title: Sustained impairment of α2A-adrenergic autoreceptor signaling mediates neurochemical and behavioral sensitization to amphetamine.
abstract: BACKGROUND
  In rodents, drugs of abuse induce locomotor hyperactivity, and repeating injections enhance this response. This effect, called behavioral sensitization, persists months after the last administration. It has been shown that behavioral sensitization to amphetamine develops parallel to an increased release of norepinephrine (NE) in the prefrontal cortex (PFC).
  
  
  METHODS
  Rats and mice were repeatedly treated with amphetamine (1 or 2 mg/kg intraperitoneally, respectively) to obtain sensitized animals. The NE release in the PFC was measured by microdialysis in freely moving mice (n = 55). Activity of locus coeruleus (LC) noradrenergic neurons was determined in anaesthetized rats (n = 15) by in vivo extracellular electrophysiology. The α2A-adrenergic autoreceptor (α2A-AR) expression was assessed by autoradiography on brain slices, and Gαi proteins expression was measured by western blot analysis of LC punches.
  
  
  RESULTS
  In sensitized rats LC neurons had a higher spontaneous firing rate, and clonidine-an α2A-adrenergic agonist-inhibited LC neuronal firing less efficiently than in control animals. Clonidine also induced lower levels of NE release in the PFC of sensitized mice. This desensitization was maintained by a lower density of Gαi1 and Gαi2 proteins in the LC of sensitized mice rather than weaker α2A-AR expression. Behavioral sensitization was facilitated by α2A-AR antagonist, efaroxan, during amphetamine injections and abolished by clonidine treatment.
  
  
  CONCLUSIONS
  Our data indicate that noradrenergic inhibitory feedback is impaired for at least 1 month in rats and mice repeatedly treated with amphetamine. This work highlights the key role of noradrenergic autoreceptor signaling in the persistent modifications induced by repeated amphetamine administration.
authors: Laboratoire de Physiopathologie des Maladies du Système Nerveux Central, Team Physiopathology of Addiction and Relapse, Université Pierre et Marie Curie, Paris, France.
authors: Emilie L
authors: EL
authors: Doucet
authors: Ana-Clara
authors: AC
authors: Bobadilla
authors: Vanessa
authors: V
authors: Houades
authors: Christophe
authors: C
authors: Lanteri
authors: Gérard
authors: G
authors: Godeheu
authors: Laurence
authors: L
authors: Lanfumey
authors: Susan J
authors: SJ
authors: Sara
authors: Jean-Pol
authors: JP
authors: Tassin
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D017660:Autoreceptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059333:Central Nervous System Sensitization / Q000187:drug effects*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000187:drug effects / Q000378:metabolism; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D017660:Autoreceptors; D018341:Receptors, Adrenergic, alpha-2; D000661:Amphetamine; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D009638:Norepinephrine