidirectional dopamine-opioid interaction is that the release of dopamine within reward pathways could

6 392 Evaluation & the Health Professions / December 2002 have a potent influence on the perception of pain. As we discuss below, this provides a plausible (albeit as yet untested) basis for believing that placebo analgesia may at least in part be related to dopamine release and that by stimulating dopamine release, placebos might play a role in substitution therapy for drug addiction. PLACEBO EFFECT AND DOPAMINE RELEASE IN PARKINSON S DISEASE AND OTHER CONDITIONS Parkinson s disease is a common condition, estimated to affect more than 1 million North Americans. The disorder is characterized by rest tremor, bradykinesia (slowness of movement)/akinesia (lack of movement initiation), and postural instability. Although other neurotransmitters may be involved either primarily or secondarily in advanced Parkinson s, the cardinal pathological feature, which is both necessary and sufficient for disease expression, is loss of the dopamine-producing cells of the substantia nigra pars compacta. These neurons project to the striatum (caudate and putamen). It is estimated that one must lose 80% of striatal dopamine before symptoms appear thus, patients with moderately advanced disease have profound reductions in the striatal concentration of dopamine. Interestingly, it is well recognized that patients with Parkinson s may display a strong response to placebo in trials of medication (Goetz, Leurgans, Ramman, & Stebbins, 2000; Shetty, Friedman, Kieburtz, Marshall, & Oakes, 1999) or surgery (Freeman et al., 1999; Watts et al., 2001). We recently demonstrated placebo-induced dopamine release in both the dorsal (de la Fuente-Fernández et al., 2001) and ventral (de la Fuente-Fernández et al., in press) striatum in patients with Parkinson s disease. We argued that these observations (in particular the release of dopamine in the ventral striatum) support a link between the placebo effect and reward mechanisms. Interestingly, our results suggest that it is the expectation of reward (in this case, the expectation of clinical benefit) that triggers the release of dopamine. Thus, patients who reported clinical benefit after placebo administration ( salt injection ) released the same amount of dopamine in the ventral striatum as those who perceived no clinical placebo effect. As clinical improvement must be a rewarding experience, this observation supports that the release of dopamine is related to the expectation (not the

7 de la Fuente-Fernández, Stoessl / BIOCHEMICAL BASES FOR REWARD 393 experience) of a reward. Other authors have also concluded that the placebo effect is related to the expectation of benefit (see, e.g., Mayberg et al., 2002). A most tantalizing possibility is that the release of dopamine in the ventral striatum could be a common mechanism for the placebo effect encountered in other medical conditions. If, as we argue, the placebo effect is an example of expectation of therapeutic benefit, as a major component of the reward circuitry, the dopaminergic system is indeed a suitable candidate. Thus, for example, the release of dopamine in the nucleus accumbens could modify pain transmission and pain perception (see above). In keeping with this notion, it has been shown that pain, opioids, and placebo analgesics activate cortical and subcortical areas that receive dopaminergic projections (Petrovic, Kalso, Petersson, & Ingvar, 2002; Zubieta et al., 2001). Experiments on rewarding effects also support this theory. Thus, mice lacking dopamine D2 receptors are unable to display the rewarding effects of opioids after exposure to morphine (Maldonado et al., 1997), and the same occurs in mice lacking the receptor for substance P (Murtra, Sheasby, Hunt, & De Felipe, 2000). In both cases, impaired dopaminergic transmission in the nucleus accumbens could be the key factor. Interestingly, substance-p-receptor-knockout mice do respond when cocaine or food are used as rewards, which suggests biochemical specificity of reward mechanisms (Murtra et al., 2000). These observations suggest that although dopamine is necessary for the rewarding effects of opioids, such effects are finally expressed through endogenous opioid systems. If our hypothesis that dopamine release is common to the placebo response in multiple medical conditions proves to be correct, it would represent a major advance in our understanding of self-healing (mind-body interactions). PLACEBO EFFECT AND OPIOID RELEASE It should be emphasized that the first clue to the biochemistry of the placebo effect came from experiments on placebo analgesia (Levine, Gordon, & Fields, 1978). Levine and colleagues (1978) found that placebo analgesia was inhibited by naloxone and suggested that the placebo effect in pain disorders is due to the release of endogenous

