The first experience with alcohol is a learning situation, and as such it is associated with changes in neurochemistry and the activity of specific neuronal subsets. The perceived, euphoric “high” induced by alcohol and other commonly abused drugs, such as cocaine and amphetamines, has been attributed to activation neurons in the dopamine pathway. Increased dopaminergic neuron activity in the ventral tegmental area (VTA) and the nucleus accumbens (NAc) also leads to the formation of goal-oriented and reward-based behaviors, and neurons expressing dopamine receptor D1 (D1) and –dopamine receptor D2 (D2) comprise a network of reward-action learning circuits throughout the brain. Previous work has shown that D1 neurons play a crucial role in alcohol learning and reinforcement. In a recent study published in The Journal of Neuroscience, a research team led by Dr. Dorit Ron at the University of California, San Francisco examined whether a single exposure to alcohol can induce memory and behavioral changes that could promote future drinking. The researchers examined synaptic plasticity in D1 and D2 neurons in C57BL/6J (000664) and C57BL/6J-background mice after a single alcohol experience, assessed molecular changes associated with these stimuli, and measured the likelihood that the mice would voluntarily drink again. Their data suggest that the perceived benefits of alcohol are registered and stored in memory from the first encounter. Further, synaptic changes in D1 neurons required the activity of mTORC1. Together, these data advance our understanding of the neurological changes that accompany alcohol and related substance abuse and addiction, and highlight a previously unappreciated molecular pathway in alcohol-based learning.
In order to assess how a first alcohol exposure affects synaptic plasticity of D1 and D2 neurons, the UCSF researchers generated mice with fluorescently labeled D1 and D2 neurons by crossing Drd1-Cre or Drd2-Cre with Ai14 mice (B6.Cg-Gt(ROSA)26Sortm14(CAG-tdTomato)Hze/J, (007914). These mice were subjected to a two-bottle drinking test in which one bottle contained water and the other 20% alcohol for 24 h. The next day, brains from the treated mice were harvested, and D1 and D2 neuron physiology in the NAc was measured by patch-clamp assay. An increased ratio of AMPA/NMDA glutamate receptors, indicative of altered synaptic plasticity and excitatory neuron synaptic transmission, was observed in D1 neurons but not in D2 neurons compared to control mice who only had water to drink. Similar changes were observed following a single intraperitoneal dose of alcohol to Drd1-Cre-Ai14 or Drd2-Cre-Ai14 mice that had not been exposed to alcohol previously. These data indicate that a first, and perhaps even a single, alcohol experience can change synaptic properties in D1 neurons in the NAc.
To understand the molecular biology that underlies the synaptic changes induced by first alcohol exposure, Dr. Ron’s team examined activation of mammalian target of rapamycin complex 1 (mTORC1) and its associated pathway members. mTORC1 promotes translation in many cell types, including synaptic proteins in neurons, and is necessary for some synaptic alterations. Phosphorylated Akt and Erk2, both of which activate mTORC1, were increased in total brain homogenates isolated from mice exposed to a single 4 hour binge alcohol event. Further, phosphorylation of the mTORC1 target S6 kinase and its downstream substrate, ribosomal protein S6, was significantly upregulated in synaptosomal fractions. Most tellingly, translation of GluA1 and Homer, two proteins whose translation is regulated by mTORC1, was increased in synaptic fractions. These data suggest that from the very first alcohol experience, D1 neurons in the NAc rapidly and robustly activate the mTORC1 pathway to stimulate the translation of gene products that reinforce synaptic circuits that underlie reward-based learning.
This study expands our current understanding about the neurological changes that accompany initial alcohol exposure, and suggest that similar alterations may underlie the reward-based learning associated with alcohol and other substance abuse. The data also identifies the mTORC1 pathway as a potential therapeutic target for developing drugs to help patients dealing with addiction.