Experience‐dependent escalation of glucose drinking and the development of glucose preference over fructose – association with glucose entry into the brain

Abstract Glucose, a primary metabolic substrate for cellular activity, must be delivered to the brain for normal neural functions. Glucose is also a unique reinforcer; in addition to its rewarding sensory properties and metabolic effects, which all natural sugars have, glucose crosses the blood–brain barrier and acts on glucoreceptors expressed on multiple brain cells. To clarify the role of this direct glucose action in the brain, we compared the neural and behavioural effects of glucose with those induced by fructose, a sweeter yet metabolically equivalent sugar. First, by using enzyme‐based biosensors in freely moving rats, we confirmed that glucose rapidly increased in the nucleus accumbens in a dose‐dependent manner after its intravenous delivery. In contrast, fructose induced a minimal response only after a large‐dose injection. Second, we showed that naive rats during unrestricted access consumed larger volumes of glucose than fructose solution; the difference appeared with a definite latency during the initial exposure and strongly increased during subsequent tests. When rats with equal sugar experience were presented with either glucose or fructose in alternating order, the consumption of both substances was initially equal, but only the consumption of glucose increased during subsequent sessions. Finally, rats with equal glucose–fructose experience developed a strong preference for glucose over fructose during a two‐bottle choice procedure; the effect appeared with a definite latency during the initial test and greatly amplified during subsequent tests. Our results suggest that direct entry of glucose in the brain and its subsequent effects on brain cells could be critical for the experience‐dependent escalation of glucose consumption and the development of glucose preference over fructose.