Studies of a possible interaction between cholinergic and benzodiazepine receptor mediated systems underlying spatial learning in the rat

Guy, Andrew Peter (1990) Studies of a possible interaction between cholinergic and benzodiazepine receptor mediated systems underlying spatial learning in the rat. University of Southampton, Doctoral Thesis.

Abstract

A novel two-trial form of the Morris water maze task has been developed which requires spatial learning for its efficient completion. The amnestic effect of the muscarinic cholinergic antagonist atropine sulphate (ATR S) has been demonstrated, and this is in contrast to the quarternary ammonium salt of atropine, atropine methyl nitrate, which is not readily absorbed into the central nervous system and is inactive in the water maze model. The effect of ATR S is reversed by the cholinergic agonist oxotremorine. The benzodiazepine receptor agonist diazepam (DIAZ) has also been tested, and induced a similar effect to ATR S. The amnestic effect of DIAZ was fully reversed by the benzodiazepine receptor antagonist Ro 15-1788, and also by the cholinergic agonist oxotremorine. The amnestic effect of ATR S was reversed by a number of benzodiazepine receptor inverse agonists (ie. agents having the opposite effect to DIAZ on γ-aminobutyric acid neurotransmission) from three distinct chemical classes (β-carbolines, imidazobenzodiazepines and pyrazoloquinolines). In turn, the effect of these agents was inhibited by Ro 15-1788 at a dose which had no effect on the ATR S-induced amnesia, suggesting that they were acting at benzodiazepine receptors, and eliminating the likelihood of direct effects at cholinergic receptors. These data suggest a functional interaction between cholinergic and benzodiazepine mechanisms involved in learning. In addition to the effects of benzodiazepine receptor inverse agonists in ATR S treated animals, all of the agents tested (with the exception of Ro 15-1788 and CGS 9896) evoked a deficit in learning when given alone to normal animals. This adverse effect on learning was fully reversed by Ro 15-1788. The data obtained in this study suggest that there may be a balance between cholinergic and y-aminobutyric acid mediated systems in the brain which have a potent influence on spatial learning. The results are discussed in terms of the relevance of such an interaction to learning, and with respect to recent hypotheses of memory dysfunction in dementia.

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