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TitleCocaine potentiates excitatory drive in the perifornical/lateral hypothalamus.
Publication TypeJournal Article
Year of Publication2012
AuthorsYeoh, Jiann Wei, Morgan H. James, Phillip Jobling, Jaideep S. Bains, Brett A. Graham, and Christopher V. Dayas
JournalJ Physiol
IssuePt 16
Date Published2012 Aug 15
Keywordsalpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, Animals, Cocaine, Hypothalamus, Intracellular Signaling Peptides and Proteins, Male, N-Methylaspartate, Neuronal Plasticity, Neurons, Neuropeptides, Rats, Rats, Sprague-Dawley

The hypothalamus is a critical controller of homeostatic responses and plays a fundamental role in reward-seeking behaviour. Recently, hypothalamic neurones in the perifornical/lateral hypothalamic area (PF/LHA) have also been implicated in drug-seeking behaviour through projections to extra-hypothalamic sites such as the ventral tegmental area. For example, a population of neurones that expresses the peptide orexin has been strongly implicated in addiction-relevant behaviours. To date, the effect of addictive drugs on synaptic properties in the hypothalamus remains largely unexplored. Previous studies focusing on the PF/LHA neurones, however, have shown that the orexin system exhibits significant plasticity in response to food or sleep restriction. This neuroadaptive ability suggests that PF/LHA neurones could be highly susceptible to modifications by drug exposure. Here, we sought to determine whether cocaine produces synaptic plasticity in PF/LHA neurones. Whole-cell patch-clamp techniques were used to examine the effects of experimenter-administered (passive) or self-administered (SA) cocaine on glutamatergic synaptic transmission in PF/LHA neurones. These experiments demonstrate that both passive and SA cocaine exposure increases miniature excitatory postsynaptic current (mEPSC) frequency in PF/LHA neurones. In addition, SA cocaine reduced the paired-pulse ratio but the AMPA/NMDA ratio of evoked excitatory inputs was unchanged, indicative of a presynaptic locus for synaptic plasticity. Dual-labelling for orexin and excitatory inputs using the vesicular glutamate transporter (VGLUT2), showed that passive cocaine exposure increased VGLUT2-positive appositions onto orexin neurones. Further, a population of recorded neurones that were filled with neurobiotin and immunolabelled for orexin confirmed that increased excitatory drive occurs in this PF/LHA population. Given the importance of the PF/LHA and the orexin system in modulating drug addiction, we suggest that these cocaine-induced excitatory synapse-remodelling events within the hypothalamus may contribute to persistence in drug-seeking behaviour and relapse.

Alternate JournalJ. Physiol. (Lond.)
PubMed ID22641785
PubMed Central IDPMC3476627