alpha2A-adrenergic receptors heterosynaptically regulate glutamatergic transmission in the bed nucleus of the stria terminalis

Neuroscience. 2009 Sep 29;163(1):339-51. doi: 10.1016/j.neuroscience.2009.06.022. Epub 2009 Jun 12.


Stress is a major driving force in reinstatement of drug-seeking behavior. The bed nucleus of the stria terminalis (BNST) has been identified as a key brain region in this behavior, and receives a dense input of the stress-neurotransmitter norepinephrine through the ventral noradrenergic bundle. Activation of alpha(2)-adrenergic receptors (alpha(2)-ARs) in the BNST blocks stress-induced reinstatement of drug-seeking, indicating a potentially important role for these receptors. Currently, it is unclear how alpha(2)-AR agonists elicit this behavioral action, or through which alpha(2)-AR subtype. Activation of alpha(2)-ARs decreases glutamatergic transmission in the BNST, an effect which is nearly absent in the alpha(2A)-AR knockout mouse. Here, we take advantage of a knock-in mouse in which a hemagglutinin-tagged alpha(2A)-AR was inserted into the endogenous locus, along with the alpha(2A)-AR selective agonist guanfacine, to further study the role of the alpha(2A)-AR subtype in modulation of neurotransmission in the BNST. Using immunohistochemistry, we find that alpha(2A)-ARs are highly expressed in the BNST, and that this expression is more similar in distribution to the vesicular glutamate transporters than to either norepinephrine transporter or tyrosine hydroxylase positive terminals. Using whole cell patch-clamp recordings, we show that guanfacine causes a depression of evoked excitatory and, to a more limited extent, inhibitory fast synaptic transmission. In total, these data support a prominent heterosynaptic role for alpha(2A)-ARs in modulating fast synaptic transmission in the BNST.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenergic alpha-Agonists / pharmacology
  • Animals
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Gene Knock-In Techniques
  • Glutamic Acid / metabolism*
  • Guanfacine / pharmacology
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Norepinephrine / metabolism*
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • Receptors, Adrenergic, alpha-2 / drug effects
  • Receptors, Adrenergic, alpha-2 / genetics
  • Receptors, Adrenergic, alpha-2 / metabolism*
  • Septal Nuclei / cytology
  • Septal Nuclei / drug effects
  • Septal Nuclei / metabolism*
  • Stress, Psychological / metabolism
  • Stress, Psychological / physiopathology
  • Substance-Related Disorders / metabolism
  • Substance-Related Disorders / physiopathology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*
  • Time Factors


  • Adra2a protein, mouse
  • Adrenergic alpha-Agonists
  • Receptors, Adrenergic, alpha-2
  • Guanfacine
  • Glutamic Acid
  • Norepinephrine