Alpha1-adrenergic receptor-induced heterosynaptic long-term depression in the bed nucleus of the stria terminalis is disrupted in mouse models of affective disorders

Neuropsychopharmacology. 2008 Sep;33(10):2313-23. doi: 10.1038/sj.npp.1301635. Epub 2007 Nov 28.

Abstract

The glutamatergic synapse in specific brain regions has been shown to be a site for convergence of stress and addictive substances. The bed nucleus of the stria terminalis (BNST), a nucleus that relays between higher order processing centers and classical reward and stress pathways, receives dense noradrenergic inputs that are known to influence behavioral paradigms of both anxiety and stress-induced relapse to drug seeking. Alpha(1)-adrenergic receptors (alpha(1)-ARs) within this region have been implicated in modulation of the HPA axis and anxiety responses. We found that application of an alpha(1)-AR agonist produced a long-term depression (LTD) of excitatory transmission in an acute mouse BNST slice preparation. This effect was mimicked by a 20 min, but not a 10 min, application of 100 microM norepinephrine (NE) in a prazosin-sensitive manner. This alpha(1)-AR LTD was independent of N-methyl-D-aspartate receptor (NMDAR) function unlike previously described alpha(1)-AR LTD in the hippocampus and visual cortex; however, it was dependent on the activation of L-type voltage gated calcium channels (VGCCs). In addition, alpha(1)-AR LTD was induced independently of the activation of mGluR5 which can also induce LTD in this region. Furthermore, alpha(1)-AR LTD was intact in mice receiving an intraperitoneal injection of cocaine but was disrupted in alpha(2a)-AR and NE transporter (NET) knockout (KO) mice. Thus a loss of this plasticity at glutamatergic synapses in BNST could contribute to affective behavioral phenotypes of these mice.

Publication types

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

MeSH terms

  • Adrenergic alpha-Agonists / pharmacology
  • Animals
  • Brain Chemistry / drug effects
  • Brain Chemistry / genetics
  • Calcium Channels, L-Type / drug effects
  • Calcium Channels, L-Type / metabolism
  • Cocaine / pharmacology
  • Disease Models, Animal
  • Dopamine Uptake Inhibitors / pharmacology
  • Glutamic Acid / metabolism
  • Long-Term Synaptic Depression / drug effects
  • Long-Term Synaptic Depression / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mood Disorders / genetics*
  • Mood Disorders / metabolism
  • Mood Disorders / physiopathology*
  • Neural Pathways / metabolism
  • Neural Pathways / physiopathology
  • Norepinephrine / metabolism
  • Norepinephrine / pharmacology
  • Norepinephrine Plasma Membrane Transport Proteins / genetics
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • Receptors, Adrenergic, alpha-1 / drug effects
  • Receptors, Adrenergic, alpha-1 / genetics*
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Receptors, Adrenergic, alpha-2 / genetics
  • Receptors, Glutamate / metabolism
  • Septal Nuclei / metabolism
  • Septal Nuclei / physiopathology*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / genetics*

Substances

  • Adra2a protein, mouse
  • Adrenergic alpha-Agonists
  • Calcium Channels, L-Type
  • Dopamine Uptake Inhibitors
  • Norepinephrine Plasma Membrane Transport Proteins
  • Receptors, Adrenergic, alpha-1
  • Receptors, Adrenergic, alpha-2
  • Receptors, Glutamate
  • Glutamic Acid
  • Cocaine
  • Norepinephrine