, 2002), reinforcing the suppression of food intake and opposing the effects of ghrelin (see above). Interestingly, leptin stimulates

the transcription factor STAT3, which in conjunction with the transcription factor Nhlh2 regulates transcription of prohormone-converting enzymes 1 (PC1) and 2 (PC2) (Fox and Good, 2008). These enzymes are involved in the conversion of POMC to various hormones, such as ACTH, and various types of melanocyte-stimulating hormones (MSH) (reviewed in Mountjoy, 2010). Central administration of α-MSH reduces appetite Tariquidar and increases energy expenditure (Cone, 2006) via its actions on melanocortin receptors (Mc3r and Mc4r) (Cone, 2006). Lack of Mc3r in mice leads to reduced FAA under restricted feeding conditions, and the expression of the clock genes Npas2 and Per2 in the cortex is also reduced ( Sutton et al., 2008). These observations are consistent with the reported reduction or absence of FAA in mutant Bortezomib mice that lack clock components Npas2 or Per2, respectively ( Dudley et al., 2003 and Feillet et al., 2006). Collectively, it appears that circadian leptin in the serum binds to its

receptors in a time-dependent fashion, thereby activating neurons in the ARC and modulating transcription of target genes in a 24 hr cycle. However, the details of how this is achieved are still a matter of investigation. There is surmounting evidence to support the theory that the consumption of both food and drugs of abuse converge on a shared pathway within the limbic system that mediates motivated behaviors (reviewed in Simerly, 2006). Much of the research has focused on the mesolimbic dopamine pathway because common drugs of abuse increase dopamine signaling from nerves that originate in the ventral Chlormezanone tegmental area (VTA) and project to the nucleus accumbens (NAc), which is part of the striatum (Figure 5) (Nestler and Carlezon, 2006). An increase in dopaminergic transmission is thought to occur either by direct action of drugs on dopaminergic neurons (cocaine, nicotine) or indirectly by inhibition of GABAergic interneurons in the VTA (alcohol, opiates). In addition, the peptide neurotransmitter

orexin, which is expressed in a subset of neurons in the lateral hypothalamus (LH) that have projections to the VTA, is also implicated in mediating drug-induced activation of dopaminergic neurons in the VTA (Borgland et al., 2006). Interestingly, the activation of orexin neurons appears to be under circadian control (Marston et al., 2008), linking arousal and drug-induced behavior by the circadian clock mechanism. Natural rewards such as food induce similar responses in the mesolimbic dopamine pathway (Kelley and Berridge, 2002). Presentation of palatable food induces the release of dopamine into the NAc, which in turn promotes the animal’s behavioral attempts to obtain food rewards via increased arousal and psychomotor activation.