Caffeine and sclareol take the edge off the sedative effects of linalool, possibly through the GABAA interaction pathway: molecular insights through in vivo and in silico studies.

Linalool (LIN) has some important neuropharmacological activities, including anxiolytic and sedative effects. It is also clear that it protects experimental animals from convulsions and Alzheimer's disease. On the other hand, caffeine (CAF) and sclareol (SCL) have neurostimulatory potential. This study evaluates the sedative effect and possible molecular mechanisms of CAF with LIN and/or SCL through in vivo and in silico studies. For this, CAF (10 mg/kg) alone or with LIN (50 mg/kg) and/or SCL (10 mg/kg) was intraperitoneally (i.p.) treated before thirty minutes of thiopental sodium (TS) injection (40 mg/kg, i.p.) to the mice and observed for latency and duration of sleep up to 4 h. To understand the possible action mechanisms of these drugs, we also performed molecular docking and pharmacokinetics profile studies with gamma-aminobutyric acid (GABAA) receptor respective subunits. Findings suggest that LIN exerted significant (p < 0.05) sedative effects on the animals. CAF and SCL alone or in their combinations significantly reduced LIN's effects in mice. CAF, LIN, and SCL showed binding affinities of ‒6.2, ‒5.5, and ‒7.3 kcal/mol with 6X3X of the GABAA receptor (α1 and β2 subunits), respectively. Taken together, LIN exerted significant sedative effects, whereas CAF and SCL, either alone or in combination, attenuated this effect in mice. These findings suggest that LIN, CAF, and SCL modulate sedation through interactions with the GABAA receptor pathway. Further clinical studies are required to confirm these results.