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. 2023 Apr 4:16:954319.
doi: 10.3389/fnbeh.2022.954319. eCollection 2022.

Negative and positive allosteric modulators of the α7 nicotinic acetylcholine receptor regulates the ability of adolescent binge alcohol exposure to enhance adult alcohol consumption

Zachary A Rodd  1   2 , H Scott Swartzwelder  3 , R Aaron Waeiss  1   2 , Serhii O Soloviov  4   5 , Debomoy K Lahiri  1   2   6   7   8 , Eric A Engleman  1   2 , William A Truitt  2   9 , Richard L Bell  1   2 , Sheketha R Hauser  1   2
Affiliations

Negative and positive allosteric modulators of the α7 nicotinic acetylcholine receptor regulates the ability of adolescent binge alcohol exposure to enhance adult alcohol consumption

Zachary A Rodd et al. Front Behav Neurosci. .

Abstract

Rationale and Objectives: Ethanol acts directly on the α7 Nicotinic acetylcholine receptor (α7). Adolescent-binge alcohol exposure (ABAE) produces deleterious consequences during adulthood, and data indicate that the α7 receptor regulates these damaging events. Administration of an α7 Negative Allosteric Modulator (NAM) or the cholinesterase inhibitor galantamine can prophylactically prevent adult consequences of ABAE. The goals of the experiments were to determine the effects of co-administration of ethanol and a α7 agonist in the mesolimbic dopamine system and to determine if administration of an α7 NAM or positive allosteric modulator (PAM) modulates the enhancement of adult alcohol drinking produced by ABAE. Methods: In adult rats, ethanol and the α7 agonist AR-R17779 (AR) were microinjected into the posterior ventral tegmental area (VTA), and dopamine levels were measured in the nucleus accumbens shell (AcbSh). In adolescence, rats were treated with the α7 NAM SB-277011-A (SB) or PNU-120596 (PAM) 2 h before administration of EtOH (ABAE). Ethanol consumption (acquisition, maintenance, and relapse) during adulthood was characterized. Results: Ethanol and AR co-administered into the posterior VTA stimulated dopamine release in the AcbSh in a synergistic manner. The increase in alcohol consumption during the acquisition and relapse drinking during adulthood following ABAE was prevented by administration of SB, or enhanced by administration of PNU, prior to EtOH exposure during adolescence. Discussion: Ethanol acts on the α7 receptor, and the α7 receptor regulates the critical effects of ethanol in the brain. The data replicate the findings that cholinergic agents (α7 NAMs) can act prophylactically to reduce the alterations in adult alcohol consumption following ABAE.

Keywords: adolescence; alcohol; alpha7 acetylcholine receptor; dopamine; prevention.

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Conflict of interest statement

ZR, SH, RW, and RB have used the current dataset to apply for a 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. All have no direct influence on the research presented here. DL 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. DL is the Editor-in-Chief of the journal “Current Alzheimer Research”. DL also had prior funding from Baxter and Forest Research Labs. All have no direct influence on the research presented here. Finally, DL declares no other actual or potential competing interests in the subject matter of this article. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Graphical Abstract
Graphical Abstract
Created with BioRender.com.
Figure 1
Figure 1
Depicts a timeline for the (A) microinjection-microdialysis experiments and (B) adult alcohol intake experiments.
Figure 2
Figure 2
Depicts the average extracellular DA levels in the AcbSh in P rats following microinjects of EtOH, AR, or EtOH+AR into the posterior VTA. *indicates in 100 E + 500 AR >50 E + 500 AR >500 AR >aCSF and 100 E . +indicates that two E + AR >500 AR >aCSF and 100 E. #indicates 50 E + 500 AR >all other groups.
Figure 3
Figure 3
Depicts the average alcohol intake in female P rats administered the α7 NAM SB-277011-A 2 h before ABAE treatment during adolescence on the adult consumption of EtOH. *indicates EtOH consumption in water-ABAE rats >1 mg and 5 mg/kg SB rats. +indicates 1 mg/kg >5 mg/kg SB rats. #indicates water-ABAE and 1 mg/kg SB >5 mg/kg SB rats.
Figure 4
Figure 4
Depicts the mean (+ SEM) for female alcohol-preferring (P) rats during relapse EtOH drinking. *indicates EtOH consumption exceeds baseline intake. +indicates that rat pretreated with saline prior to ABAE exposure (water and 1 mg/kg SB) consumed more alcohol than corresponding CON group.
Figure 5
Figure 5
Depicts the mean (+ SEM) weekly average intake (g/kg/day) of alcohol (beer) in male Wistar rats administered a subthreshold dose of EtOH during adolescence and the α7 PAM PNU. There was a significant increase in alcohol consumption in all groups during the experiment, but not effects of ABAE or PNU treatment.
Figure 6
Figure 6
Depicts the mean (+ SEM) number of EtOH (beer) lever responses in female Wistar rats as a product of exposure to low-dose ABAE (2 g/kg) and treatment with the α7 PAM PNU. During Acquisition of responding (left panel), female rats treated with 2 g/kg ABAE and 5 mg/kg PNU during adolescence responded more on the lever associated with the delivery of beer (7.7% West Coast IPA; *indicates significant difference from all other groups). Rats treated with 2 g/kg ABAE and 5 mg/kg PNU during adolescence responded more on the lever previously associated with the delivery of beer during the first four Extinction training sessions (middle panel; *indicates significant difference from all other groups). During context-induced EtOH-seeking (right panel), female Wistar rats treated with 2 g/kg ABAE and 5 mg/kg PNU during adolescence responded more on the lever previously associated with the delivery of beer than all other groups during sessions 1–3. +sign indicates that all groups displayed an increase in responding compared to extinction baseline, and 2 g/kg ABAE and 5 mg/kg PNU are significantly higher than all other groups. #sign indicates that 2 g/kg ABAE and 5 mg/kg PNU are significantly higher than all other groups and higher than extinction baseline.
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