title: Repeated in vivo exposure of cocaine induces long-lasting synaptic plasticity in hypocretin/orexin-producing neurons in the lateral hypothalamus in mice.
abstract: Hypocretin (orexin), a neuropeptide synthesized exclusively in the perifornical/lateral hypothalamus, is critical for drug seeking and relapse, but it is not clear how the circuitry centred on hypocretin-producing neurons (hypocretin neurons) is modified by drugs of abuse and how changes in this circuit might alter behaviours related to drug addiction. In this study, we show that repeated, but not single, in vivo cocaine administration leads to a long-lasting, experience-dependent potentiation of glutamatergic synapses on hypocretin neurons in mice following a cocaine-conditioned place preference (CPP) protocol. The synaptic potentiation occurs postsynaptically and probably involves up-regulation of AMPA-type glutamate receptors on hypocretin neurons. Phosphorylation of cAMP response element-binding protein (CREB) is also significantly increased in hypocretin neurons in cocaine-treated animals, suggesting that CREB-mediated pathways may contribute to synaptic potentiation in these cells. Furthermore, the potentiation of synaptic efficacy in hypocretin neurons persists during cocaine withdrawal, but reverses to baseline levels after prolonged abstinence. Finally, the induction of long-term potentiation (LTP) triggered by a high-frequency stimulation is facilitated in hypocretin neurons in cocaine-treated mice, suggesting that long-lasting changes in synapses onto hypocretin neurons would probably be further potentiated by other stimuli (such as concurrent environmental cues) paired with the drug. In summary, we show here that hypocretin neurons undergo experience-dependent synaptic potentiation that is distinct from that reported in other reward systems, such as the ventral tegmental area, following exposure to cocaine. These findings support the idea that the hypocretin system is important for behavioural changes associated with cocaine administration in animals and humans.
authors: Department of 1OB/GYN and Reproductive Science, Yale University School of Medicine, New Haven, CT 06520, USA. yanrao@uic.edu
authors: Yan
authors: Y
authors: Rao
authors: Yann S
authors: YS
authors: Mineur
authors: Geliang
authors: G
authors: Gan
authors: Alex Hanxiang
authors: AH
authors: Wang
authors: Zhong-Wu
authors: ZW
authors: Liu
authors: Xinyuan
authors: X
authors: Wu
authors: Shigetomo
authors: S
authors: Suyama
authors: Luis
authors: L
authors: de Lecea
authors: Tamas L
authors: TL
authors: Horvath
authors: Marina R
authors: MR
authors: Picciotto
authors: Xiao-Bing
authors: XB
authors: Gao
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D003213:Conditioning, Psychological; D019706:Excitatory Postsynaptic Potentials; D007031:Hypothalamus / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D017774:Long-Term Potentiation; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009479:Neuropeptides / Q000502:physiology*; D000068797:Orexins; D013569:Synapses / Q000187:drug effects* / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D003042:Cocaine