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. 2020 Sep;237(9):2601-2611.
doi: 10.1007/s00213-020-05557-1. Epub 2020 Jun 30.

Regulation of the deleterious effects of binge-like exposure to alcohol during adolescence by α7 nicotinic acetylcholine receptor agents: prevention by pretreatment with a α7 negative allosteric modulator and emulation by a α7 agonist in alcohol-preferring (P) male and female rats

Zachary A Rodd  1   2 , Sheketha R Hauser  3   4 , H Scott Swartzwelder  3   4 , R Aaron Waeiss  3   4 , Debomoy K Lahiri  3   4 , Richard L Bell  3   4
Affiliations

Regulation of the deleterious effects of binge-like exposure to alcohol during adolescence by α7 nicotinic acetylcholine receptor agents: prevention by pretreatment with a α7 negative allosteric modulator and emulation by a α7 agonist in alcohol-preferring (P) male and female rats

Zachary A Rodd et al. Psychopharmacology (Berl). 2020 Sep.

Abstract

Rationale and objectives: Binge-like alcohol consumption during adolescence associates with several deleterious consequences during adulthood including an increased risk for developing alcohol use disorder (AUD) and other addictions. Replicated preclinical data has indicated that adolescent exposure to binge-like levels of alcohol results in a reduction of choline acetyltransferase (ChAT) and an upregulation in the α7 nicotinic receptor (α7). From this information, we hypothesized that the α7 plays a critical role in mediating the effects of adolescent alcohol exposure.

Methods: Male and female P rats were injected with the α7 agonist AR-R17779 (AR) once during 6 time points between post-natal days (PND) 29-37. Separate groups were injected with the α7 negative allosteric modulator (NAM) dehydronorketamine (DHNK) 2 h before administration of 4 g/kg EtOH (14 total exposures) during PND 28-48. On PND 75, all rats were given access to water and ethanol (15 and 30%) for 6 consecutive weeks (acquisition). All rats were then deprived of EtOH for 2 weeks and then, alcohol was returned (relapse).

Results: Administration of AR during adolescence significantly increased acquisition of alcohol consumption during adulthood and prolonged relapse drinking in P rats. In contrast, administration of DHNK prior to binge-like EtOH exposure during adolescence prevented the increase in alcohol consumption observed during acquisition of alcohol consumption and the enhancement of relapse drinking observed during adulthood.

Discussion: The data indicate that α7 mediates the effects of alcohol during adolescence. The data also indicate that α7 NAMs are potential prophylactic agents to reduce the deleterious effects of adolescent alcohol abuse.

Keywords: Acquisition; Addiction; Adolescence; Alcohol; Alcohol-preferring (P) rats; Ethanol; Relapse.

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Conflict of interest statement

Disclosures. DKL is a member of the advisory boards for Entia Biosciences, Drug Discovery and Therapy World Congress, and Provaidya LLC. He also has stock options from QR Pharma for patents or patents pending on AIT-082, Memantine, Acamprosate, and GILZ analogues. DKL is the Editor-in-Chief of the journal ‘Current Alzheimer Research’. DKL also had prior funding from Baxter and Forest Research Labs. All have no direct influence on the research presented here. Finally, DKL declares no other actual or potential competing interests in the subject matter of this paper. Conflict of Interest: ZAR, SRH, RAW, and RLB have used the current data set to apply for a provisional patent titled ‘THE USE OF ALPHA-7 NICOTINIC RECEPTOR NEGATIVE ALLOSTERIC MODULATORS FOR THE PREVENTION OF ADOLESCENT ALCOHOL CONSUMPTION PRODUCING ALCOHOL USE DISORDER (AUD) AND DRUG ADDICTION DURING ADULTHOOD’ with the US and EU patent office.

Figures

Figure 1.
Figure 1.
Depicts the experiment timeline for the a7 agonist (AR, top panel) and DHNK (bottom panel) used in the current experiments.
Figure 2.
Figure 2.
Depicts the average alcohol intake in female (top) and male (bottom) rats administered AR-R17779 during adolescence on adult alcohol consumption. * indicates 10 mg/kg AR-R17779 > 3 mg/kg and saline. # indicates 3 mg/kg > saline.
Figure 3.
Figure 3.
Depicts the mean (+ SEM) for female (top) and male (bottom) alcohol-preferring (P) rats during relapse EtOH drinking. * indicates EtOH consumption exceeds baseline intake.+ indicates that rats administered 10 mg/kg AR-R177779 during adolescence consumed more alcohol than saline controls.
Figure 4.
Figure 4.
Depicts the average alcohol intake in male (top) and female (bottom) rats administered DHNK 2 hours prior to AIE or CON treatment during adolescence.* indicates AIE-Saline rats consumed more alcohol than all other groups.
Figure 5.
Figure 5.
Depicts the mean (+ SEM) for female (top) and male (bottom) alcohol-preferring (P) rats during relapse EtOH drinking. * indicates EtOH consumption exceeds baseline intake.+ indicates that rat pretreated with saline prior to AIE exposure (AIE - Saline) consumed more alcohol than any other group.
See this image and copyright information in PMC

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