title: Lateral paracapsular GABAergic synapses in the basolateral amygdala contribute to the anxiolytic effects of beta 3 adrenoceptor activation.
abstract: Norepinephrine (NE) is known to play an integral role in the neurobiological response to stress. Exposure to stressful stimuli increases NE levels in brain regions that regulate stress and anxiety, like the basolateral amygdala (BLA). NE is thought to increase excitability in these areas through alpha- and beta-adrenoceptors (ARs), leading to increased anxiety. Surprisingly, recent studies have shown that systemic beta 3-AR agonist administration decreases anxiety-like behaviors, suggesting that beta 3-ARs may inhibit excitability in anxiety-related brain regions. Therefore, in this study we integrated electrophysiological and behavioral approaches to test the hypothesis that the anxiolytic effects of beta 3-AR agonists may be mediated by an increase in BLA GABAergic inhibition. We examined the effect of a selective beta 3-AR agonist, BRL37344 (BRL), on GABAergic synapses arising from local circuit interneurons and inhibitory synapses originating from a recently described population of cells called lateral paracapsular (LPCS) interneurons. Surprisingly, BRL selectively enhanced LPCS-evoked inhibitory postsynaptic currents (eIPSCs) with no effect on local GABAergic inhibition. BRL also had no effect on glutamatergic synaptic excitation within the BLA. BRL potentiation of LPCS eIPSCs was blocked by the selective beta 3-AR antagonist, SR59230A, or by intracellular dialysis of Rp-CAMPS (cAMP-dependent protein kinase inhibitor), and this enhancement was not associated with any changes in spontaneous IPSCs or LPCS paired-pulse ratio. BRL also increased the amplitude of unitary LPCS IPSCs (uIPSCs) with no effect on uIPSC failure rate. Finally, bilateral BLA microinjection of BRL reduced anxiety-like behaviors in an open-field assay and the elevated plus-maze. Collectively, these data suggest that beta 3-AR activation selectively enhances LPCS, but not local, BLA GABAergic synapses, and that increases in LPCS-mediated inhibition may contribute to the anxiolytic profile of beta 3-AR agonists.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Silberman
authors.forename: Olusegun J
authors.initials: OJ
authors.lastname: Ariwodola
authors.forename: Ann M
authors.initials: AM
authors.lastname: Chappell
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Yorgason
authors.forename: Jeff L
authors.initials: JL
authors.lastname: Weiner
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000679:Amygdala / Q000166:cytology*; D000818:Animals; D001007:Anxiety / Q000188:drug therapy* / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004983:Ethanolamines / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D018756:GABA Antagonists / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D007395:Interneurons / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008845:Microinjections / Q000379:methods; D009025:Morpholines / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D011433:Propranolol / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism*; D013873:Thionucleotides / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D022702:Receptors, Adrenergic, beta-3; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D005680:gamma-Aminobutyric Acid; C057368:BRL 37344; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D011433:Propranolol; D000242:Cyclic AMP
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