This FIRCA proposal will investigate changes in acetylcholine (ACh) and dopamine (DA) release from the nucleus accumbens shell (NA) following chronic ethanol treatment. Chronic ethanol is known to cause damage to cholinergic neurons (Arendt, 1993) and to sensitize DA neurons to glutamate excitotoxicity (Crews et a1. 1998). Recent studies have indicated that endogenous opiates are involved in alcohol addiction, leading to the approval of naltrexone, an opiate antagonist, for treatment of alcohol dependence. Studies of morphine and ethanol dependence have indicated changes in the interaction of DA and ACh during dependence and physical withdrawal and sustained changes during prolonged abstinence. Fiserova et.al.,1998 found that acute morphine decreases ACh release whereas a morphine challenge weeks after chronic morphine during prolonged abstinence results in an increase in ACh response to morphine. Endogenous opiates in the NA regulate DA release which regulates release from ACh interneurons in the NA. The reversal of the opiate response is consistent with studies of the effects of chronic ethanol on ACh release in hippocampus. These studies will be extended to NA with additional investigations of the interaction of DA and opiates on DA and ACh release.
The Specific aims are: 1. It is hypothesized that physical withdrawal from chronic ethanol treatment will alter ACh release in the NA. A chronic binge ethanol treatment protocol well known to cause substantial physical dependence will be used. Levels of microdialysate ACh will be determined in diet controls or ethanol-treated groups just after the last dose and throughout the physical withdrawal syndrome (0-96hrs) as well as during prolonged abstinence, e.g., 15 and 35 days after the last dose of ethanol. It is expected that the hyperexcitability of withdrawal will damage ACh neurons, reducing basal ACh release levels during prolonged abstinence and altering neuronal architecture and/or receptor density. 2.
Aim 2 will test the hypothesis that DA microdialysate levels decrease during withdrawal from chronic ethanol and remain decreased throughout prolonged abstinence due to changes in DA neuronal architecture and/or receptor density. 3.
Aim 3 will test the hypothesis that chronic ethanol treatment followed by prolonged abstinence results in changes in the interaction of DA and ACh. In these studies challenges with various receptor specific drugs will be used to investigate mechanisms of changes in neurotransmission. Post mortem studies will determine if changes in the density or distribution of receptors occur that could underlie changes in neurotransmission.
