EFFECTS OF INTRACRANIAL INFUSIONS OF CHLORDIAZEPOXIDE ON SPATIAL-LEARNING IN THE MORRIS WATER MAZE .2. NEUROPHARMACOLOGICAL SPECIFICITY

In the preceding paper(22) it was found that infusions of chlordiazepo xide (CDP) into the medial septal region, but not several other region s possessing a high density of benzodiazepine receptors, impaired spat ial learning, but not cue learning or swim speed, in the Morris water maze. The present investigation sought to further characterize the neu ropharmacological profile of this effect. Initially, it was reconfirme d that systemically administered CDP impaired spatial learning, but no t cue learning or swim speed, in the water maze. Additionally, it was found that systemically administered scopolamine, a muscarinic antagon ist, impaired both spatial and cue learning, but not swim speed, confi rming the detrimental effects of cholinergic hypofunction on maze lear ning. In new rats, a dose-response assessment revealed that 60 and 30 nmol, but not 10 nmol, CDP infused into the medial septum impaired spa tial learning, but not cue learning or swim speed. On the following da y, rats from each dose group, now undrugged, acquired a reversed platf orm location at control levels, suggesting that the previously observe d impairment was not due to a neurotoxic effect. Additionally, it was found that systemically administered flumazenil (10 mg/kg) blocked the spatial learning deficit produced by the 60 nmol dose of CDP infused into the medial septum. However, intraseptal infusions of flumazenil ( 10, 20, or 30 nmol) Failed to attenuate the spatial learning deficit p roduced by systematically administered CDP. Finally, systemically admi nistered tetrahydroaminoacridine (1 or 3 mg/kg), an acetylcholinestera se inhibitor, failed to attenuate the spatial learning deficit produce d by intraseptal CDP (60 nmol). Together these results implicate benzo diazepine receptors in the medial septum in the amnesic actions of CDP but suggest that additional sites also mediate this action. The prese nt results fair to support the idea that the spatial learning deficit produced by intraseptal infusions of CDP is due to a suppression of se pto-hippocampal cholinergic activity and it is proposed that CDP impai rs spatial learning by exacerbating hippocampal inhibition by inhibiti ng septo-hippocampal GABAergic projection neurons.