审稿人意见

Reviewer comments:

Reviewer #1 (Technical Comments to the Author):

Please

see

comments

to

the

Author.

Regarding

the

question

the

manuscript

written

clearly

using Standard English?

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

when

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.