The Role of the Dynorphin/Kappa Opioid Receptor System in the Actions of Alcohol

Round 1

Reviewer 1 Report

This is a very well written review, focusing on a very interesting and important system. There are only some typos that need to be taken care of, such as: 

-Line 103. "We then the involvement"....the verb is missing. 

-Line 173. "This research team..." Please specify who is the research team. Is it the same one in reference 31-33?

-Line 279, correct "affectuve" with "affective"

-Line 327, correct "these finding" with "these findings"

Author Response

We greatly appreciate the supportive comments and the changes requested by this reviewer. We have made all the changes requested and corrected the typos.

Author Response File: Author Response.docx

Reviewer 2 Report

This manuscript presents a comprehensive review of the literature regarding the DYN/KOR system and alcohol. The authors performed an extensive literature search and discussed many of the preclinical studies demonstrating that the DYN/KOR system plays a significant role in the behavioral and neurobiological changes associated with alcohol, including increases in alcohol consumption and stress-related behaviors associated with withdrawal. Overall, the authors conclude that targeting KORs, especially using KOR antagonists, may be an effective treatment for alcohol use disorders.

Comments:

1)    The authors do provide an extensive summary of the preclinical work examining this topic and I commend them for their hard work and diligence. My main comment is that it does not really go too far beyond simply highlighting the literature. For example, in the conclusion and application, the authors suggest the use of KOR antagonists as potential therapeutic agents. However, there is no discussion of the potential limitations and drawbacks that have been seen with the current long-acting antagonists that were mainly used in the preclinical studies described. There should also be discussion of some of the more recently developed KOR antagonists such as LY2456302, which has been studied in humans and is shown to be relatively safe. Providing more analysis of where this area of research may be headed should be included.

2)    The authors should provide a deeper analysis in some areas they discuss in the manuscript where the studies appear to conflict. For example, they highlight how Logrip et al., the KOR agonist U50,488 decreases alcohol intake but then later discuss how other studies have found that KOR antagonists reduce alcohol drinking. While there is some discussion of how this may depend on the animals’ prior history of alcohol exposure, this discussion should be more strongly connected.

3)    The authors should be more precise with language when describing the results of experiments or conclusions throughout the paper to avoid confusion or vague descriptions. For example (and related to the above comment), when the authors write on page 10, line 222 “that depends on whether the subject is dependent or not”, a statement such as the conflicting results regarding both enhancing and suppressing KOR activation may be dependent on the subjects’ prior exposure to alcohol and history of dependence.”

4)    When discussing impacts of sex and age, there should be a clearer separation when describing how sex and/or gender and age may affect alcohol consumption in humans vs. the results of the animal studies. For instance, the first paragraph of the sex/gender section mainly discusses the differences seen in men and women regarding alcohol use disorders. The end of the paragraph and the start of the next paragraph then begin to discuss preclinical work without it being entirely clear that these are animal studies. A similar type of issue is seen in the section regarding impacts of age.

Author Response

We greatly appreciate the reviewer for the critical review and insightful comments. The reviewer raised excellent points, which we addressed in our manuscript as follows:

1)    The authors do provide an extensive summary of the preclinical work examining this topic and I commend them for their hard work and diligence. My main comment is that it does not really go too far beyond simply highlighting the literature. For example, in the conclusion and application, the authors suggest the use of KOR antagonists as potential therapeutic agents. However, there is no discussion of the potential limitations and drawbacks that have been seen with the current long-acting antagonists that were mainly used in the preclinical studies described. There should also be discussion of some of the more recently developed KOR antagonists such as LY2456302, which has been studied in humans and is shown to be relatively safe. Providing more analysis of where this area of research may be headed should be included.

Response: We have added the limitations and drawbacks of KOR antagonists and more discussion about the newer KOR antagonists and their clinical utility (please see the Conclusion and Application section of the revised manuscript).

2)    The authors should provide a deeper analysis in some areas they discuss in the manuscript where the studies appear to conflict. For example, they highlight how Logrip et al., the KOR agonist U50,488 decreases alcohol intake but then later discuss how other studies have found that KOR antagonists reduce alcohol drinking. While there is some discussion of how this may depend on the animals’ prior history of alcohol exposure, this discussion should be more strongly connected.

Response: We have deepened the discussion regarding this issue (please see section 3.2 of the revised manuscript).

3)    The authors should be more precise with language when describing the results of experiments or conclusions throughout the paper to avoid confusion or vague descriptions. For example (and related to the above comment), when the authors write on page 10, line 222 “that depends on whether the subject is dependent or not”, a statement such as the conflicting results regarding both enhancing and suppressing KOR activation may be dependent on the subjects’ prior exposure to alcohol and history of dependence.”

Response: We have modified this sentence and include prior alcohol experience and history of alcohol dependence, as suggested by the reviewer.

4)    When discussing impacts of sex and age, there should be a clearer separation when describing how sex and/or gender and age may affect alcohol consumption in humans vs. the results of the animal studies. For instance, the first paragraph of the sex/gender section mainly discusses the differences seen in men and women regarding alcohol use disorders. The end of the paragraph and the start of the next paragraph then begin to discuss preclinical work without it being entirely clear that these are animal studies. A similar type of issue is seen in the section regarding impacts of age.

Response: We have modified these two sections and included that these are from animal studies to be distinct from human studies.

Round 2

Reviewer 2 Report

This manuscript presents a comprehensive review of the literature regarding the DYN/KOR system and alcohol. The manuscript is significantly improved from the previous version, and I commend the authors for their hard work and diligence. I only have minor comments with regards to wording.

1)    p. 14, line 405: change “male alcoholics” to “males with an AUD”

2)    p. 15, line 480: change “cocaine addicts” to “cocaine-dependent individuals”

3)    While the authors do a fine job of using the appropriate terminology when referring to people with a history of substance use disorder, it may be helpful to do another thorough proofread to ensure that are not any further isolated uses of outdated terms such as those above.

Author Response

We greatly appreciate the reviewer for the positive note and the critical review of our manuscript. We made additional changes requested by this reviewer. I also made a few minor changes in the table where alcoholics were stated and those were also changes to individuals with an AUD, as recommended by the reviewer.