Brandon M Fritz1, Braulio Muñoz1, Brady K Atwood1,2. 1. Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana. 2. Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana.
Abstract
BACKGROUND: Although it is widely acknowledged that the risk of developing an alcohol use disorder (AUD) is strongly influenced by genetic factors, very little is known about how this genetic predisposition may alter neurotransmission in a way that promotes AUD susceptibility. The dorsal striatum has garnered increased attention as a brain region of interest in AUD development given its significant roles in goal-directed and habitual behavior. METHODS: In the present work, dorsal striatal neurotransmission parameters were measured in preclinical mouse models of high and low AUD risk. We performed brain slice whole-cell patch clamp electrophysiological recordings from medium spiny neurons (MSNs) in the dorsomedial (DMS) and dorsolateral (DLS) striatum of naïve adult male and female selectively bred high- and low-alcohol-preferring lines of mice (HAP and LAP). RESULTS: We found that MSNs of HAP mice were significantly more excitable than those of LAP mice, specifically in the DLS. Additionally, the frequencies of spontaneous glutamate- and GABA-mediated currents were both elevated in HAP mice relative to LAP mice in both dorsal striatal subregions, whereas amplitude differences were more variable between lines and subregions. AMPAR/NMDAR current ratios were significantly lower in HAP mice in both DLS and DMS. CONCLUSIONS: Collectively, these results suggest that genetic predisposition for high or low alcohol consumption produces significantly different basal functional states within both DLS and DMS which may be important factors in the behavioral phenotypes of HAP and LAP mice.
BACKGROUND: Although it is widely acknowledged that the risk of developing an alcohol use disorder (AUD) is strongly influenced by genetic factors, very little is known about how this genetic predisposition may alter neurotransmission in a way that promotes AUD susceptibility. The dorsal striatum has garnered increased attention as a brain region of interest in AUD development given its significant roles in goal-directed and habitual behavior. METHODS: In the present work, dorsal striatal neurotransmission parameters were measured in preclinical mouse models of high and low AUD risk. We performed brain slice whole-cell patch clamp electrophysiological recordings from medium spiny neurons (MSNs) in the dorsomedial (DMS) and dorsolateral (DLS) striatum of naïve adult male and female selectively bred high- and low-alcohol-preferring lines of mice (HAP and LAP). RESULTS: We found that MSNs of HAPmice were significantly more excitable than those of LAPmice, specifically in the DLS. Additionally, the frequencies of spontaneous glutamate- and GABA-mediated currents were both elevated in HAPmice relative to LAPmice in both dorsal striatal subregions, whereas amplitude differences were more variable between lines and subregions. AMPAR/NMDAR current ratios were significantly lower in HAPmice in both DLS and DMS. CONCLUSIONS: Collectively, these results suggest that genetic predisposition for high or low alcohol consumption produces significantly different basal functional states within both DLS and DMS which may be important factors in the behavioral phenotypes of HAP and LAPmice.
Authors: Gregory G Grecco; David L Haggerty; Emma H Doud; Brandon M Fritz; Fuqin Yin; Hunter Hoffman; Amber L Mosley; Edward Simpson; Yunlong Liu; Anthony J Baucum; Brady K Atwood Journal: J Neurochem Date: 2020-11-16 Impact factor: 5.546