8 394 Evaluation & the Health Professions / December 2002 opioids (Levine et al., 1978). Neuroimaging studies (using either positron-emission tomography or single-photon-emission computed tomography) would be expected to provide evidence for (or against) placebo-induced release of opioids. As indicated previously, the release of dopamine in the reward circuitry (e.g., the nucleus accumbens) could mediate placebo analgesia by controlling opioid release, especially through the connections that this circuitry establishes with the periaqueductal gray. Nevertheless, opioid release could also be a primary mechanism in placebo analgesia. Still, we think that, if this were the case, such placebo-induced release of opioids should preferentially occur as a reward-related mechanism integrated within the reward circuitry. This is somewhat supported by the recent demonstration that placebo analgesia is associated with increased blood flow in the rostral anterior cingulate cortex, a region that shares dopamineand opioid-containing projections (Petrovic et al., 2002). PLACEBO EFFECT AND OTHER NEUROACTIVE SUBSTANCES In addition to dopamine and opioids, other neuroactive substances such as norepinephrine and nitric oxide could also be involved in mediating the placebo effect (Stefano, Fricchione, Slingsby, & Benson, 2001). Based on observations derived from the relaxation response, Stefano and colleagues (2001) note that although the brain reward circuitry plays a critical role in mediating the placebo effect, the peripheral nervous system may also participate (Stefano et al., 2001). Naturally, the specific contribution of each of the biochemical components implicated in the placebo response may vary from one disorder to another. For example, opioid release may predominate in placebo analgesia, but activation of serotonin-containing pathways may be especially involved in mediating the placebo effect in disorders associated with depression (Mayberg et al., 2002). We have provided evidence for placebo-induced release of dopamine in Parkinson s disease. However, as mentioned earlier, it remains unknown whether the release of dopamine is also a mechanism for the placebo effect encountered in other disorders.

9 de la Fuente-Fernández, Stoessl / BIOCHEMICAL BASES FOR REWARD 395 CONCLUSION There is convincing evidence for a strong clinical placebo effect in pain, depression, and Parkinson s disease (de la Fuente-Fernández et al., 2002; de la Fuente-Fernández & Stoessl, 2002). Other disorders can also improve with placebo interventions (de la Fuente-Fernández et al., 2002; Stefano et al., 2001). Much progress has been made in understanding the brain areas activated in response to placebos for different medical conditions, and some of the biochemical bases of the placebo effect have already been worked out. Thus, the release of dopamine in the striatum is the biochemical substrate of the placebo effect in Parkinson s disease (de la Fuente-Fernández et al., 2001). We propose that the placebo effect is related to reward mechanisms and that the release of dopamine within the brain reward circuitry plays a key role in the placebo effect. Other neuroactive substances, however, are also likely to be involved, perhaps following a specific pattern for different disorders (e.g., opioid release in placebo analgesia, serotonin release/regulation in response to placebo antidepressants). Finally, the relation between placebo and reward supports the use of placebos in substitution programs for the treatment of drug addiction (de la Fuente-Fernández et al., 2002; de la Fuente-Fernández & Stoessl, 2002). REFERENCES Alexander, G. E., DeLong, M. R., & Strick, P. L. (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience, 9, Altier, N., & Stewart, J. (1999). The role of dopamine in the nucleus accumbens in analgesia. Life Science, 65, Amanzio, M., & Benedetti, F. (1999). Neuropharmacological dissection of placebo analgesia: Expectation-activated opioid systems versus conditioning-activated specific subsystems. Journal of Neuroscience, 19, Beecher, H. K. (1955). The powerful placebo. Journal of the American Medical Association (JAMA), 159, Beecher, H. K. (1961). Surgery as placebo: A quantitative study of bias. JAMA, 176, Beitz, A. J. (1982). The organization of afferent projections to the midbrain periaqueductal gray of the rat. Neuroscience, 7, Benedetti, F., Arduino, C., & Amanzio, M. (1999). Somatotopic activation of opioid systems by target-directed expectations of analgesia. Journal of Neuroscience, 19,

