L‐Type Voltage‐Gated Calcium Channels Are Involved in the in Vivo and in Vitro Expression of Fear Conditioning

Abstract

Fear conditioning, a behavioral model of fear learning and cue‐related anxiety, causes enhanced neuronal transmission in the thalamic to lateral amygdala pathway.1,2 In the expression phase of learned fear, this increased transmission recorded in vitro is revealed in increased amplitudes of excitatory postsynaptic currents (EPSCs) and occlusion of paired‐pulse facilitation (PPF) implicating a presynaptic increase in transmitter release. Here we examined the contribution of L‐type calcium channels in fear conditioning. We measured the effect of nimodipine (Nim, 1.5–20 mg/kg), an L‐type calcium channel antagonist, on fear‐potentiated startle in which startle was assessed in animals receiving paired or unpaired tone and foot shock. Nim administered intraperitoneally blocked fear‐potentiated startle but not baseline startle in a dose‐dependent manner. We also analyzed the effect of Nim (10 μM) in vitro on synaptic facilitation of EPSCs and PPF in slices from naïve control, unpaired control, and fear‐conditioned animals. In neurons from naïve control animals, Nim had no effect on EPSC amplitude or PPF, but in slices from fear‐conditioned rats, Nim reduced EPSC amplitude, suggesting the recruitment of L‐type calcium channels within the fear‐conditioning pathway. Nim increased PPF in slices from fear‐conditioned animals, suggesting that L‐type calcium channels may contribute to increased probability of release in fear conditioning. In slices from unpaired animals, Nim decreased synaptic transmission but had little effect on PPF, suggesting that stress or contextual fear learning may induce L‐type channel activity in fear‐conditioned and unpaired control animal groups. We also analyzed protein expression of the α1C and α1D L‐type calcium channel subunits isolated from the amygdala and found that α1C protein was significantly increased in fear‐conditioned animals. These findings suggest that L‐type calcium channels play a role in the amygdala in cued fear conditioning and have important implications in the treatment of anxiety and in emotional learning and plasticity.

Role of L-type Ca2+channel isoforms in the extinction of conditioned fear

“…As these synapses have been implicated in fear conditioning (Rogan and LeDoux 1995), the inhibition of extinction by LTCC antagonists may, at least in part, be due to blockade of LTCC activity in these synapses. This hypothesis is further supported by another study showing that LTCC blockers such as nimodipine reduce the amplitude of excitatory postsynaptic currents (EPSC) of lateral amygdala neurons in animals subjected to fear conditioning, but not in naive controls (Shinnick-Gallagher et al 2003), thus suggesting that these synapses are sensitized by conditioned fear. Using two different DHPs, nifedipine and nimodipine, effects of LTCC blockers on the extinction of fear memory in mice has first been discovered by Cain et al (2002), demonstrating that these drugs selectively impair extinction, while acquisition or expression of conditioned fear was not affected.…”

L-Type Ca2+Channels Mediate Adaptation of Extracellular Signal-Regulated Kinase 1/2 Phosphorylation in the Ventral Tegmental Area after Chronic Amphetamine Treatment

“…LTCCs have been suggested to play a role in the augmented dopamine release observed during the expression of sensitized behaviors (Pierce and Kalivas, 1997). Although the neuronal distribution and physiology of Cav1.2 do not support a role in neurotransmitter release, LTCCs have been found to be involved in neurotransmitter release (Watanabe et al, 1998;Evans and Pocock, 1999;Okita et al, 2000), and Cav1.2 recently has been suggested to play this role in fearmediated behavior (Shinnick-Gallagher et al, 2003). Additional experiments are required to explore further the relevance of this mechanism in contributing to longterm changes in neurotransmitter release in forebrain targets innervated by VTA neurons, which may contribute to recurrent psychostimulant-induced behaviors.…”

Differential Effects of Corticosterone on the Slow Afterhyperpolarization in the Basolateral Amygdala and CA1 Region: Possible Role of Calcium Channel Subunits

“…The fact that we 1) now looked 1 h after corticosterone application as opposed to 1-4 h after the agonist in the earlier study and 2) did not restrict investigation of transcript level to the principals cells from which electrophysiological recordings were obtained may explain why, presently, the difference did not reach significance. After fear conditioning (a highly stressful situation), Cav1.2 protein level was also reported to be elevated (Shinnick-Gallagher et al 2003). Thus contrary to the CA1 area, stress levels of corticosterone may affect Cav1.2 expression in the BLA.…”