Effects of cholinergic drugs on learning impairment in ventral globus pallidus-lesioned rats

The excitotoxin kainic acid (10 nmol/microliter) was used to produce bilateral lesions in the nucleus basalis magnocellularis (NBM) of rats which provides extensive cholinergic innervation to the cerebral cortex. The behavioral effects of physostigmine, THA (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) and NIK-247 (9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline monohydrate hydrochloride) were investigated by observing locomotor activity, shock sensitivity and passive avoidance response in the NBM-lesioned rats. Evaluation of locomotor activity and shock sensitivity in the experimental animals did not reveal any sensorimotor disturbances caused by the lesions. Oral administration of 1 and 2 mg/kg physostigmine reduced the locomotor activity in the NBM-lesioned rats, while physostigmine (0.5 mg/kg), THA (1 or 3 mg/kg) and NIK-247 (1 or 3 mg/kg) had no effect on locomotor activity. Compared with the sham-operated controls, the NBM-lesioned rats exhibited a significantly lesser deficit in the retention of the passive avoidance response. THA (1 or 3 mg/kg) and NIK-247 (1 or 3 mg/kg) elicited good retention of the passive avoidance response. Rats with NBM lesions showed impaired acquisition of a passive avoidance response when trained repeatedly at 24-h intervals. Also, when post-training NBM lesions were induced, there was rapid extinction of the acquired passive avoidance response. THA or NIK-247 administered at doses of 3 mg/kg significantly increased response latencies of post-trained NBM-lesioned rats. THA or NIK-247 administered once a day in doses of 1 or 3 mg/kg p.o. produced a very significant increase of acetylcholine in the cerebral cortex of NBM-lesioned rats after the 21st administration. These finding suggest that THA and NIK-247 exert an ameliorating effect on memory disturbance induced by NBM lesions in rats.