title: α(2) Adrenergic and imidazoline receptor agonists prevent cue-induced cocaine seeking.
abstract: BACKGROUND
  Drug-associated cues can elicit stress-like responses in addicted individuals, indicating that cue- and stress-induced drug relapse may share some neural mechanisms. It is unknown whether α(2) adrenergic receptor agonists, which are known to attenuate stress-induced reinstatement of drug seeking in rats, also reduce cue-induced reinstatement.
  
  
  METHODS
  Rats were tested for reinstatement of drug seeking following cocaine self-administration and extinction. We first evaluated the effects of clonidine, an agonist at α(2) and imidazoline-1 (I(1)) receptors, on relapse to cocaine seeking. To explore possible mechanisms of clonidine's effects, we then tested more specific α(2) or I(1) agonists, postsynaptic adrenergic receptor (α(1) and β) antagonists, and corticotropin-releasing factor receptor-1 antagonists.
  
  
  RESULTS
  We found that clonidine, and the more selective α(2) agonists UK-14,304 and guanfacine, decreased cue-induced reinstatement of cocaine seeking. The specific I(1) receptor agonist moxonidine reduced cue-induced as well as cocaine-induced reinstatement. Clonidine or moxonidine effects on cue-induced reinstatement were reversed by the selective α(2) receptor antagonist RS-79948, indicating a role for α(2) receptors. Prazosin and propranolol, antagonists at the α(1) and β receptor, respectively, reduced cue-induced reinstatement only when administered in combination. Finally, the corticotropin-releasing factor receptor-1 antagonist CP-154,526 reduced cue-induced reinstatement, as previously observed for stress-induced reinstatement, indicating possible overlap between stress and cue mechanisms.
  
  
  CONCLUSIONS
  These results indicate that α(2) and I(1) receptor agonists are novel therapeutic options for prevention of cue-induced cocaine relapse. Given that α(2) receptor stimulation is associated with sedation in humans, the I(1) agonist moxonidine seems to have substantial potential for treating addictive disorders.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina. Electronic address: smithrac@musc.edu.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Smith
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Gary
authors.initials: G
authors.lastname: Aston-Jones
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000068438:Brimonidine Tartrate; D003000:Clonidine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003463:Cues; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005108:Extinction, Psychological / Q000187:drug effects; D016316:Guanfacine / Q000494:pharmacology; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology; D054755:Imidazoline Receptors / Q000819:agonists*; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009287:Naphthyridines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012646:Self Administration / Q000523:psychology
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; C101628:CP 154526; D007093:Imidazoles; D054755:Imidazoline Receptors; D007546:Isoquinolines; D009287:Naphthyridines; D011743:Pyrimidines; D011758:Pyrroles; D011810:Quinoxalines; C104875:RS 79948-197; C410887:imidazoline I1 receptors; D016316:Guanfacine; D000068438:Brimonidine Tartrate; D011433:Propranolol; C043482:moxonidine; D003042:Cocaine; D003000:Clonidine; D011224:Prazosin