Fear conditioning selectively disrupts noradrenergic facilitation of GABAergic inhibition in the basolateral amygdala

Neuropharmacology. 2017 Feb;113(Pt A):231-240. doi: 10.1016/j.neuropharm.2016.10.003. Epub 2016 Oct 5.


Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For example, α1-ARs promote GABA release from local inhibitory interneurons, while β3-ARs potentiate neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, β1/2-ARs amplify excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local and LPC synapses using α1-and β3-AR agonists (1 μM A61603 and 10 μM BRL37344), and found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of glutamatergic signaling via a β1/2-AR agonist (1 μM isoproterenol). Taken together, these studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of noradrenaline.

Keywords: Fear-potentiated startle; GABA release; Norepinephrine; α1 Adrenoreceptor; β1/2 Adrenoreceptor; β3 Adrenoreceptor.

MeSH terms

  • Adrenergic alpha-1 Receptor Agonists / pharmacology
  • Adrenergic beta-3 Receptor Agonists / pharmacology
  • Animals
  • Basolateral Nuclear Complex / drug effects
  • Basolateral Nuclear Complex / physiology*
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology
  • Fear / drug effects
  • Fear / physiology*
  • Fear / psychology
  • GABAergic Neurons / physiology*
  • Imidazoles / pharmacology
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / physiology*
  • Male
  • Norepinephrine / physiology*
  • Rats
  • Rats, Long-Evans
  • Tetrahydronaphthalenes / pharmacology


  • A 61603
  • Adrenergic alpha-1 Receptor Agonists
  • Adrenergic beta-3 Receptor Agonists
  • Imidazoles
  • Tetrahydronaphthalenes
  • Norepinephrine