Placebo Effect And Reward Circuitry

Reward Circuitry Depression

Fig. 1. Theoretical model for the placebo effect: The expectation of reward (i.e., expectation of clinical benefit) after placebo administration activates dopamine (DA) neurons of the ventral tegmental area (VTA), which leads to the release of dopamine (DA) not only in the ventral striatum (nucleus accumbens, NAcc), but also in the prefrontal cortex (PFC). This PFC activation, in turn, sets in motion disease-specific mechanisms, such as DA release in the dorsal striatum to improve motor function (which explains the clinical placebo effect in Parkinson's disease), the release of opioids to alleviate pain (placebo analgesia) and, perhaps, activation of serotonin (5-HT) pathways to reduce depression. While the release of dopamine in the ventral striatum may function as a gate (permissive component) for placebo responses, the activation of PFC-dependent pathways represents a higher cognitive component of the placebo effect (modified from Lidstone et al., 2005)

Fig. 1. Theoretical model for the placebo effect: The expectation of reward (i.e., expectation of clinical benefit) after placebo administration activates dopamine (DA) neurons of the ventral tegmental area (VTA), which leads to the release of dopamine (DA) not only in the ventral striatum (nucleus accumbens, NAcc), but also in the prefrontal cortex (PFC). This PFC activation, in turn, sets in motion disease-specific mechanisms, such as DA release in the dorsal striatum to improve motor function (which explains the clinical placebo effect in Parkinson's disease), the release of opioids to alleviate pain (placebo analgesia) and, perhaps, activation of serotonin (5-HT) pathways to reduce depression. While the release of dopamine in the ventral striatum may function as a gate (permissive component) for placebo responses, the activation of PFC-dependent pathways represents a higher cognitive component of the placebo effect (modified from Lidstone et al., 2005)

reward expectation such as the orbitofrontal cortex, the dorsolateral prefrontal cortex, and the anterior cingulated gyrus, which suggests the involvement of high cognitive processing in placebo responses (de la Fuente-Fernandez et al., 2002b, 2004). On the other hand, as dopamine is a major neurotransmitter in reward processing (Schultz, 1998), the release of dopamine may be a common phenomenon in any placebo response. There are studies underway to prove (or disprove) this prediction.

There is evidence to suggest that, in addition to dopamine, other neurotransmitters and neuropeptides are also involved in both reward and placebo mechanisms (de la Fuente-Fernandez et al., 2004). Indeed, it is tempting to speculate with the possibility that different endogenous neuroactive substances contribute to placebo responses in a disease-specific fashion (de la Fuente-Fernandez et al., 2002b) (Fig. 1). For example, while opioids could be particularly implicated in placebo analgesia (Levine et al., 1978), serotonin might play a major role in mediating the placebo effect in depression.

Conclusions

The placebo effect in Parkinson's disease reflects the release of dopamine in the stria-tum. It has been proposed that the placebo effect is related to reward mechanisms. As dopamine is a major neurotransmitter in reward processing, it follows that the release of dopamine in the ventral striatum may be a common phenomenon in placebo responses encountered in other medical disorders. Further research is necessary to determine how cortical processing interacts with the reward circuitry to elicit a disease-specific placebo response.

References

Beecher HK (1955) The powerful placebo. JAMA 159: 1602-1606

Benedetti F, Colloca L, Torre E, Lanotte M, Melcarne A, Pesare M, Bergamasco B, Lopiano L (2004) Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. Nat Neurosci 7: 587-588 de la Fuente-Fernandez R (2004) Uncovering the hidden placebo effect in deep-brain stimulation for Parkinson's disease. Parkinsonism Relat Disord 10: 125-127

de la Fuente-Fernandez R, Phillips AG, Zamburlini M, Sossi V, Calne DB, Ruth TJ, Stoessl AJ (2002a) Dopamine release in human ventral striatum and expectation of reward. Behav Brain Res 136: 359-363

de la Fuente-Fernandez R, Ruth TJ, Sossi V, Schulzer M, Calne DB, Stoessl AJ (2001) Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease. Science 293: 1164-1166 de la Fuente-Fernandez R, Schulzer M, Stoessl AJ (2002b) The placebo effect in neurological disorders. Lancet Neurol 1: 85-91 de la Fuente-Fernandez R, Schulzer M, Stoessl AJ

(2004) Placebo mechanisms and reward circuitry: clues from Parkinson's disease. Biol Psychiatry 56: 67-71

Levine JD, Gordon NC, Fields HL (1978) The mechanism of placebo analgesia. Lancet 2: 654-657 Lidstone S, de la Fuente-Fernandez R, Stoessl AJ

(2005) The placebo response as a reward mechanism. Semin Pain Med 3: 37-42

McRae C, Cherin E, Yamazaki TG, Diem G, Vo AH, Russell D, Ellgring JH, Fahn S, Greene P, Dillon S, Winfield H, Bjugstad KB, Freed CR (2004) Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial. Arch Gen Psychiatry 61: 412-420

Schultz W (1998) Predictive reward signal and dopamine neurons. J Neurophysiol 80: 1-27

Author's address: Dr. R. de la Fuente-Fernandez, Division of Neurology, Hospital A. Marcide, 15405 Ferrol, Spain, e-mail: [email protected]

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