Neural networks – which form the backbone of information processing in the mammalian central nervous system – are primarily constructed using the two major neurotransmitters, those which mediate so-called fast excitatory and inhibitory synaptic transmission (glutamate and GABA, respectively). Long-term alterations (plasticity) in the function of these synaptic receptors appear to be critically involved in neuroadaptive responses to drugs of abuse. My research is aimed at increasing our basic understanding of the synaptic alterations in these critical neurotransmitter systems which underlie alcohol-related brain disorders and alcoholism. Originally, my work dealt specifically with ethanol actions in hippocampal structures which had particular relevance to cognitive and hyperexcitability (seizure) aspects of alcoholism and withdrawal. My lab was the first to adopt organotypic explant preparations to define how chronic ethanol exposure can directly modulate NMDA receptor function in a system devoid of complicating factors of in vivo ethanol exposure (Thomas et al., JPET, 1998; Hendricson et al., JPET, 2007). However, in the past fifteen years, my lab has focused upon mechanisms involving ethanol dependence and craving and we are now solely directed at investigating mechanisms of ethanol modulation of information processing in mesocorticolimbic structures – specifically the nucleus accumbens (Maldve et al., Nature Neuroscience, 2002; Jeanes et al., JPET, 2011 and Neuroscience, 2014) and the ventral tegmental area as well (Theile et al., 2008, 2009, 2011).
Funded Projects (as (PI or Co-PI):
1) NIAAA R01AA15167
“Ethanol, Dependence and Mesolimbic Plasticity“:
The overarching hypothesis of this proposal is that the shell and core of the nucleus accumbens differentially encode the different phases of ethanol dependence development. We use a combined approach to study alterations in synaptic transmission in these structures – as a means to identify the neuroadaptations which underlie ethanol dependence and craving. The main electrophysiological technique is whole-cell patch clamp recording of synaptic transmission (miniature synaptic current analysis of Glu or GABA transmission, AMPA/NMDA ratios, Glu receptor rectification) following either
- passive chronic intermittent ethanol vapor exposure model now widely adopted model originally devised by the Becker group, or
- operant ethanol self-administration.
Recently, we discovered a cell-type specificity for glutamatergic plasticity in the shell sub-region of the nucleus accumbens such that D1-dopamine receptor expressing medium spiny neurons (MSNs) of the so-called DIRECT pathway show distinct differences in sensitivity to intermittent ethanol vapor (Jeanes et al., Neuroscience, 2014) in comparison to the IN-DIRECT pathway D2-dopamine receptor-expressing MSNs. We use the TdTomato-drd1 transgenic mice engineered to express the tomato fluorophore under the control of the D1-dopamine receptor promoter for our studies directed at understanding the neuroadaptations in these pathways which may underlie excessive ethanol intake.
2) NIAAA U01AA16651
“Target Validation by Accumbal Plasticity Screening”
This project is a component of the Integrative Neuroscience Initiative on Alcoholism (INIA-WEST), a multi-site consortium directed at identification of novel targets for medications development for excessive alcohol intake. In our component, we proposed to screen novel gene targets identified by INIA-West components for modulation of accumbal plasticity under baseline conditions and following intermittent ethanol exposure in order to help identify which targets may be especially suitable for medications development.
3) NIAAAA R01AA14874 (Rueben Gonzales, PI)
“Mu Receptors and Ethanol/Dopamine Interactions”
Naltrexone, one of the few clinically effective drugs approved to reduce relapse in alcoholism, is a broad spectrum opioid receptor antagonist, but its mechanism of action to reduce relapse is not known. Mu opioid receptors are anatomically located in the ventral tegmental area
(VTA) and are thought to control VTA dopamine neuron activity through the inhibition of GABA interneurons. However, the role of this mechanism in ethanol’s regulation of dopamine release, and the role of particular opioid receptor subtypes has not been firmly established. Gonzales’ preliminary studies show that mu opioid receptors are involved in the mechanism by which ethanol stimulates dopamine release in the shell of the nucleus accumbens in the Long-Evans rat. However, it is still unknown whether mu opioid receptors are involved in the stimulation of mesolimbic dopamine system before or during voluntary ethanol administration. Additionally, the mechanism of the stimulation of mesolimbic dopamine during operant self-administration may involve an increase in the firing rate of dopamine neurons in the ventral tegmental area, but this has not been measured in vivo. Hence, our component of this project is to perform real-time tetrode array recordings from VGTA DA neurons during operant ethanol self-administration and to determine how modulation of mu opiate receptor function modulates VTA DA firing and operant performance.