On 2017 Jan 12, Meg Waraczynski commented:

Thank you for your insights. In hindsight, we should have been much clearer in indicating that we were only strongly inferring the involvement of CaV1.3 channels in our behavioral results, but that we have no direct evidence for this. The inference was based on the facts reviewed in the Introduction, that (1) only CaV1 type channels have been linked to the activity of basal forebrain medium spiny neurons (reference 4); (2) of the CaV1 family, only 1.2 and 1.3 type channels are abundant in the brain (reference 3); and (3) the activation dynamics of 1.3 channels correspond much more closely to the activity state dynamics of medium spiny neurons than do the activation dynamics of 1.2 channels (reference 26). We hoped to use 1.3-specific drugs but, as noted in the Introduction, all such drugs we could find required the use of brain-toxic solvents. The dosages we used were selected based on dosages used by others who intracerebrally injected these drugs to affect behavior (references 1, 6, 7, and 16). We did not intend to focus on implicating CaV1.3 channels specifically in our observations, nor did we intend to have others use our paper as evidence that diltiazem and verapamil are CaV1.3-specific. We regret if this occurs. Our tentative conclusions as to the reward-relevant function of the system we are studying would remain the same even if it were found that our drug injections acted on mechanisms other than CaV1.3 channels specifically. We will be much more cautious when referring to this work in the future to emphasize these functional conclusions and not to implicate CaV1.3 channels specifically.

On 2017 Jan 03, Joerg Striessnig commented:

From a pharmacological point of view this is a very poor paper. It is common knowledge that verapamil and diltiazem have never been shown to be selective for Cav1.3 channels. Differential interaction with subdomains of the channel (their ref 19) has been studied with skeletal muscle channels and later with Cav1.2 (class C) L-type channels. Moreover, due to the higher concentrations for L-type channel block, verapamil and diltiazem also tend to inhibit other ion channels, such as Cav2 channels (PMIDs: 8574653, 10385261), at concentrations also inhibiting L-type channels. Here concentrations of 5 micrograms drug/0.5 microliter were infused, corresponding to about 20 mM concentrations, 10 times higher than the extracellular calcium concentration. There is no published evidence justifying their interpretation of a specific involvement of Cav1.3, as misleadigly mentioned even in the title. This interpretation by the authors and the failure by the reviewers to point out these limitations confuses readers and may even trigger further misleading experiments citing this paper as evidence for Cav1.3-selectivity of diltiazem and verapamil.

On 2017 Jan 03, Joerg Striessnig commented:

From a pharmacological point of view this is a very poor paper. It is common knowledge that verapamil and diltiazem have never been shown to be selective for Cav1.3 channels. Differential interaction with subdomains of the channel (their ref 19) has been studied with skeletal muscle channels and later with Cav1.2 (class C) L-type channels. Moreover, due to the higher concentrations for L-type channel block, verapamil and diltiazem also tend to inhibit other ion channels, such as Cav2 channels (PMIDs: 8574653, 10385261), at concentrations also inhibiting L-type channels. Here concentrations of 5 micrograms drug/0.5 microliter were infused, corresponding to about 20 mM concentrations, 10 times higher than the extracellular calcium concentration. There is no published evidence justifying their interpretation of a specific involvement of Cav1.3, as misleadigly mentioned even in the title. This interpretation by the authors and the failure by the reviewers to point out these limitations confuses readers and may even trigger further misleading experiments citing this paper as evidence for Cav1.3-selectivity of diltiazem and verapamil.

On 2017 Jan 12, Meg Waraczynski commented:

Thank you for your insights. In hindsight, we should have been much clearer in indicating that we were only strongly inferring the involvement of CaV1.3 channels in our behavioral results, but that we have no direct evidence for this. The inference was based on the facts reviewed in the Introduction, that (1) only CaV1 type channels have been linked to the activity of basal forebrain medium spiny neurons (reference 4); (2) of the CaV1 family, only 1.2 and 1.3 type channels are abundant in the brain (reference 3); and (3) the activation dynamics of 1.3 channels correspond much more closely to the activity state dynamics of medium spiny neurons than do the activation dynamics of 1.2 channels (reference 26). We hoped to use 1.3-specific drugs but, as noted in the Introduction, all such drugs we could find required the use of brain-toxic solvents. The dosages we used were selected based on dosages used by others who intracerebrally injected these drugs to affect behavior (references 1, 6, 7, and 16). We did not intend to focus on implicating CaV1.3 channels specifically in our observations, nor did we intend to have others use our paper as evidence that diltiazem and verapamil are CaV1.3-specific. We regret if this occurs. Our tentative conclusions as to the reward-relevant function of the system we are studying would remain the same even if it were found that our drug injections acted on mechanisms other than CaV1.3 channels specifically. We will be much more cautious when referring to this work in the future to emphasize these functional conclusions and not to implicate CaV1.3 channels specifically.