Tacrine Treatment at High Dose Suppresses the Recognition Memory in Juvenile and Adult Mice with Attention to Hepatotoxicity

Abstract

It is well established that cholinergic over-stimulation can interfere with memory processes. The aim of this study was to evaluate the effect of tacrine, an acetylcholinesterase inhibitor, on recognition memory as well as the associated hepatotoxicity in juvenile (20-day-old) and adult (100-day-old) ICR male mice. Recognition memory was assessed by open-field test and step-through task without footshocks for three sessions between 08:00 and 13:00, with a 24-hr retention interval. Tacrine (10 or 40 lmol ⁄ kg) or vehicle was administered (s.c.) 20 min. prior to the first session. During the acquisition session, tacrine suppressed the open-field behaviours, including locomotor activity, rearing, grooming and defecation (by 77-100%) in mice of both ages. During the recall (observable in both ages) and re-recall (observable in juvenile mice) session, the locomotor activity and rearing number were significantly increased, indicative of impairment in recognition memory, in mice treated with tacrine 40 lmol ⁄ kg. During the training trial, tacrine decreased the step-through number in mice of both ages. In contrast, during the retention and re-retention trials, the step-through number was increased (by 92% and 93%, respectively), indicative of impairment in step-through memory, in juvenile but not adult mice treated with tacrine 40 lmol ⁄ kg. Tacrine 40 lmol ⁄ kg elevated the serum alanine aminotransferase (ALT) activity (by 135%) in juvenile mice, but reduced the ALT activity (by 42%) in adult mice. The results indicated that 20-day-old mice seemed to be more sensitive than 100-day-old mice to tacrine-induced impairment in recognition memory and the associated liver damage.The cholinergic system in the brain is closely related to the regulation of learning and memory processes. However, studies have shown that cholinergic dysfunction, including insufficiency and hyperfunction caused by cholinergic agent, can impair the memory and behaviours. Patients suffering from Alzheimer's disease (AD) are characterized by cholinergic dysfunction in the brain, which eventually lead to a progressive memory loss and other cognitive symptoms that result in occupational and social disabilities [1,2]. Validated scales for clinical diagnosis of AD now take into consideration not only cognitive dimensions but also behavioural symptoms, with the introduction of behavioural psychological symptoms of dementia [3,4]. Ageing is accompanied by the decline in mental performance, including deficits in memory formation, learning and adaptation to novel environment, and the administration of cholinesterase inhibitors has been found to be useful in slowing the progression of the mild-to-moderate stage of AD or ageing with amnesia [5]. In this regard, micro-injections of tacrine or nicotine into the core of the nucleus accumbens were found to enhance the open-field habituation learning or memory [6,7]. On the other hand, tacrine is a nootropics that can produce amnesic effects in normal animals [8,9]. In addition, an open-field memory impai...

Enduring effects of tacrine on cocaine-reinforced behavior: Analysis by conditioned-place preference, temporal separation from drug reward, and reinstatement

“…Dose-related hepatotoxicity occurs in mice, rats, and humans that receive tacrine, and can also be shown using in vitro methods (Pan et al, 2011). Increases in plasma transaminases (alanine transaminase and aspartate transaminase) occur after rats receive single 40 mg oral doses of tacrine, and are accompanied by hepatocyte swelling without either steatosis or necrosis (Ma et al, 2003).…”

Tacrine and Bis(7)-Tacrine Attenuate Cycloheximide-Induced Amnesia in Mice, with Attention to Acute Toxicity

“…The decrease in locomotor activity of mice during the recall session reflects a habituation or remembrance to the conditioning apparatus, which is a manifestation of openfield memory [21][22][23]. Memory loss, as assessed by the openfield test and manifested in hyperlocomotion in the recall session, has been observed in mice treated with high doses of scolopamine and tacrine [14,24,25].…”

Drug Development for Alzheimer’s Disease: Microglia Induced Neuroinflammation as a Target?

“…Tacrine is the first approved drug for mild to moderate AD [107]. Because of its safety issue on hepatotoxicity and its uncertain efficacy, it was discontinued in the USA in 2013 [108,109,110,111]. Rivastigmine and galantamine are proved to have a beneficial effect in the treatment of mild to moderate dementia of the Alzheimer’s type [112,113,114,115], while donepezil is used for the treatment of mild, moderate, and severe dementia in AD [116,117].…”