Optical Intracranial Self-Stimulation (oICSS): A New Behavioral Model for Studying Drug Reward and Aversion

Brain-stimulation reward, also known as intracranial self-stimulation (ICSS), is a commonly used procedure for studying brain reward function and drug reward. In electrical ICSS, an electrode is surgically implanted into the medial forebrain bundle in the lateral hypothalamus or the ventral tegmental area in the midbrain. Operant lever responding leads to the delivery of electrical pulse stimulation. The alteration in the stimulation frequency-lever response curve is used to evaluate the impact of pharmacological agents on brain reward function. If a test drug induces a leftward or upward shift in the ICSS response curve, it implies a reward-enhancing or abuse-like effect. Conversely, if a drug causes a rightward or downward shift in the functional response curve, it suggests a reward-attenuating or aversive effect. A significant drawback of electrical ICSS is the lack of cellular selectivity in understanding the neural substrates underlying drug reward versus aversion. Excitingly, recent advancements in optical ICSS (oICSS) have facilitated the development of at least three cell type-specific oICSS models – dopamine-, glutamate-, and GABA-dependent oICSS. In these new models, a comparable frequency-rate response curve has been established and employed to study the substrate-specific mechanisms underlying brain reward function and a drug's rewarding versus aversive effects. In this review article, we summarize recent progress in this exciting research area. The findings in these new behavioral models have not only increased our understanding of the neural mechanisms underlying drug reward and addiction but have also introduced a novel experimental approach in preclinical medication development for treating substance use disorders.