Chronic Exposure of Rats to Cognition Enhancing Drugs Produces a Neuroplastic Response Identical to that Obtained by Complex Environment Rearing

Abstract

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 diseasemodifying 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 memoryassociated 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.

Novel Regulation of Fibroblast Growth Factor 2 (FGF2)-mediated Cell Growth by Polysialic Acid

“…FGF2 binding of impaired polySia biosynthesized in such brains might be expected in schizophrenic brains. The expression of polySia is reported to change depending on drug usage (47) and alcohol exposure (48). The quality and quantity of polySia might be well regulated on cell surfaces, and the concentration of polySia-binding molecules may be finely tuned to activate or inactivate cells through receptors spatiotemporally, likely in conjunction with other regulatory molecules, such as HS.…”

Structural and Functional Impairments of Polysialic Acid by a Mutated Polysialyltransferase Found in Schizophrenia

“…The quality and quantity of polySia-NCAM might be strictly regulated. In this regard, imbalances of the polySia expression on NCAM due to low activity or altered expression levels of STX bring about serious consequences for neuronal function and brain diseases other than schizophrenia, such as Alzheimer disease (58,59), Parkinson disease (60,61), and drug abuse (62).…”

Cognitive Enhancement: Methods, Ethics, Regulatory Challenges

“…It is not always clear whether they do so by curing the damage or by amplifying (enhancing) capacities that compensate for the loss, or whether the distinction is even always meaningful. Comparing chronic exposure to cognition-enhancing drugs with an enriched rearing environment, one study in rats found that both conditions improved memory performance and produced similar changes in the neural matter (Murphy et al 2006). The improvements in the drug-treated group persisted even after cessation of treatment.…”