Pharmacologically Counteracting a Phenotypic Difference in Cerebellar GABAA Receptor Response to Alcohol Prevents Excessive Alcohol Consumption in a High Alcohol-Consuming Rodent Genotype

Abstract

Cerebellar granule cell GABA A receptor responses to alcohol vary as a function of alcohol consumption phenotype, representing a potential neural mechanism for genetic predilection for alcohol abuse (Kaplan et al., 2013; Mohr et al., 2013). However, there are numerous molecular targets of alcohol in the cerebellum, and it is not known how they interact to affect cerebellar processing during consumption of socially relevant amounts of alcohol. Importantly, direct evidence for a causative role of the cerebellum in alcohol consumption phenotype is lacking. Here we determined that concentrations of alcohol that would be achieved in the blood after consumption of 1-2 standard units (9 mM) suppresses transmission through the cerebellar cortex in low, but not high, alcohol consuming rodent genotypes (DBA/2J and C57BL/6J mice, respectively). This genotype-selective suppression is mediated exclusively by enhancement of granule cell GABA A receptor currents, which only occurs in DBA/2J mice. Simulating the DBA/2J cellular phenotype in C57BL/6J mice by infusing the GABA A receptor agonist, 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol hydrochloride, into cerebellar lobules IV-VI, in vivo, significantly reduced their alcohol consumption and blood alcohol concentrations achieved. 4,5,6,7-Tetrahydroisoxazolo-[5,4-c]pyridine-3-ol hydrochloride infusions also significantly decreased sucrose consumption, but they did not affect consumption of water or general locomotion. Thus, genetic differences in cerebellar response to alcohol contributes to alcohol consumption phenotype, and targeting the cerebellar GABA A receptor system may be a clinically viable therapeutic strategy for reducing excessive alcohol consumption.

Alcohol and the Brain: Neuronal Molecular Targets, Synapses, and Circuits

“…Rossi and colleagues observed a differential balance between the GABA-potentiating and inhibiting effects of ethanol in C57Bl6J and DBA mouse strains (Kaplan et al, 2013) that correlate with differences in ethanol intake. More recent studies indicate that enhancing GABAergic transmission in the cerebellum of C57Bl6J mice decreases ethanol drinking to levels seen in DBA mice (Kaplan et al, 2016).…”

Diverse types of genomic evidence converge on alcohol use disorder risk genes

“…Recently, brain cerebellum was highlighted as an important neuroanatomical region in alcohol consumption model mice 45. Some drugs targeting this region have been successfully reduced the alcohol consumption in model mice 46. The function of brain frontal cortex is featured by complex cognitive behaviour, personality expression, decision making and moderating social behaviour.…”

The Cerebellar GABAAR System as a Potential Target for Treating Alcohol Use Disorder

“…Furthermore, detailed temporal analysis of EtOH bout patterns indicate that the effect of modulating GABA A Rs globally, with the synthetic GABA A R-enhancing neurosteroid ganaxolone, can be complex even within a single model and set of animals (Ramaker et al 2011). Such variability with systemic application of GABA A R ligands likely reflects the widespread expression of GABA A Rs across the brain, with different brain regions playing different roles in various aspects of EtOH-induced responses (Ramaker et al 2015; Kaplan et al 2016b; Nowak et al 1998; Nie et al 2011; Pina et al 2015; Rewal et al 2009). However, even within a given brain region, such as the nucleus accumbens, the role of GABA A Rs in EtOH consumption is complex, with either blocking or activating extrasynaptic GABA A Rs able to reduce EtOH consumption (Rewal et al 2009; Nie et al 2011; Ramaker et al 2015).…”

“…As discussed above, the cerebellum is exquisitely sensitive to EtOH, with concentrations as low as 10 mM significantly altering cerebellar neural signaling (Kaplan et al 2013, 2016b; Welsh et al 2011; He et al 2013; Richardson and Rossi 2017) and, consequently, known cerebellar-dependent behaviors (Gallaher et al 1996). Importantly in the context of genetic predilection to AUD, over the last several years we have discovered that the response of key cerebellar processes to low [EtOH] varies across mammalian genotypes in a manner that correlates with, and appears to influence EtOH consumption phenotype (Mohr et al 2013; Kaplan et al 2013, 2016a, b; Richardson and Rossi 2017).…”

“…As discussed above, the cerebellum is exquisitely sensitive to EtOH, with concentrations as low as 10 mM significantly altering cerebellar neural signaling (Kaplan et al 2013, 2016b; Welsh et al 2011; He et al 2013; Richardson and Rossi 2017) and, consequently, known cerebellar-dependent behaviors (Gallaher et al 1996). Importantly in the context of genetic predilection to AUD, over the last several years we have discovered that the response of key cerebellar processes to low [EtOH] varies across mammalian genotypes in a manner that correlates with, and appears to influence EtOH consumption phenotype (Mohr et al 2013; Kaplan et al 2013, 2016a, b; Richardson and Rossi 2017). While there are many molecular targets of EtOH in the cerebellum, which collectively affect almost all cells and synapses within the cerebellar cortical circuit (Dar 2015; He et al 2013; Kaplan et al 2013; Richardson and Rossi 2017; Welsh et al 2011; Valenzuela and Jotty 2015), only a few targets have been identified that are sensitive to 10 mM EtOH, including T-type Ca 2+ channels in the Inferior Olivary neurons that provide climbing fiber inputs to Purkinje cells (Welsh et al 2011), the NMDA receptors in the climbing fiber to Purkinje cell synapse (He et al 2013; Zamudio-Bulcock et al 2018), and the GABA A R synapse from Golgi cells to granule cells, which has both Golgi cell and postsynaptic targets (Kaplan et al 2013).…”