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Departments of
1 Psychiatry
4 Neurobiology, Yale University School of Medicine and the Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT 06508, USA
2 Department of Biology, Abo Akademi University, Finland
3 Neuroscience Center, Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, Finland
Recent studies indicate that the histaminergic system, which is critical for wakefulness, also influences learning and memory by interacting with cholinergic systems in the brain. Histamine-containing neurones of the tuberomammillary nucleus densely innervate the cholinergic and GABAergic nucleus of the medial septum/diagonal band of Broca (MSDB) which projects to the hippocampus and sustains hippocampal theta rhythm and associated learning and memory functions. Here we demonstrate that histamine, acting via H1 and/or H2 receptor subtypes, utilizes direct and indirect mechanisms to excite septohippocampal GABA-type neurones in a reversible, reproducible and concentration-dependent manner. The indirect mechanism involves local ACh release, is potentiated by acetylcholinesterase inhibitors and blocked by atropine methylbromide and 4-DAMP mustard, an M3 muscarinic receptor selective antagonist. This indirect effect, presumably, results from a direct histamine-induced activation of septohippocampal cholinergic neurones and a subsequent indirect activation of the septohippocampal GABAergic neurones. In double-immunolabelling studies, histamine fibres were found in the vicinity of both septohippocampal cholinergic and GABAergic cell types. These findings have significance for Alzheimer's disease and other neurodegenerative disorders involving a loss of septohippocampal cholinergic neurones as such a loss would also obtund histamine effects on septohippocampal cholinergic and GABAergic functions and further compromise hippocampal arousal and associated cognitive functions.
(Received 12 July 2004;
accepted after revision 7 October 2004;
first published online 14 October 2004)
Corresponding author M. Alreja: Department of Psychiatry, CMHC 335A, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508, USA. Email: meenakshi.alreja{at}yale.edu
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