Dopamine synthesis in alcohol drinking-prone and -resistant mouse strains

Abstract

Alcoholism is a prevalent and debilitating neuropsychiatric disease, and much effort has been aimed at elucidating the neurobiological mechanisms underlying maladaptive alcohol drinking in an effort to design rational treatment strategies. In preclinical literature, the use of inbred mouse lines has allowed for the examination of ethanol effects across vulnerable and resistant phenotypes. C57BL/6J mice consistently show higher rates of ethanol drinking compared to most mouse strains. Conversely, DBA/2J mice display low rates of ethanol consumption. Given that the reinforcing and rewarding effects of ethanol are thought to be in part mediated by its actions on dopamine neurotransmission, we hypothesized that alcohol-preferring C57BL/6J and alcohol-avoiding DBA/2J mice would display basal differences in dopamine system function. By administering an L-aromatic acid decarboxylase inhibitor and measuring L-Dopa accumulation via high-performance liquid chromatography as a measure of tyrosine hydroxylase activity, we found no difference in dopamine synthesis between mouse strains in the midbrain, dorsal striatum, or ventral striatum. However, we did find that quinpirole-induced inhibition of dopamine synthesis was greater in the ventral striatum of C57BL/6J mice, suggesting increased presynaptic D2-type dopamine autoreceptor sensitivity. To determine whether dopamine synthesis or autoreceptor sensitivity was altered by a history of ethanol, we exposed C57BL/6J mice to one or two weekly cycles of chronic intermittent ethanol (CIE) exposure and withdrawal. We found that there was an attenuation of baseline dopamine synthesis in the ventral striatum after two cycles of CIE. Finally, we examined tissue content of dopamine and dopamine metabolites across recombinant inbred mice bred from a C57BL/6J × DBA/2J cross (BXD). We found that low dopaminergic activity, as indicated by high dopamine/metabolite ratios, was positively correlated with drinking. Together, these findings show differential autoreceptor effects on dopamine synthesis between C57BL/6J and DBA/2J mice, and suggest that decreased dopaminergic activity is associated with excessive drinking.

Molecular mechanisms underlying striatal synaptic plasticity: relevance to chronic alcohol consumption and seeking

“…Molecule quantities were either taken from prior striatal models (Oliveira et al ., ; Kim et al ., ) or experimental publications or adjusted to reproduce experimentally measured concentrations of downstream molecules; for example, the balance of adenylyl cyclase and phosphodiesterase was adjusted to produce a 30 n m basal cAMP concentration (Bacskai et al ., ; Mironov et al ., ). Changes in molecule quantity due to chronic alcohol treatment were based on published experiments showing increase in Gβγ (Bowers et al ., ), increase in metabotropic glutamate receptor types 1/5 (mGluR1/5) (Obara et al ., ; Meinhardt et al ., ), lower evoked dopamine (Hirth et al ., ; Siciliano et al ., ), changes in Gs‐coupled signaling (Lucchi et al ., ; May et al ., ; Nestby et al ., ; Kashem et al ., ), or increased calcium influx due to increases in NMDA receptor 2B (NR2B) subunits relative to NR2A subunits (Wang et al ., ; Chen et al ., ; Ma et al ., ). Initial conditions specifying molecule quantities are available on github (https://github.com/neurord/D1pathways/blob/master/IC_SPNspineAChm4R_AC1_coupleGqhigh.xml).…”

Alcohol hangover impacts learning and reward processing within the medial‐frontal cortex

“…Given that alcohol intoxication results in reduced performance in a variety of tasks (Hendrie, Gao, Hall, Hui, & Unverzagt, 1996;Starkey & Charlton, 2014;Van Dyke & Filmore, 2014) and its potential to influence dopaminergic reward systems (Siciliano et al, 2017), it is not surprising that a number of studies have sought to investigate its effects on the medial frontal system via its impact on the aforementioned ERP components (Henry, 2013;Nelson, Collins, Lang, & Bernat, 2011, Ridderinkhof, Cohen, & Forstmann, 2012. Nelson et al (2011) found that intoxication impaired the performance of the aforementioned medial-frontal error evaluation system.…”

Substance use disorder a bio-directional subset of reward deficiency syndrome

“…These effects result initially in everincreasing tolerance, withdrawal and continued drug seeking, while, withdrawal from opiates and alcohol, for example, can also lead to a hyperdopaminergic state (44). Chronic use of these substances including cocaine also induces a hypodopaminergic state © 1996-2017 leading to tolerance (45)(46)(47). Specifically, Siciliano et al, (46) found that there was an attenuation of baseline dopamine synthesis in the ventral striatum after two cycles of chronic intermittent ethanol (CIE).…”

“…Chronic use of these substances including cocaine also induces a hypodopaminergic state © 1996-2017 leading to tolerance (45)(46)(47). Specifically, Siciliano et al, (46) found that there was an attenuation of baseline dopamine synthesis in the ventral striatum after two cycles of chronic intermittent ethanol (CIE). They also found that low dopaminergic activity was positively correlated with drinking as indicated by high dopamine/metabolite ratios.…”