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

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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 20 min, but not a 10 min, application of 100 μM 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.

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