Original Article

Neuropsychopharmacology (2008) 33, 2313–2323; doi:10.1038/sj.npp.1301635; published online 28 November 2007

α1-Adrenergic Receptor-Induced Heterosynaptic Long-Term Depression in the Bed Nucleus of the Stria Terminalis Is Disrupted in Mouse Models of Affective Disorders

Zoé A McElligott1 and Danny G Winder1,2,3

  1. 1Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN, USA
  2. 2Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA
  3. 3Kennedy Center For Human Development, Vanderbilt University Medical Center, Nashville, TN, USA

Correspondence: Dr DG Winder, Department of Molecular Physiology & Biophysics, Room 724B, RRB 1, Vanderbilt University School of Medicine, Nashville, TN 37232-0615, USA. Tel: +615 322 1144; Fax: +615 343 0490; E-mail: danny.winder@vanderbilt.edu

Received 23 May 2007; Revised 10 October 2007; Accepted 25 October 2007; Published online 28 November 2007.

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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. α1-Adrenergic receptors (α1-ARs) within this region have been implicated in modulation of the HPA axis and anxiety responses. We found that application of an α1-AR agonist produced a long-term depression (LTD) of excitatory transmission in an acute mouse BNST slice preparation. This effect was mimicked by a 20min, but not a 10min, application of 100μM norepinephrine (NE) in a prazosin-sensitive manner. This α1-AR LTD was independent of N-methyl-D-aspartate receptor (NMDAR) function unlike previously described α1-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, α1-AR LTD was induced independently of the activation of mGluR5 which can also induce LTD in this region. Furthermore, α1-AR LTD was intact in mice receiving an intraperitoneal injection of cocaine but was disrupted in α2a-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.

Keywords:

synaptic plasticity, heterosynaptic neuromodulation, catecholamine, norepinephrine, anxiety, depression

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