YOUNG INVESTIGATOR PERSPECTIVE Ghrelin and Dopamine: New Insights on the Peripheral Regulation of Appetite Alfonso Abizaid Neuroscience Institute, Carleton University, Ottawa, ON, Canada. The emergence of obesity as the single most important cause for poor health and early death in Western societies (1) has fuelled an intense search for strategies to curb weight gain including the active search for endogenous substances that directly modulate appetite, and the generation of pharmacological agents that can stimulate or prevent these substances from modulating appetite. An example of this has been the discovery of ghrelin, a hormone pro- duced by the stomach, and one found to be the endogenous ligand to the growth hormone secretagogue receptor (GHS-R) (2, 3).The discovery of ghrelin, a 28-amino acid peptide hormone, has gener- ated a substantial amount of attention for a number of reasons. Initially, ghrelin was heralded as the long sought endogenous ligand for the orphan GHS-Rs. Soon, however, it became evident that ghrelin was implicated in a variety of physiological processes, including cell proliferation, metabolism, cell protection, reproduc- tion, amongst others. Of these, the effects of ghrelin on food intake and metabolism have had the biggest impact; unlike other periph- eral signals associated with energy balance, ghrelin increases appe- tite and leads to the accumulation of body fat. Nevertheless, the more that becomes known about ghrelin, the more it is obvious that ghrelin produces its metabolic effects via a multitude of cen- tral and peripheral mechanisms working in parallel to modulate the effects of ghrelin in energy regulation. This review summarises evi- dence supporting the role of ghrelin on reward-seeking behaviours. The effects of ghrelin on other physiological processes can be found in several excellent recent reviews (4–6). Ghrelin and food intake: hypothalamic regulation The effects of ghrelin on food intake were foreshadowed by a num- ber of studies showing that GHS-Rs increased food intake and adi- posity via the stimulation of orexigenic peptides in the hypothalamic arcuate nucleus (ARC) (7–9). After the discovery of ghrelin, it was soon established that, similar to the growth hor- mone secretagogues, peripheral and central delivery of ghrelin stim- ulated food intake and adiposity (10, 11). Furthermore, these studies showed that ghrelin acted centrally possibly via the hypo- thalamic ARC, and particularly on neurones producing neuropeptide Y (NPY) / agouti-related peptide (AgRP), to produce its orexigenic and adipogenic effects (10, 11). Interestingly, even though the effects of chronic peripheral ghrelin on food intake subside, they do not decrease when ghrelin is administered chronically into the Journal of Neuroendocrinology Correspondence to: Alfonso Abizaid, Neuroscience Institute, Carleton University, Ottawa, ON, K1S 5B6 Canada (e-mail: alfonso_abizaid@carleton.ca). A review is provided of current evidence supporting the actions of the stomach-derived peptide ghrelin on ventral tegmental area (VTA) dopamine cells to increase food intake and other appeti- tive behaviours. Ghrelin is a 28 amino-acid peptide that was first identified as an endogenous ligand to growth hormone secretagogue receptors (GHS-R). In addition to the hypothalamus and brain stem, GHS-R message and protein are distributed throughout the brain, with high expression being detected in regions associated with goal directed behaviour. Of these, the VTA shows relatively high levels of mRNA transcript and protein. Interestingly, ghrelin infusions into the VTA increase food intake dramatically, and stimulate dopamine release from the VTA. More- over, VTA dopamine neurones increase their activity in response to ghrelin in slice preparations, suggesting that ghrelin increases food intake by modulating the activity of dopaminergic neuro- nes in the VTA. On the basis of these data as well as the fact that VTA dopamine cells respond to other metabolic hormones such as insulin and leptin, it is proposed that VTA dopamine cells, similar to cells in the mediobasal hypothalamus, are first-order sensory neurones that regulate appetitive behaviour in response to metabolic and nutritional signals. Key words: ghrelin, GHS-R, dopamine, VTA, food Intake, energy balance. doi: 10.1111/j.1365-2826.2009.01896.x Journal of Neuroendocrinology 21, 787–793 ª 2009 The Author. Journal Compilation ª 2009 Blackwell Publishing Ltd Journal of Neuroendocrinology From Molecular to Translational Neurobiology