10 396 Evaluation & the Health Professions / December 2002 Bjorklund, A., & Lindvall, O. (1984). Dopamine-containing systems in the CNS. In A. Bjorklund & T. Hokfelt (Eds.), Handbook of chemical neuroanatomy (pp ). Amsterdam: Elsevier Science. Brody, H. (1980). Placebos and the philosophy of medicine: Clinical, conceptual, and ethical issues. Chicago: University of Chicago Press. Cameron, A. A., Khan, I. A., Westlund, K. N., Cliffer, K. D., & Willis, W. D. (1995). The efferent projections of the periaqueductal gray in the rat: A phaseolus vulgaris-leucoagglutinin study. I. Ascending projections. Journal of Comparative Neurology, 351, Christie, M. J., James, L. B., & Beart, P. M. (1986). An excitatory amino acid projection from rat prefrontal cortex to periaqueductal gray. Brain Research Bulletin, 16, de la Fuente-Fernández, R., Phillips, A. G., Zamburlini, M., Sossi, V., Calne, D. B., Ruth, T. J., et al. (in press). Dopamine release in human ventral striatum and expectation of reward. Behavioural Brain Research. de la Fuente-Fernández, R., Ruth, T. J., Sossi, V., Schulzer, M., Calne, D. B., & Stoessl, A. J. (2001). Expectation and dopamine release: Mechanism of the placebo effect in Parkinson s disease. Science, 293, de la Fuente-Fernández, R., Schulzer, M., & Stoessl, A. J. (2002). The placebo effect in neurological disorders. Lancet Neurology, 1, de la Fuente-Fernández, R., & Stoessl, A. J. (2002). The placebo effect in Parkinson s disease. Trends in Neuroscience, 25, Di Chiara, G., & Imperato, A. (1988). Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proceedings of the National Academy of Sciences of the United States of America, 85, Eberhart, J. A., Morrell, J. I., Krieger, M. S., & Pfaff, D. W. (1985). An autoradiographic study of projections ascending from the midbrain central gray, and from the region lateral to it, in the rat. Journal of Comparative Neurology, 241, Fibiger, H. C., & Phillips, A. G. (1986). Reward, motivation, and cognition: Psychobiology of the mesotelencephalic dopamine systems. In F. E. Bloom & S. R. Geiger (Eds.), Handbook of physiology: The nervous system, Vol. 4. Intrinsic regulatory systems of the brain (pp ). Bethesda, MD: American Physiological Society. Freeman, T. B., Vawter, D. E., Leaverton, P. E., Godbold, J. H., Hauser, R. A., Goetz, C. G., et al. (1999). New England Journal of Medicine, 341, Garris, P. A., Kilpatrick, M., Bunin, M. A., Michael, D., Walker, Q. D., & Wightman, R. M. (1999). Dissociation of dopamine release in the nucleus accumbens from intracranial selfstimulation. Nature, 398, Goetz, C. G., Leurgans, S., Ramman, R., & Stebbins, G. T. (2000). Objective changes in motor function during placebo treatment in PD. Neurology, 54, Herrero, M. T., Insausti, R., & Gonzalo, L. M. (1991). Cortically projecting cells in the periaqueductal gray matter of the rat: A retrograde fluorescent tracer study. Brain Research, 543, Holt, D. J., Graybiel, A. M., & Saper, C. B. (1997). Neurochemical architecture of the human striatum. Journal of Comparative Neurology, 384, Kirsch, I. (1997). Specifying nonspecifics: Psychological mechanisms of placebo effects. In A. Harrington (Ed.), The placebo effect: An interdisciplinary exploration (pp ). Cambridge, MA: Harvard University Press. Koenig, H. G., George, L. K., Hays, J. C., Larson, D. B., Cohen, H. J., & Blazer, D. G. (1998). The relationship between religious activities and blood pressure in older adults. International Journal of Psychiatry in Medicine, 28, Koenig, H. G., Larson, D. B., & Larson, S. S. (2001). Religion and coping with serious medical illness. Annals of Pharmacotherapy, 35,

