Dopamine (DA) neurons of the ventral midbrain are a major component of the brain reward circuit. Acute ethanol administration stimulates dopaminergic transmission. This effect is thought to underlie the reinforcing properties of ethanol, as pharmacological blockade of dopaminergic transmission in target regions suppresses various forms of ethanol reinforced behavior. Conversely, chronic ethanol exposure leads to compensatory neuroadaptations resulting in decreases in DA neuron firing when ethanol is withdrawn. The resulting hypodopaminergic state is believed to underlie the negative affective state associated with ethanol withdrawal. In vivo, DA neurons alternate between tonic, single-spike firing and phasic, burst firing, with the bursts frequently followed by brief pauses in firing. These two firing patterns each produce distinct signals in DA target regions. The phasic DA signal consists of massive synaptic DA release on a subsecond timescale and is believed to function as a teaching signal responsible for reward-based reinforcement learning. This phasic DA signal is particularly relevant to alcoholism, as addiction is viewed as a maladaptive form of reinforcement learning. Despite the fact that the burst-associated pauses could play an important role in regulating the phasic DA signal, the effects of ethanol on the mechanisms underlying the pause are not well understood. This proposal will test the hypothesis that acute ethanol exposure inhibits, whereas repeated ethanol exposure enhances, the mechanisms underlying the burst-associated pauses, thereby contributing to the changes in the frequency of bursts seen in vivo. In an in vitro brain slice preparation, stimulation of glutamatergic afferents or iontophoresis of aspartate onto DA neurons evokes an NMDA receptor-mediated burst followed by a metabotropic glutamate receptor (mGluR)-mediated pause in firing that closely resembles burst-pause firing in vivo. With this model, electrophysiological recordings of DA neurons in midbrain slices can be utilized to examine the effects of both acute and repeated exposure to ethanol on the mGluR-mediated pause. I will combine this approach with pharmacological techniques as well as flash photolysis of caged compounds and confocal calcium imaging to characterize the effects of ethanol exposure on the cellular mechanims underlying the mGluR signaling pathway. This research will expand our knowledge of the mechanisms through which ethanol modulates the firing patterns of DA neurons, contributing to our understanding of the rewarding and addictive properties of alcohol and the future development of treatments for alcoholism. ? ? ?
| Perra, Simona; Clements, Michael A; Bernier, Brian E et al. (2011) In vivo ethanol experience increases D(2) autoinhibition in the ventral tegmental area. Neuropsychopharmacology 36:993-1002 |
