Unlearning Fear: Calcium Channel Blockers and the Process of Extinction
Byline: Deborah A. Lott
Psychiatric Times talked to Mark Barad, M.D., Ph.D., the newly named faculty scholar of the Tennenbaum Family Interdisciplinary Center for Initiatives in Brain Research at the University of California, Los Angeles, about the recent publication of his group's paper, "L-type voltage-gated calcium channels are required for extinction, but not for acquisition or expression, of conditional fear in mice" (J Neurosci 2002;22:9113-9121). This is the first paper to demonstrate a unique molecular mechanism for the induction of the behavioral mechanism of extinction.
PT: How are laboratory studies on the extinction of fear in mice significant for clinical work?
Barad: Extinction of fear is the explicit model for the behavioral and cognitive-behavioral treatments of anxiety disorders. Joseph Wolpe, M.D., developed one of the first systematic behavioral therapies based directly on his studies of fear extinction in cats [Wolpe, 1969].
What is known about the molecular mechanisms that underlie conditioned learning?
The simplest form of conditioning is Pavlovian [Pavlov, 1927]: Pavlov rings his bell and the dog salivates. In Pavlov's experiments, dogs learned to associate the conditioned stimulus-the ringing of the bell-with the unconditioned stimulus-the meat. So the question for basic science is how does the brain take two stimuli and put them together or associate them?
A real breakthrough came with the discovery of the N-methyl-D-aspartate (NMDA) receptor, a glutamate receptor that was shown to be critical to associative learning [Kim et al., 1991; Miserendino et al., 1990; Morris et al., 1986].
Are NMDA receptors also involved in extinction?
Our original assumption was that the rules for learning processes were universal, so that the same molecules had to underlie different kinds of learning. Then Gregory Quirk [Ph.D.] and his group showed that the NMDA receptor, so critical for the induction of associative learning, was not necessary for extinction. Animals with their NMDA receptors completely blocked still showed extinction [Santini et al., 2001]. It turns out that NMDA receptors are required for the long-term retention of extinction, but not for its induction. So there had to be some other biochemical mechanism.
Why did you decide to look at L-type voltage-gated calcium channels?
Marc Weisskopf, Ph.D., had shown that a form of synaptic strengthening in the amygdala could be induced without NMDA receptors, and depended instead on L-type voltage-gated calcium channels (LVGCCs) [Weisskopf et al., 1999]. Synaptic strengthening in the amygdala is involved in auditory fear conditioning [Rogan and LeDoux, 1995], leading investigators to explore just what part these calcium channels played in conditional fear [Bauer et al., 2002; Blair et al., 2001]. We asked how these neuroreceptors were involved in acquisition, expression and/or extinction of fear.
What did you do in your study?
We blocked the LVGCCs by giving the mice nifedipine (Adalat, Procardia) and nimodipine (Nimotop), two calcium channel blockers commonly used to treat hypertension. We gave the mice these drugs and then trained them to be afraid. They learned to associate a tone with a foot shock, and they learned perfectly well. There was no blocking of...