11 de la Fuente-Fernández, Stoessl / BIOCHEMICAL BASES FOR REWARD 397 Levine, J. D., Gordon, N. C., & Fields, H. L. (1978). The mechanism of placebo analgesia. Lancet, ii, Li, Y. Q., Rao, Z. R., & Shi, J. W. (1990). Midbrain periaqueductal gray neurons with substance P- or enkephalin-like immunoreactivity send projection fibers to the nucleus accumbens in the rat. Neuroscience Letters, 119, Ma, Q. P., & Han, J. S. (1991). Neurochemical studies on the mesolimbic circuitry of antinociception. Brain Research, 566, Maldonado, R., Saiardi, A., Valverde, O., Samad, T. A., Roques, B. P., & Borrelli, E. (1997). Absence of opiate rewarding effects in mice lacking dopamine D2 receptors. Nature, 388, Mantyh, P. W. (1982). Forebrain projections to the periaqueductal gray in the monkey, with observations in the cat and rat. Journal of Comparative Neurology, 206, Mayberg, H. S., Silva, J. A., Brannan, S. K., Tekell, J. L., Mahurin, R. K., McGinnis, S., et al. (2002). The functional neuroanatomy of the placebo effect. American Journal of Psychiatry, 159, Morris, D. B. (1997). Placebo, pain, and belief: A biocultural model. In A. Harrington (Ed.), The placebo effect: An interdisciplinary exploration (pp ). Cambridge, MA: Harvard University Press. Murtra, P., Sheasby, A. M., Hunt, S. P., & De Felipe, C. (2000). Rewarding effects of opiates are absent in mice lacking the receptor for substance P. Nature, 405, Oxman, T. E., Freeman, D. H., Jr., & Manheimer, E. D. (1995). Lack of social participation or religious strength and comfort as risk factors for death after cardiac surgery in the elderly. Psychosomatic Medicine, 57, Petrovic, P., Kalso, E., Petersson, K. M., & Ingvar, M. (2002). Placebo and opioid analgesia Imaging a shared neuronal network. Science, 295, Pontieri, F. E., Tanda, G., & Di Chiara, G. (1995). Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the shell as compared with the core of the rat nucleus accumbens. Proceedings of the National Academy of Sciences of the United States of America, 92, Robinson, T. E., & Berridge, K. C. (1993). The neural basis of drug craving: An incentivesensitization theory of addiction. Brain Research Reviews, 18, Schultz, W. (1998). Predictive reward signal of dopamine neurons. Journal of Neurophysiology, 80, Shapiro, A. K., & Shapiro, E. (1997). The placebo: Is it much ado about nothing? In A. Harrington (Ed.), The placebo effect: An interdisciplinary exploration (pp ). Cambridge, MA: Harvard University Press. Shetty, N., Friedman, J. H., Kieburtz, K., Marshall, F. J., & Oakes, D. (1999). The placebo response in Parkinson s disease: Parkinson study group. Clinical Neuropharmacology, 22, Spanagel, R., Herz, A., & Shippenberg, T. S. (1990). The effects of opioid peptides on dopamine release in the nucleus accumbens: An in vivo microdialysis study. Journal of Neurochemistry, 55, Spyraki, C., Fibiger, H. C., & Phillips, A. G. (1983). Attenuation of heroin reward in rats by disruption of the mesolimbic dopamine system. Psychopharmacology, 79, Stefano, G. B., Fricchione, G. L., Slingsby, B. T., & Benson, H. (2001). The placebo effect and relaxation response: Neural processes and their coupling to constitutive nitric oxide. Brain Research Reviews, 35, Watts, R. L., Freeman, T. B., Hauser, R. A., Bakay, R. A., Ellias, S. A., Stoessl, A. J., et al. (2001). A double-blind, randomised, controlled, multicenter clinical trial of the safety and efficacy of stereotaxic intrastriatal implantation of fetal porcine ventral mesencephalic tissue

12 398 Evaluation & the Health Professions / December 2002 (Neurocell TM -PD) vs. imitation surgery in patients with Parkinson s disease (PD). Parkinsonism and Related Disorders, 7, S87. Wise, R. A., & Rompre, P. P. (1989). Brain dopamine and reward. Annual Review of Psychology, 40, Wyss, J. M., & Sripanidkulchai, K. (1984). The topography of the mesencephalic and pontine projections from the cingulate cortex of the rat. Brain Research, 293, Yu, L. C., & Han, J. S. (1989). Involvement of arcuate nucleus of hypothalamus in the descending pathway from nucleus accumbens to periaqueductal grey subserving an antinociceptive effect. International Journal of Neuroscience, 48, Zubieta, J.-K., Smith, Y. R., Bueller, J. A., Xu, Y., Kilbourn, M. R., Jewett, D. M., et al. (2001). Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science, 293,