The orexin system is particularly important for driving drug-seeking behavior elicited by environmental cues associated with drug use (for review, see James et al., 2017). Orexin (hypocretin) cells in the perifornical/lateral hypothalamic area (LHA) play a key role in motivated behavior, including drug-seeking (( Harris et al., 2005 Mahler et al., 2014 Sakurai, 2014 James et al., 2017b). These effects are likely mediated, at least in part, by normalization of presynaptic plasticity at orexin cells that occurs as a result of cocaine exposure. Together, these data indicate that agonism of LHA group III mGluRs reduces orexin cell activity in- vivo and is an effective strategy to suppress cocaine-seeking behavior following withdrawal. L-AP4 had no effect on measures of postsynaptic plasticity in cocaine-exposed animals. #15mgh tonegenerator Patch#Finally, using whole-cell patch clamp recordings from identified orexin cells in orexin-GFP transgenic mice, we show that enhanced presynaptic drive to orexin cells persists for up to 14d into withdrawal and that this plasticity is normalized by L-AP4. L-AP4 had no effect on general motor activity of sucrose self-administration. Next, we extended these findings to show that intra-LHA L-AP4 infusions reduced discriminative stimulus-driven cocaine-seeking following withdrawal. First, we verified that group III mGluRs regulate orexin cell activity in vivo by showing that intra-LHA infusions of the selective agonist L-(+)-2-Amino-4-phosphonobutyric acid (L-AP4) reduces Fos expression in orexin cells following 24h food deprivation. Therefore, we examined the group III mGluR system as a potential target to reduce orexin cell excitability in- vivo, and tested whether activating these receptors could normalize orexin cell activity following cocaine and reduce cocaine-seeking elicited by drug-associated stimuli during abstinence. Studies in hypothalamic slices from drug-naïve animals indicate that agonism of group III metabotropic glutamate receptors (mGluRs) reduces presynaptic glutamate release onto orexin cells. These changes may augment orexin cell reactivity to drug-related cues during abstinence and contribute to relapse-like behavior. Cocaine exposure is associated with presynaptic plasticity at LHA orexin cells such that excitatory input to orexin cells is enhanced, both acutely and into withdrawal. The perifornical/lateral hypothalamic area (LHA) orexin (hypocretin) system is involved in drug-seeking behavior elicited by drug-associated stimuli.
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