Effects of intracranial infusions of chlordiazepoxide on spatial learning in the Morris water maze. II. Neuropharmacological specificity.

In the preceding paper it was found that infusions of chlordiazepoxide (CDP) into the medial septal region, but not several other regions possessing a high density of benzodiazepine receptors, impaired spatial learning, but not cue learning or swim speed, in the Morris water maze. The present investigation sought to further characterize the neuropharmacological profile of this effect. Initially, it was reconfirmed that systemically administered CDP impaired spatial learning, but not cue learning or swim speed, in the water maze. Additionally, it was found that systemically administered scopolamine, a muscarinic antagonist, impaired both spatial and cue learning, but not swim speed, confirming the detrimental effects of cholinergic hypofunction on maze learning. In new rats, a dose-response assessment revealed that 60 and 30 nmol, but not 10 nmol, CDP infused into the medial septum impaired spatial learning, but not cue learning or swim speed. On the following day, rats from each dose group, now undrugged, acquired a reversed platform location at control levels, suggesting that the previously observed 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 produced by systemically administered CDP. Finally, systemically administered tetrahydroaminoacridine (1 or 3 mg/kg), an acetylcholinesterase inhibitor, failed to attenuate the spatial learning deficit produced by intraseptal CDP (60 nmol). Together these results implicate benzodiazepine receptors in the medial septum in the amnesic actions of CDP but suggest that additional sites also mediate this action. The present results fail to support the idea that the spatial learning deficit produced by intraseptal infusions of CDP is due to a suppression of septo-hippocampal cholinergic activity and it is proposed that CDP impairs spatial learning by exacerbating hippocampal inhibition by inhibiting septo-hippocampal GABAergic projection neurons.