Chronic exposure of rats to cognition enhancing drugs produces a neuroplastic response identical to that obtained by complex environment rearing.
Recent data suggest that Alzheimer's patients who discontinue treatment with cholinesterase inhibitors have a significantly delayed cognitive decline as compared to patients receiving placebo. Such observations suggest cholinesterase inhibitors to provide a disease-modifying effect as well as symptomatic relief and, moreover, that this benefit remains after drug withdrawal. Consistent with this suggestion, we now demonstrate that chronic administration of tacrine, nefiracetam, and deprenyl, drugs that augment cholinergic function, increases the basal frequency of dentate polysialylated neurons in a manner similar to the enhanced neuroplasticity achieved through complex environment rearing. While both drug-treated and complex environment reared animals continue to exhibit memory-associated activation of hippocampal polysialylated neurons, the magnitude is significantly reduced suggesting that such interventions induce a more robust memory pathway that can acquire and consolidate new information more efficiently. This hypothesis is supported by our findings of improved learning behavior and enhanced resistance to cholinergic deficits seen following either intervention. Furthermore, the level of enhancement of basal neuroplastic status achieved by either drug or environmental intervention correlates directly with improved spatial learning ability. As a combination of both interventions failed to further increase basal polysialylated cell frequency, complex environment rearing and chronic drug regimens most likely enhanced cognitive performance by the same mechanism(s). These findings suggest that improved memory-associated synaptic plasticity may be the fundamental mechanism underlying the disease modifying action of drugs such as cholinesterase inhibitors. Moreover, the molecular and cellular events underpinning neuroplastic responses are identified as novel targets in the search for interventive drug strategies for the treatment of neurodegenerative and neuropsychiatric disorders.
Department of Pharmacology, Applied Neurotherapeutics Research Group, Conway Institute, University College Dublin, Belfield, Dublin, Ireland. keith.murphy@ucd.ie
Keith J
KJ
Murphy
Andrew G
AG
Foley
Alan W
AW
O'connell
Ciaran M
CM
Regan
D000109:Acetylcholine / Q000037:antagonists & inhibitors; D000647:Amnesia / Q000139:chemically induced / Q000517:prevention & control / Q000523:psychology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004777:Environment; D018756:GABA Antagonists / Q000494:pharmacology; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects / Q000502:physiology; D018727:Muscarinic Antagonists; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology*; D010091:Oximes / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D012601:Scopolamine; D012642:Selegiline / Q000494:pharmacology; D012794:Sialic Acids / Q000378:metabolism; D013619:Tacrine / Q000494:pharmacology
D018756:GABA Antagonists; D018727:Muscarinic Antagonists; D019006:Neural Cell Adhesion Molecules; D018696:Neuroprotective Agents; D009557:Nipecotic Acids; D018697:Nootropic Agents; D010091:Oximes; D011760:Pyrrolidinones; D012794:Sialic Acids; C021319:polysialic acid; C078793:NNC 711; C058876:nefiracetam; D012642:Selegiline; D013619:Tacrine; D012601:Scopolamine; D000109:Acetylcholine