Neuropharmacological profiles of Tetrahydrofuran

Abstract

The primary objective of this research was to study behavioral effects of tetrahydrofuran (THF) in comparison to those of gamma-butyrolactone (GBL) which might probably display a similar profile and eventually related to the possible conversion of THF to gamma-hydroxybutyric acid (GHB) which acts through GABAᵦ or GHB specific receptors. Many animal behavioral models in mice were used to test the validity of this hypothesis including locomotor activity, righting reflex, rotarod, open-field, elevated plus maze, Y-maze, Morris water maze, open-space swimming, and conditioned place preference tests. The results indicated that both THF and GBL caused marked CNS depression. THF was less potent than GBL as considered from intraperitoneal TD₅₀ values derived from righting reflex (15.18 mmol/kg versus 4.60 mmol/kg) and rotarod tests (7.00 mmol/kg versus 0.85 mmol/kg). THF and GBL had a different pattern of depressant effects on locomotor activity. At a dose range of 3, 5, and 10 mmol/kg, THF reduced locomotor activity in a dose-dependent manner for the entire 150-min test period. At a low dose range (1, 3, and 5 mmol/kg), GBL induced short-lived depressant effects on locomotor activity (60-80 min) and then locomotor activity was returned to baseline. However, at a dose of 10 mmol/kg, GBL suppressed locomotor activity for the entire 150-min test period. THF and GBL did not demonstrate anxiolytic property in the open-field and elevated plus maze tests. In addition, THF and GBL at the doses of 0.1 and 0.3 mmol/kg had no effects on working (short-term) spatial memory in the Y-maze test. However, deficits in retrieval and relearning of spatial long-term memory were observed with repeated administration of THF (1 and 3 mmol/kg) and GBL (1 mmol/kg) in Morris water maze test. At doses of 0.1 and 0.3 mmol/kg, THF and GBL did not demonstrate antidepressant effects in the openspace swimming test. Subacute treatment with THF (10 mmol/kg) followed by a challenging dose of THF (15 mmol/kg) showed marked tolerance on the sedative-hypnotic effects. However, THF (3 and 5 mmol/kg) and GBL (0.5 and 1 mmol/kg) did not possess reinforcing properties as considered from the conditioned place preference test. The study with different antagonists demonstrated that effects of THF on impairment of motor function in the rotarod test could be antagonized for a short duration by CGP-35348, a GABAᵦ receptor antagonist. It is suggestive that THF possessed a similar profile of CNS depressive effects to that of GBL, as considered from various behavioral tests in mice. However, THF showed a less potency with a longer duration of action than those of GBL. The mechanism of THFinduced CNS depression, at least in the motor impairment, may involve the GABAB receptor.