审稿人意见

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-mediated 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):

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

reward

circuitry...".

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