Blocking Stress Hormone Receptors to Curb Alcohol Dependence

Alcohol addiction hijacks the brain's stress systems, making withdrawal feel unbearable and driving continued drinking. We investigated whether a brain chemical called hypocretin/orexin—which plays key roles in both stress and reward—might be a promising target for treating alcohol dependence. This work was conducted in collaboration with the Schmeichel Lab.

The Research Question

We wanted to understand whether blocking different types of hypocretin receptors (called HCRT-R1 and HCRT-R2) could reduce alcohol drinking in dependent rats. Additionally, we asked whether hypocretin signals traveling from the lateral hypothalamus to the central amygdala—a brain region critical for stress and emotion—drive compulsive alcohol seeking during dependence.

What We Did

We made rats dependent on alcohol using chronic intermittent alcohol vapor exposure, which mimics the patterns of heavy drinking and withdrawal seen in human alcohol use disorder. Then we tested three different drugs: one that blocks only HCRT-R1 receptors (SB-408124), one that blocks only HCRT-R2 receptors (NBI-80713), and one that blocks both receptor types simultaneously (NBI-87571).

We also measured the levels of hypocretin receptor genes in the central amygdala and nucleus accumbens of dependent versus non-dependent rats to see if alcohol dependence changes the expression of these receptors.

Finally, we used a cutting-edge viral approach to selectively knock down hypocretin in neurons that project from the lateral hypothalamus to the central amygdala. This allowed us to test whether this specific brain pathway drives alcohol drinking in dependent animals.

Key Findings

The HCRT-R1 blocker reduced alcohol drinking in both dependent and non-dependent rats at the highest dose, suggesting it may have general effects on consumption. However, the HCRT-R2 blocker and the dual blocker specifically reduced drinking only in alcohol-dependent rats—suggesting these approaches target the compulsive drinking that characterizes dependence rather than normal alcohol consumption.

Importantly, none of the drugs affected water drinking, indicating they weren't simply making rats sick or unable to respond.

We found that alcohol-dependent rats had significantly lower levels of HCRT-R1 gene expression in the central amygdala during withdrawal compared to non-dependent rats. This suggests the hypocretin system undergoes changes in this stress-related brain region during alcohol dependence.

Most striking were our results with the viral knockdown approach. When we selectively reduced hypocretin in the pathway from the lateral hypothalamus to the central amygdala, alcohol-dependent rats showed sustained reductions in alcohol self-administration over several weeks. This demonstrates that this specific brain circuit is necessary for maintaining compulsive alcohol drinking during dependence.

Why This Matters

These findings reveal that hypocretin signaling—particularly at HCRT-R2 receptors and in the pathway to the central amygdala—is critical for the compulsive alcohol seeking that defines dependence. This is important because it suggests that drugs targeting these receptors might help people with severe alcohol use disorder reduce their drinking.

Interestingly, dual-acting drugs that block both hypocretin receptor types are already FDA-approved for treating insomnia (like suvorexant and lemborexant). Our research suggests these medications—or similar compounds—might be repurposed to help treat alcohol addiction, particularly in people with severe dependence who experience intense cravings and withdrawal symptoms.

The specificity of these effects for dependent drinking is particularly encouraging. It suggests that targeting the hypocretin system might reduce the compulsive, harmful drinking associated with addiction without completely blocking the ability to enjoy moderate alcohol consumption in non-dependent individuals—though this would need to be tested clinically.

Our circuit-specific findings also open doors for understanding exactly how stress and reward systems become hijacked during addiction, potentially leading to even more targeted treatments in the future.

For more information about the study see the article below.

Article: Aldridge GM, Zarin TA, Brandner AJ, George O, Gilpin NW, Repunte-Canonigo V, Sanna PP, Koob GF, Vendruscolo LF, Schmeichel BE. Effects of single and dual hypocretin-receptor blockade or knockdown of hypocretin projections to the central amygdala on alcohol drinking in dependent male rats. Addict Neurosci. 2022 Sep;3:100028. doi: 10.1016/j.addicn.2022.100028. Epub 2022 Jun 23.

https://pubmed.ncbi.nlm.nih.gov/35965958/