Addictive drugs act on brain reward systems, although the brain evolved to respond not to drugs but to natural rewards, such as food and sex. Appropriate responses to natural rewards were evolutionarily important for survival, reproduction, and fitness. In a quirk of evolutionary fate, humans discovered how to stimulate this system artificially with drugs. Many molecular features of neural systems instantiating reward, and of those systems affected by addictive drugs, are conserved across species from Drosophilae to rats to humans and include dopamine (DA), G-proteins, protein kinases, amine transporters, and transcription factors such as cAMP response element-binding protein (CREB). A better understanding of natural brain reward systems will therefore enhance understanding of the neural causation of addiction.

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We elaborate herein a novel theory of basal ganglia function that accounts for why palatable, energy-dense foods retain high incentive value even when immediate physiological energy requirements have been met. Basal ganglia function has been studied from the perspective of topographical segregation of processing within parallel circuits, with primary focus on motor control and cognition. Recent findings suggest, however, that the striatum can act as an integrated unit to modulate motivational state. We describe evidence that the striatal enkephalin system, which regulates the hedonic impact of preferred foods, undergoes coordinated gene expression changes that track current motivational state with regard to food intake. Striatal enkephalin gene expression is also downregulated by an intrastriatal infusion of a cholinergic muscarinic antagonist, a manipulation that greatly suppresses food intake. To account for these findings, we propose that signaling through a hypothalamic-midline thalamic-striatal axis impinges on the cholinergic interneurons of the striatum, which via their large, overlapping axonal fields act as a network to modulate enkephalin-containing striatal output neurons. A key relay in this circuit is the paraventricular thalamic nucleus, which receives convergent input from orexin-coded hypothalamic energy-sensing and behavioral state-regulating neurons, as well as from circadian oscillators, and projects to cholinergic interneurons throughout the striatal complex. We hypothesize that this system evolved to coordinate feeding and arousal, and to prolong the feeding central motivational state beyond the fulfillment of acute energy needs, thereby promoting "overeating" and the consequent development of an energy reserve for potential future food shortages.