Reviewer comments:
Reviewer #1 (Technical Comments to the Author):
Please see comments to the Author. Regarding the question "Is the manuscript written clearly using Standard English?" - there are some minor grammatical errors that can be easily corrected.
Reviewer #1 (Remarks to the Author):
In the manuscript by Kong and colleagues, the authors investigate the potential contribution of the NAD-SIRT1 pathway to cocaine reward. The authors report that NAMPT, NAD, NMN and SIRT1 are elevated in the VTA with cocaine CPP and that cocaine reward (as measured by CPP) is blunted when NAMPT was inhibited during training. Further, overexpressing NAMPT, supplementing NMN or performing the experiment in SIRT1 knockout mice overcame this effect. The manuscript reports an interesting, thoroughly investigated finding. However, several questions need to be addressed:
1. How were CPP scores calculated? Further, the variable strength of CPP is a concern, ranging from 160 to 550 seconds within a 900 second test across experiments. An example would be the Veh/Coc group in Fig. 2A and the GFP/Coc group in Fig. 3B. Were the same Methods used across CPP experiments?
2. The full statistics, not just p values, need to be reported.
3. Please show cannula placement for infusions with FK866 and GFP spread with lentivirus injection.
4. Do the authors mean "intra-VTA" when "intracerebrally" is used? It is not clear from the Methods if this is the case for the cannulation experiments.
5. Figure 1B does not have brain region labels.
6. Is there a significant difference in Fig. 5 between the Con/Coc and FK866+Sal/Coc groups?
6. Figure 6 is confusing. Why are the statistical comparisons being made to saline-treated animals, rather than between the cocaine-associated experimental groups? Further, can the authors comment on why there is no increase in NAD with LV-NAMPT?
Reviewer #2 (Technical Comments to the Author):
Kong et al. make significant insights into the molecular pathway through which cocaine induces its rewarding effects in the Ventral Tegmental Area (VTA). In particular, they establish a model whereby cocaine-induced condition place preference (CPP) results in an up-regulation in nicotinamide phosphoribosyltransferase (NAMPT), an enzyme which mediates the conversation of nicotinamide to nicotinamide mononucleotide (NMN) followed by the conversion to nicotinamide adenine dinucleotide (NAD), which ultimately results in the NAD-mediated activation of Sirt1. Furthermore, the authors show evidence that NAMPT mediates cocaine-conditioning in a Sirt1-dependent manner.
This body of work nicely integrates a number of behavioral, pharmacological, transgenic, and biochemical approaches to establish and interrogate their model for NAMPT-mediate
d activation of Sirt1 during cocaine conditioning. As far as I know, although Sirt1's role in mediating cocaine-induced place conditioning as been heavily studied before, surprisingly little had been known regarding the cocaine-induced signaling cascade that occurs immediately upstream of Sirt1 activation. Moreover, as far as I know, this is the first paper to demonstrate the involvement of NAMPT and NAD in cocaine reward. Yet, there are corrections and additions that can be made to this manuscript that would serve to improve the way these findings are communicated to the reader. Importantly, after noticing numerous erroneous citations, possibly owed to a citation manager error, I have very little confidence in the veracity of the citations throughout this paper. Special attention should be made to identify
and correct all citation errors.
Reviewer #2 (Remarks to the Author):
comparisons
1. For the first paragraph in the introduction (page 3, paragraph 1, third sentence), change the sentence to "The nucleus accumbens (NAc) is another important region in the
brain's ".
2. For the second paragraph in the introduction (page 3, paragraph 2, first sentence), the citations (7,8) do not support the claim that NAT is "critical for neuronal energy metabolism and survival"; in fact the focus of citation #7's paper was not neurons, but rather, beta-cells. Please add the appropriate supporting citations or remove this sentence from the introduction.
3. There are a number of grammatical errors that should be addressed. The authors would benefit greatly by consulting someone for whom English is their first language.
4. Figure 7, the LV-NAMPT-COC and LV-GFP-COC labels are switched, correct this.
5. Citation 38, as cited in the first sentence found on page 13 was likely mistakenly included.
6. Citation 19 on page 4, is inappropriate and should be changed, as this review paper merely mentions H4K16, without referencing H3K9 and H3K14.
7. Citation 12 on page 4 is, inappropriate and should be changed, as the Michan et al (2010) paper does not involve a single cocaine-related experiment.
8. Citation 22 on page 4, is absolutely incorrect and misleading, as cocaine studies were not involved in the Gao et al. (2010) paper.
9. In page 5, change the sentence to "NAMPT expression in different brain regions was first investigated by western blotting analysis.
10. X-axis labels appear to be missing from figure 1B (i.e., forebrain, striatum, hippocampus).

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