title: Interactions between VTA orexin and glutamate in cue-induced reinstatement of cocaine seeking in rats.
abstract: BACKGROUND
  Glutamate and orexin/hypocretin systems are involved in Pavlovian cue-triggered drug seeking.
  
  
  OBJECTIVE
  Here, we asked whether orexin and glutamate interact within ventral tegmental area (VTA) to promote reinstatement of extinguished cocaine seeking in a rat self-administration paradigm.
  
  
  RESULTS
  We first found that bilateral VTA microinjections of the orexin 1 receptor (OX1R) antagonist SB-334867 (SB) or a cocktail of the AMPA and NMDA glutamate receptor antagonists CNQX/AP-5 reduced reinstatement of cocaine seeking elicited by cues. In contrast, neither of these microinjections nor systemic SB reduced cocaine-primed reinstatement. Additionally, unilateral VTA OX1R blockade combined with contralateral VTA glutamate blockade attenuated cue-induced reinstatement, indicating that VTA orexin and glutamate are simultaneously necessary for cue-induced reinstatement. We further probed the receptor specificity of glutamate actions in VTA, finding that CNQX, but not AP-5, dose-dependently attenuated cue-induced reinstatement, indicating that AMPA but not NMDA receptor transmission is required for this type of cocaine seeking. Given the necessary roles of both OX1 and AMPA receptors in VTA for cue-induced cocaine seeking, we hypothesized that these signaling pathways interact during this behavior. We found that PEPA, a positive allosteric modulator of AMPA receptors, completely reversed the SB-induced attenuation of reinstatement behavior. Intra-VTA PEPA alone did not alter cue-induced reinstatement, indicating that potentiating AMPA activity with this drug specifically compensates for OX1R blockade, rather than simply inducing or enhancing reinstatement itself.
  
  
  CONCLUSIONS
  These findings show that cue-induced, but not cocaine-primed, reinstatement of cocaine seeking is dependent upon orexin and AMPA receptor interactions in VTA.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, 403 BSB, 173 Ashley Ave., Charleston, SC 29425, USA.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Mahler
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Smith
authors.forename: Gary
authors.initials: G
authors.lastname: Aston-Jones
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000008:administration & dosage / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage*; D003463:Cues; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior; D018698:Glutamic Acid / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D009287:Naphthyridines; D009479:Neuropeptides / Q000378:metabolism*; D064446:Orexin Receptors; D000068797:Orexins; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D018013:Receptors, Neuropeptide / Q000187:drug effects / Q000378:metabolism; D012646:Self Administration; D015398:Signal Transduction; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000378:metabolism*
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; C578627:Hcrtr1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D018091:Receptors, AMPA; D043562:Receptors, G-Protein-Coupled; D016194:Receptors, N-Methyl-D-Aspartate; D018013:Receptors, Neuropeptide; D018698:Glutamic Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; D014508:Urea; D003042:Cocaine