An important goal of contemporary health research is to understand the adaptations that occur in the brain that cause excessive alcohol drinking. Using a well-established preclinical model of alcohol (ethanol) dependence and relapse, our laboratory recently demonstrated increased glutamatergic transmission in the nucleus accumbens (NAc), a brain region important for regulating motivated behaviors. Glutamatergic afferents reaching the NAc come from several different regions, but the ventral hippocampus (vHC) provides particularly rich innervation to the NAc Shell. Preliminary data indicate that inactivating the vHC using chemogenetic procedures reduces ethanol drinking. Further, inactivating the vHC to NAc pathway reduces (GLU) glutamate release, while activating this same pathway increases GLU release in the NAc. Expression of pre-synaptic mGluR2 receptors, important regulators of neuronal glutamate release, is reduced in the NAc Shell of ethanol dependent mice. Because of the dense vHC to NAc Shell projections, the reduction in mGluR2 receptors likely contributes to the increased glutamate transmission we reported previously. Our proposed studies will determine if this is the case. Taken together, these exciting new findings implicate a relatively un-studied pathway (vHC to NAc) in ethanol drinking and glutamate release in the NAc. The overarching hypothesis of this proposal is that activity of the vHC-NAc pathway regulates ethanol drinking (Aim 1) and significantly contributes to glutamate release in the NAc of dependent mice (Aim 2).
In Aim 1, we will determine effects of manipulating activity of the vHC-NAc pathway on ethanol drinking in dependent and non-dependent mice. Our working hypothesis is that increasing activity of the pathway will increase drinking, while decreasing activity of the pathway will reduce drinking.
In Aim 2, we will determine whether increased activity of the vHC-NAc pathway leads to increased glutamate levels in the NAc and, additionally, whether adaptations in mGluR2 expression contribute to dependence-related increased glutamate activity and escalated drinking. Our working hypothesis for Aim 2 is that glutamate release will be greater in ethanol dependent mice because mGluR2 expression is reduced on the terminals of this pathway. Identification of critical pathway(s) involving the NAc, whether it is the VHC-NAc, or another pathway, will inform and guide subsequent targeted medication development to prevent and/or treat alcohol addiction.
Identifying the neural circuitry and neural adaptations associated with increased alcohol consumption in alcohol dependent mice is critical to advancing translational science. Such elucidation may help address the perplexing question of why alcohol dependent individuals continue to drink excessively.