Effects of tacrine on deficits in active avoidance performance induced by AF64A in rats

Abstract

Effects of tacrine (1,2,3,4-tetrahydro-9-aminocridine) on memory deficits in rats treated with ethylcholine aziridinium ion (AF64A) were studied using active avoidance test in the two-way shuttle box. Neurotoxin AF64A injected at a dose of 6 nmol (i.c.v., bilaterally) causes nonspecific tissue damage in hippocampal fields CA2 and CA3. Two weeks after treatment with 6 nmol, AF64A active avoidance performance of toxin-treated rats was significantly deteriorated compared to vehicle-treated animals estimated in learning test (68 +/- 3.5 and 83 +/- 3.2% of correct responses, respectively; p < 0.01) and in retention test (53 +/- 5 and 76 +/- 3.6%, respectively; p < 0.01). Under these conditions, chronic treatment with tacrine at a daily dose of 1 mg/kg for 12-14 d reverses the effect of AF64A on the active avoidance performance both in learning (78 +/- 3.2%) and retention (72 +/- 4%) tests. It is supposed that behavioral effects of tacrine considerably depend on a severity of neurodegeneration in the hippocampus.

Dimebon improves learning in animals with experimental Alzheimer's disease

“…AF64A degrades in vivo within 24 h [12]; therefore, test drugs were administered one day after AF64A administration in order to avoid its interaction with the test drugs. The daily doses were chosen on the basis of our previous studies demonstrating that tacrine in a dose of 1 ~tg/kg improved TWAA performance [14].…”

“…One or two days after administration of 1-3 nmol of AF64A into the lateral cerebral ventricles, the content of AC in the cerebral cortex and hippocampus decreases and remains low for about 6 months [6,12]. Our previous studies showed that AF64A impairs acquisition of the two-way active avoidance reaction (TWAA) in rats, whereas tacrine (9-amino-1,2,3,4-tetrahydroacridine), a drug patented in the USA (trade name Cognex [5]) for the treatment of AD, can compensate these learning disorders [14]. Active avoidance paradigm allows to neglect sedative effect characteristic of some histamine receptor antagonists, including dimebon [3].…”

Effects of 17β-estradiol and its isomer 17α-estradiol on learning in rats with chronic cholinergic deficiency in the brain

“…It was shown that castration of rats for correction of their hormonal status does not change the reaction to AF64A compared to that of intact animals [11]. Neurotoxin AF64A impaired learning and retrieval (Table 1), but practically did not affect the weight of hormone-sensitive organs in castrated animals except for a considerable, but statistically insignificant decrease in the thymus weight (Table 2).…”

“…Under ether anesthesia, treated rats and group 1 control animals were stereotaxically injected (intracerebroventricularly) with 3 nmol AF64A in 3 ~tl CSF; group 2 control rats received 3 pl CSF. Ten-twelve days postinjection, the rats were trained active avoidance task in a shuttle box [ 11 ]. The criterion of conditioning in two-way avoidance paradigm was rat transition to the dark compartment after light signal (conditioned run) preceding electric shock.…”

“…It is interesting to evaluate whether or not estrogens affect cognitive functions in animals, whose physiological state is similar to that in AD. Chronic deprivation of cholinergic functions in the central nervous system produced by intracerebral administration of neurotoxic acetylcholine analogue 1-ethyl-l-(2-hydroxyethyl)-ethylenimine (AF64A) is a common model of AD [5,7,11,15]. In this case, degeneration of acetylcholine nerve endings is accompanied by long-term oxidative stress in damLaboratory of Neurochemistry, Institute of Physiologically Active Substances, Russian Academy of Sciences, Chemogolovka, Moscow region; *Jenapharm, Germany aged structures, in particular in the cortex and hippocampus [7].…”