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

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.

Adolescent alcohol and nicotine exposure alters the adult response to alcohol use

“…Maldonado-Devincci et al [ 67 ] indicated IG administration of 1.5, 3.0, or 5.0 g/kg ethanol in 4 days intervals (PND 28–31, PND 35–38, and PND 43–45) increased ethanol consumption in young adulthood (PND 60–69) in both male and female Sprague-Dawley (SD) rats, an effect more prominent in male compared to female animals. Intermittent IG ethanol exposure (PND 28–48; 2 days on/2 days off) treatment in male and female P rats resulted in increased adult ethanol consumption (PND 90+) during both operant acquisition and relapse drinking conditions [ 68 , 69 ]. In contrast, repeated gavage (every 8 h for 2 days: 6 treatments total) during adolescence (PND 30–32) decreased ethanol consumption in adulthood in Sprague Dawley rats [ 70 ].…”

“…Administration of an α7 nAChR negative allosteric modulator (NAM) dehydronorketamine (DHNK) 2 hours before AIE exposure (PND 28–48) prevented the increase of ethanol consumption during acquisition and relapse drinking during adulthood in both male and female P rats [ 68 ]. A subsequent study reported that SB-277011-A, an α7 nAChR NAM and a D3 antagonist, could also suppress ethanol consumption during acquisition and relapse drinking in female P rats [ 69 , 148 ]. In contrast, to α7 nAChR NAMs, activation of the α7 nAChR during adolescence appears to have the opposite effect on ethanol consumption in adulthood.…”

“…Intermittent adolescent treatment (PND 29, 30, 33, 35, 36, and 37) with the α7 nAChR agonist AR-17779 increased the amount of ethanol consumed during acquisition and relapse during adulthood (PND 90+) in both male and female P rats [ 68 ]. Furthermore, co-infusion of α7 nAChR agonist + ethanol into pVTA increased extracellular DA release in AcbSh to a significantly greater extent than either treatment alone in male Wistar rats [ 69 ]. In addition, administration of α7 nAChR positive allosteric modulator (PAM) PNU- 120596 followed by low-dose ethanol (gavage, 2 mg/kg) in adolescents (PND 28–48) increased operant beer acquisition, extinction, and relapse drinking in adulthood in female Wistar rats [ 69 ].…”

“…Furthermore, co-infusion of α7 nAChR agonist + ethanol into pVTA increased extracellular DA release in AcbSh to a significantly greater extent than either treatment alone in male Wistar rats [ 69 ]. In addition, administration of α7 nAChR positive allosteric modulator (PAM) PNU- 120596 followed by low-dose ethanol (gavage, 2 mg/kg) in adolescents (PND 28–48) increased operant beer acquisition, extinction, and relapse drinking in adulthood in female Wistar rats [ 69 ]. However, PNU +2 mg/kg ethanol treatment during adolescence did not affect 24-h free-choice ethanol drinking of adult male Wistar rats [ 69 ].…”