Background and Purpose Experimental Approach Children and adolescents are the top consumers of high-fructose corn syrup (HFCS) sweetened beverages. Even though the cardiometabolic consequences of HFCS consumption in adolescents are well known, the neuropsychiatric consequences have yet to be determined. Adolescent rats were fed for a month with 11% weight/volume carbohydrate containing HFCS solution, which is similar to the sugar-sweetened beverages of human consumption. The metabolic, behavioural and electrophysiological characteristics of HFCS-fed rats were determined. Furthermore, the effects of TDZD-8, a highly specific GSK-3B inhibitor, on the HFCS-induced alterations were further explored. Key Results Conclusion and Implications HFCS-fed adolescent rats displayed bipolar-like behavioural phenotype with hyperexcitability in hippocampal CA3-CA1 synapses. This hyperexcitability was associated with increased presynaptic release probability and increased readily available pool of AMPA receptors to be incorporated into the postsynaptic membrane, due to decreased expression of the neuron-specific alpha 3-subunit of Na+/K+-ATPase and an increased ser(845)-phosphorylation of GluA1 subunits (AMPA receptor subunit) respectively. TDZD-8 treatment was found to restore behavioural and electrophysiological disturbances associated with HFCS consumption by inhibition of GSK-3B, the most probable mechanism of action of lithium for its mood-stabilizing effects. This study shows that HFCS consumption in adolescent rats led to a bipolar-like behavioural phenotype with neuronal hyperexcitability, which is known to be one of the earliest endophenotypic manifestations of bipolar disorder. Inhibition of GSK-3B with TDZD-8 attenuated hyperexcitability and restored HFCS-induced behavioural alterations.