Effects of GABAergic Drugs on Physostigmine-Induced Improvement in Memory Acquisition of Passive Avoidance Learning in Mice

Abstract

1. The effect of γ-aminobutyric acid (GABA) receptor agonists and antagonists on acquisition of a step-down passive avoidance learning in mice was measured in the presence and absence of physostigmine. 2. Intraperitoneal injection of different doses of the anticholinesterase drug physostigmine (0.1–0.3 mg/kg) increased acquisition in mice dose dependently. The maximum response was obtained with 0.3 mg/kg of the drug. Higher doses of the drug impaired acquisition of the learned response. To show the effect of the GABAergic system on acquisition, GABA A receptor agonists and antagonists were challenged against 0.2 mg/kg of physostigmine. 3. Administration of the GABA A receptor agonist muscimol but not the GABA B receptor agonist baclofen decreased the acquisition of the learned task. However, the improvement induced by physostigmine (0.2 mg/kg) was decreased by both muscimol and baclofen. A combination of both agonists caused a higher inhibitory effect on the physostigmine response. 4. Pretreatment of animals with the higher doses of GABA A receptor antagonists bicuculline and picrotoxin but not the GABA B receptor antagonist phaclofen impaired learning. Both the GABA A and GABA B receptor antagonists reduced the learning improvement induced by physostigmine. The inhibitory effects of the GABA A and GABA B receptor antagonists are lost when combined together. 5. Bicuculline, picrotoxin or phaclofen increased the impairment of learning induced by muscimol, whereas a combination of either of the antagonists with baclofen did not alter the learning. The GABA A antagonists reduced the inhibitory effect of muscimol, whereas a higher dose of phaclofen increased the inhibition of the physostigmine response induced by muscimol and baclofen on physostigmine-induced learning improvement. 6. Phaclofen decreased but a higher dose of bicuculline increased the baclofen-induced inhibition of physostigmine effect. 7. It is concluded that both GABA A and GABA B activation inhibit improvement of acquisition induced by physostigmine.