Increasing Acetylcholine Levels in the Hippocampus or Entorhinal Cortex Reverses the Impairing Effects of Septal GABA Receptor Activation on Spontaneous Alternation

Abstract

Intra-septal infusions of the ␥-aminobutyric acid (GABA) agonist muscimol impair learning and memory in a variety of tasks. This experiment determined whether hippocampal or entorhinal infusions of the acetylcholinesterase inhibitor physostigmine would reverse such impairing effects on spontaneous alternation performance, a measure of spatial working memory. Male Sprague-Dawley rats were given intra-septal infusions of vehicle or muscimol (1 nmole/0.5 µL) combined with unilateral intra-hippocampal or intraentorhinal infusions of vehicle or physostigmine (10 µg/µL for the hippocampus; 7.5 µg/µL or 1.875 µg/0.25 µL for the entorhinal cortex). Fifteen minutes later, spontaneous alternation performance was assessed. The results indicated that intra-septal infusions of muscimol significantly decreased percentage-of-alternation scores, whereas intra-hippocampal or intra-entorhinal infusions of physostigmine had no effect. More importantly, intra-hippocampal or intra-entorhinal infusions of physostigmine, at doses that did not influence performance when administered alone, completely reversed the impairing effects of the muscimol infusions. These findings indicate that increasing cholinergic levels in the hippocampus or entorhinal cortex is sufficient to reverse the impairing effects of septal GABA receptor activation and support the hypothesis that the impairing effects of septal GABAergic activity involve cholinergic processes in the hippocampus and the entorhinal cortex.Extensive evidence has implicated the medial septum in learning and memory. Lesions of the medial septum impair acquisition and retention performance in a variety of behavioral paradigms (Mitchell et al. 1982;Bolhuis et al. 1988;Fibiger et al. 1991;M'Harzi and Jarrard 1992). Furthermore, memory can be enhanced or impaired by intra-septal infusions of drugs that act at a variety of neurotransmitter systems (Brioni et al. 1990;Givens and Olton 1990;Markowska et al. 1990). For example, intra-septal infusions of ␥-aminobutyric acid (GABA)ergic agonists impair memory during numerous tasks, including radial arm maze performance, inhibitory avoidance, water maze performance, spontaneous alternation, rewarded alternation, and visual discrimination (Brioni et

Unreinforced spatial (latent) learning is mediated by a circuit that includes dorsal entorhinal cortex and fimbria fornix

“…The cholinergic projections that reach EC via FF have been implicated in spatial learning (Mitchell et al, 1982), and spatial memory impairments induced by septal inactivation with muscimol can be reversed by inhibition of AChsterase in the EC (Degroot and Parent, 2000). Lesions of the FF result in the reduction of c-fos expression in the both the septum and EC (Vann et al, 2000).…”

Age-related changes in memory and in acetylcholine functions in the hippocampus in the Ts65Dn mouse, a model of Down syndrome

“…This view is supported by evidence from other studies showing that acetylcholinesterase inhibitors enhance memory in aged rats and mice (e.g., Rispoli et al, 2006;Flood et al, 1993;Normile and Altman, 1992;Riekkinen et al, 1991), and that such drugs can be effective in memory-impaired aged rats but not in young rats (Ohta et al, 1991;Castellano et al, 1989). Similarly, acetylcholinesterase inhibitors are particularly effective in enhancing memory in rats and mice with compromised cholinergic functions and with other memoryimpairing pharmacological manipulations (Chang and Gold, 2004;Degroot and Parent, 2000;Ukai et al, 1995;Walker and Gold, 1992;Beracochea et al, 1992;Stone et al, 1991;Murray and Fibiger, 1986). Acetylcholinesterase inhibitors are also effective enhancers of memory in several rodent models of Alzheimer's Disease (Maurice et al, 1996;Dong et al, 2005;Popovi et al, 1997;Santucci et al, 1991).…”

“…The acetylcholinesterase inhibitor, physostigmine, was selected as the drug with which to enhance memory because of past findings indicating that the drug enhances memory in aging and other conditions (e.g., Rispoli et al, 2006;Flood et al, 1993;Normile and Altman, 1992;Riekkinen et al, 1991;Ohta et al, 1991;Castellano et al, 1989;Chang and Gold, 2004;Degroot and Parent, 2000;Ukai et al, 1995;Walker and Gold, 1992;Beracochea et al, 1992;Stone et al, 1991;Murray and Fibiger, 1986;Maurice et la., 1996;Dong et al, 2005;Popovi et al, 1997;Santucci et al, 1991). In addition, physostigmine was selected because it is an indirect agonist that requires at least some remaining release of ACh in order to exert its pharmacological actions.…”

Cholinergic Modulation of the Hippocampus During Encoding and Retrieval of Tone/Shock-Induced Fear Conditioning

“…Physostigmine was dissolved in 1 µL of 0.9% saline solution and delivered in a volume of 0.10 µL. The concentration of physostigmine was selected from previous studies (Todd and Kesner 1978;DeGroot and Parent 2000), and the volume of physostigmine was selected on the basis of a pilot study. The criteria for selection were that there would be no major changes in activity level, no obvious side effects, but still an efficacy in producing memory problems (see Rogers and Kesner 2003).…”