The contribution of the hippocampus to learned opiate tolerance

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Project Summary The utility of opiates for treating pain is limited by the development of tolerance, a phenomenon that can lead to dose- escalation and an increased liability for dangerous side effects like dependence and overdose. Interestingly, environmental cues that are paired with opiates can dramatically influence tolerance. Specifically, animals that receive morphine in a particular context exhibit analgesic tolerance that can be eliminated by simply administering the drug in a new environment. The cellular and circuit mechanisms underlying this associative form of tolerance have not been well characterized. However, they are highly relevant clinically as many overdoses occur when addicts take large amounts of opiates in a new place. In this application, we propose to dissect the circuitry underlying associate morphine tolerance using modern behavioral neuroscience tools. Specifically, we will combine optogenetic techniques with transgenic reporter mice to identify the specific neural circuits and cells that mediate associative tolerance. Our central hypothesis is that context-specific representations in the hippocampus become associated with opiate use and produce a compensatory response in the amygdala that prevents the inhibition of pain. To test this idea, we will express light sensitive opsins in the specific neurons that are active during the expression of associative morphine tolerance. We predict that silencing these cells will prevent tolerance in a morphine-paired context. Stimulating these cells, in contrast, should induce tolerance in a novel environment that has never been paired with morphine. A similar strategy has been used to identify and manipulate neurons that encode fear memories in the amygdala, spatial memories in the hippocampus, cocaine memories in the nucleus accumbens and many others forms of memory. However, to our knowledge, this approach has never been applied to associative morphine tolerance. We believe that doing so will lead to significant advances like it has for other forms of learning and memory.