Evidence indicates that a similar key brain reward pathway is involved in both alcohol and drug abuse. In this pathway, alcohol affects the akey entry signals, mesolimbic dopamine (DA) and cortical limbic glutamate (GLU) into the extended amygdala (EA), an area integrating the stimulation for appropriate response. We hypothesized that chronic alcohol exposure and its follow-up with episodic alcohol deprivation alter the brain's wiring at the synaptic level in the EA. The key circuits between cortical limbic GLU as well as mesolimbic DA neurons and the EA medium spiny projecting GABA neurons will be studied in the alcohol preferring (P) line of rats. The key reward circuitry will be examined in three treatment groups---(a) AlcoholNaive, water over entire period of the experiment; (b) Chronic Alcohol Treatment, concurrent free access to 10, 20, and 30% alcohol for 20 weeks, (c) or Repeated Deprivation, similar access to alcohol for 6 weeks before deprivation for two weeks and followed by 3 additional cycles of repeated 2- wk water and 2-wk free choice access drinking. The brain wiring of these rats will be monitored at the synaptic level in EA using three quantitatively determined checkpoints -- the number of GLU and DA synaptic boutons using stereologic counting; autoradiography to assess the density of responsive receptors NMDA, D1, and D2; and the number and length of dendrites, density of spines, and morphometric plasticity of spines of principal medium neurons employing two-photon fluorescence microscopy and Neurolucida analysis. In the key reward circuitry of stereotypic alcohol drinking behaviors, the amplitude of the alcohol signal may alter the number of GLU and or DA synaptic boutons in EA; numbers of dendrites and spines, the sites of reception to alcohol signal; and/or changes in the density of receptors, which determines the degree of reception of the alcohol signal. As a result, the brain may set a new threshold upon the over- stimulation of alcohol. The setting of this threshold might be derailed when alcohol is cyclically deprived. Current and future study along this line will provide information enabling us to better understanding excess drinking behavior.
|Effective start/end date||9/27/01 → 8/31/05|
- National Institutes of Health: $152,455.00
- National Institutes of Health: $141,495.00
- National Institutes of Health: $148,015.00