Salvia divinorum extract (SDE) and its active compound salvinorin-A (Sal-A) increased voluntary alcohol intake in male Wistar rats. SDE boosted alcohol consumption especially in rats with a history of forced alcohol intake from a young age, while Sal-A increased alcohol intake regardless of prior alcohol exposure. Both SDE and Sal-A also prolonged tonic immobility, a sign of anxiety-like behavior, and reduced food intake. These findings suggest that activation of the kappa-opioid system by Sal-A or SDE can stimulate alcohol consumption and produce anorexigenic and anxiety-like effects in rats.
In rats undergoing alcohol withdrawal, stimulating kappa-opioid receptors (KOR) in the dorsal periaqueductal gray (D-PAG) with salvinorin A increased anxiety-like behaviors and alcohol consumption and preference, while blocking KOR with PF-04455242 reduced anxiety-like behaviors and increased exploration without affecting alcohol intake. These effects were stronger in alcohol-withdrawal rats than in alcohol-naïve rats, suggesting that KOR in the PAG become hyperreactive during alcohol withdrawal and may contribute to anxiety and increased drinking.