kt-5720 and (alpha-carboxycyclopropyl)glycine

An animal model most sensitive for measuring anticipatory anxiety is fear conditioning, which is expressed by an enduring increase in synaptic strength in the amygdala. A converse view predicts that agents that induce long-term depression (LTD) of synaptic efficacy in the amygdala may be useful in the amelioration of stress disorders. In the present study, we show that activation of group II metabotropic glutamate receptor (mGluR II) by (2S,3S, 4S)-2-(carboxycyclopropyl) glycine (l-ccg) induces an LTD in the basolateral amygdala neurons. The effect was concentration-dependent with a maximal inhibition of approximately 30%. The induction of l-CCG LTD required concurrent synaptic activity, required presynaptic but not postsynaptic Ca(2+) increases, and was independent of NMDA receptors. l-CCG LTD was associated with an increase in the ratio of paired-pulse facilitation and was not occluded by low-frequency stimulation-induced LTD, suggesting that these two forms of LTD did not share a common underlying mechanism. After eliciting LTD with l-CCG, application of isoproterenol increased the synaptic responses back to its original baseline, demonstrating that chemically depressed synapses could be potentiated by another chemical. A selective PKA inhibitor, KT 5720, by its own caused a depression of synaptic transmission and blocked l-CCG LTD, presumably by mimicking and thereby occluding any further depression. Together, these results suggest that l-CCG LTD is induced by presynaptically mGluR II-mediated inhibition of Ca(2+)-sensitive adenylyl cyclase, resulting in a decrease in cAMP formation and PKA activation, which leads to a long-lasting decrease in transmitter release.

Topics: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Adrenergic beta-Agonists; Amino Acids, Dicarboxylic; Amygdala; Animals; Calcium; Carbazoles; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Electric Stimulation; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; In Vitro Techniques; Indoles; Isoproterenol; Male; Neural Inhibition; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Time