Alpha1-adrenergic receptor-induced heterosynaptic long-term depression in the bed nucleus of the stria terminalis is disrupted in mouse models of affective disorders.
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.
McElligott
Zoé A
ZA
Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Winder
Danny G
DG
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019964:Mood Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D009434:Neural Pathways / Q000378:metabolism / Q000503:physiopathology; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics; D017470:Receptors, Glutamate / Q000378:metabolism; D012686:Septal Nuclei / Q000378:metabolism / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics*
C547769:Adra2a protein, mouse; D000316:Adrenergic alpha-Agonists; D020746:Calcium Channels, L-Type; D018765:Dopamine Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D003042:Cocaine; D009638:Norepinephrine