UCSF

Alcoholism is a devastating disease afflicting roughly 17 million Americans. While this figure is staggering, it is all the more striking that 87% of the population can drink without developing dependence, given the addictive potential of alcohol. This suggests the existence of mechanisms which curb excessive alcohol intake and prevent the majority of alcohol drinkers from developing dependence. Previously we identified a homeostatic pathway in the dorsal striatum in which the brain-derived neurotrophic factor (BDNF) is upregulated by ethanol and subsequently acts to reduce ethanol intake (McGough et al., 2004). The central aim of this dissertation is the elucidation of the molecular mechanism underlying striatal BDNF homeostasis, as well as the determination of the functional significance of BDNF homeostasis with respect to ethanol consumption and the progression to addiction.

Here I demonstrate a complete signaling pathway in which ethanol treatment of striatal neurons increases BDNF protein, resulting in the phosphorylation of its receptor TrkB and subsequent activation of the MAPK pathway. Importantly, I show that ethanol increases production of the downstream effector, preprodynorphin, via a BDNF- and MAPK-dependent mechanism.

In addition, I show that in vivo conditional deletion of BDNF increases ethanol intake. Conversely, increasing BDNF expression in brain regions including the striatum decreases ethanol intake via a dynorphin-dependent mechanism. I also demonstrate that activation of dynorphin's receptor, the kappa opioid receptor, blocks acquisition of ethanol conditioned place preference, indicating that the BDNF/dynorphin pathway may inhibit the formation of ethanol-related memories.

Finally, I reveal a role for the BDNF homeostatic pathway in the progression to addiction. Specifically, I show that BDNF homeostasis breaks down throughout the corticostriatal circuit after extensive experience with ethanol. Critically, BDNF homeostasis does not recover following two weeks of abstinence from ethanol, indicating that inhibition of corticostriatal BDNF may be a hallmark of the addictive process which underlies the propensity to relapse.

Taken together, these data establish an integral role of BDNF in the dorsal striatum, via its downstream effector dynorphin, in regulating ethanol intake and preventing the progression to addiction.