Withdrawal from Chronic Nicotine Exposure Produces Region‐Specific Tolerance to Alcohol‐Stimulated GluA1 Phosphorylation

Abstract

Background Nicotine use increases alcohol drinking, suggesting that the combination of these drugs may produce synergistic effects in activating reward circuitry. Alternatively, use of either of these drugs may facilitate the development of cross-tolerance to the other to promote intake escalation. Methods In the current study, adult male Wistar rats were chronically exposed to room air or chronic, intermittent nicotine vapor, which has been shown to produce symptoms of nicotine dependence as evidenced by elevated nicotine self-administration and a host of somatic and motivational withdrawal symptoms during withdrawal. We examined regional neuroadaptations in nicotine-experienced vs. non-experienced animals, focusing on changes in phosphorylation of the AMPA glutamate channel subunit GluA1 in reward-related brain regions since excitatory neuroadaptations are heavily implicated in both alcohol and nicotine addiction. Results During withdrawal, nicotine exposure and alcohol challenge (1g/kg) interactively produced neuroadaptations in GluA1 phosphorylation in a brain region-dependent manner. Alcohol robustly increased protein kinase A (PKA)-mediated phosphorylation of GluA1 at serine 845 in multiple regions. However, this neuroadaptation was largely absent in three areas (dorsomedial prefrontal cortex, dorsal striatum, and central amygdala) in nicotine-experienced animals. This interactive effect suggests a molecular tolerance to alcohol-stimulated phosphorylation of GluA1 in the context of nicotine dependence. Conclusions Nicotine may modify the rewarding or reinforcing effects of alcohol by altering glutamate signaling in a region-specific manner, thereby leading to increased drinking in heavy smokers.

Exposure to passive nicotine vapor in male adolescent rats produces a withdrawal-like state and facilitates nicotine self-administration during adulthood

“…Air nicotine concentrations in the 1-10 mg/m 3 range closely mimic conditions of human smoking. Moreover, other groups (Baiamonte et al, 2014;McGinn et al, 2016;Xue et al, 2018) have replicated our original findings, showing that the delivery of 7 mg/m 3 nicotine at 10 L/min produced nicotine dependence with somatic signs of withdrawal and hyperalgesia, similar to other animal models (e.g., minipumps and intravenous self-administration), and blood nicotine levels in the 10-100 ng/ml range. Another limitation of the present study was that we included male adolescent rats only.…”

“…We tested the effects of two concentrations of nicotine vapor (0.4 and 7 mg/m 3 ) over 7 days of exposure (14 h/day). Intermittent nicotine vapor exposure, with 14 h vapor ON and 10 h OFF, was used based on previous studies (Baiamonte et al, 2014;Gilpin et al, 2014;McGinn et al, 2016;Xue et al, 2018) that showed that this protocol produces nicotine dependence with somatic signs of withdrawal and hyperalgesia when exposed to high levels of nicotine (7 mg/m 3 ). This protocol is highly relevant to adolescent e-cigarette users, who often vape intermittently because of either parental or societal restrictions.…”

Neurobiological Correlates of Pain Avoidance-Like Behavior in Morphine-Dependent and Non-Dependent Rats

“…Western blot analyses for brain regional changes in protein phosphorylation were conducted as previously described (McGinn et al, 2016) in animals from group 1. Rats were sacrificed by decapitation under light isoflurane anesthesia 24 hours after the last injection (Figure 2A).…”

A Novel Role for the Endocannabinoid System in Ameliorating Motivation for Alcohol Drinking and Negative Behavioral Affect after Traumatic Brain Injury in Rats

“…Animals were sacrificed by decapitation under isoflurane anesthesia 2 weeks post-TBI, and brains were excised, flash frozen, and analyzed as previously described. 43 Ventral striatum and central amygdala punches were obtained from 0.5-mm frozen coronal brain slices and homogenized by sonication in lysis buffer (320 mM sucrose, 5 mM 4(2-hydroxyethyl)-1-piperazineethanesulfonic acid [HEPES], 1 mM egtazic acid [EGTA], 1 mM ethylenediaminetetraacetic acid [EDTA], and 1% sodium dodecyl sulphate [SDS], with protease inhibitor cocktail and phosphatase inhibitor cocktails II and III diluted 1:100; Sigma, St. Louis, MO). Protein concentration was determined by the Lowry method (Bio-Rad, Hercules, CA), and 20-lg protein samples were separated by SDSpolyacrylamide gel electrophoresis (SDS-PAGE) on 4-15% gradient acrylamide gels before transfer to polyvinylidene difluoride membranes (GE Healthcare, Piscataway, NJ).…”