Sustained impairment of α2A-adrenergic autoreceptor signaling mediates neurochemical and behavioral sensitization to amphetamine

Biol Psychiatry. 2013 Jul 15;74(2):90-8. doi: 10.1016/j.biopsych.2012.11.029. Epub 2013 Jan 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-2 Receptor Antagonists / pharmacology
  • Amphetamine / pharmacology*
  • Animals
  • Autoreceptors / antagonists & inhibitors
  • Autoreceptors / metabolism*
  • Central Nervous System Sensitization / drug effects*
  • GTP-Binding Protein alpha Subunits, Gi-Go / drug effects
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Locus Coeruleus / drug effects
  • Locus Coeruleus / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / drug effects*
  • Neurons / drug effects
  • Neurons / metabolism
  • Norepinephrine / metabolism*
  • Prefrontal Cortex / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha-2 / metabolism*


  • Adrenergic alpha-2 Receptor Antagonists
  • Autoreceptors
  • Receptors, Adrenergic, alpha-2
  • Amphetamine
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Norepinephrine