James J. Chrobak

Intraseptal administration of muscimol produces dose-dependent memory impairments in the rat.

The present study examined the effects of intraseptal administration of the GABAergic agonist muscimol on performance of a radial-arm maze (RAM) task. Male Long-Evans rats were trained to perform a RAM task in which a 1-h delay was imposed between the sample and the test session. In this task rats have access to four out of eight maze arms during a predelay session. Following a 1-h delay, rats are returned to the maze and allowed to freely choose among all eight arms. Arms not blocked during the predelay session are baited, and entry into an arm chosen during the predelay session or a repeated entry into a postdelay chosen arm constitutes an error. Following acquisition, animals were implanted with a single cannula aimed at the medial septum. A within-subjects design was utilized to examine the effects of intraseptal administration of muscimol (0.0, 0.75, 1.5 or 3.0 nmol) on performance in this task. All drugs or artificial cerebrospinal fluid were administered immediately following the predelay session. Muscimol, a GABA-A agonist, produced a dose-dependent impairment in maze performance as evidenced by fewer correct choices in the first four postdelay choices and an increase in the number of errors. Intraseptal administration of muscimol did not significantly alter latency per choice on the RAM task nor did it affect locomotor activity levels. Muscimol-induced impairments were also observed when a 4-h delay was imposed between the fourth and the fifth maze selection, suggesting that the behavioral deficit represents an inability to store or retain spatial working memories rather than a general performance deficit. These data indicated that pharmacological manipulation of GABA-A receptors within the medial septum modifies working memory processes. The potential interaction of GABAergic and cholinergic mechanisms in the modulation of working memory processes is discussed.

AF64A-induced working memory impairment: behavioral, neurochemical and histological correlates

The present studies examined the behavioral, neurochemical and histological consequences of intraventricular administration of ethylcholine aziridinium ion (AF64A). Male Long-Evans rats were trained to perform a radial arm maze task in which a one hour delay was imposed between the fourth and fifth arm selections. Following acquisition, animals were bilaterally injected with AF64A (3 nmol/side) or CSF into the lateral ventricles and allowed 14 days to recover before behavioral testing resumed. AF64A-treated animals were markedly impaired in their ability to perform this working/episodic memory task at a variety of delay intervals. In contrast to a long-lasting impairment on the radial maze task, these animals showed no impairment in their ability to acquire a simple discrimination task (reference/skill memory). Neurochemical analysis revealed a significant (50%) decrease in choline acetyltransferase (ChAT) activity in the hippocampus (HPC) 90 days following surgery. ChAT activity was not affected in the striatum, frontal and parietal cortices, cingulate or amygdala. Regional concentrations of catecholamines and indoleamines were not affected in any of these brain regions. Histological analysis of animals receiving unilateral injections of AF64A (3 nmol) into the right lateral ventricle revealed decreases in ChAT-immunoreactive (ChAT-IR) cells within the medial septum/vertical limb diagonal band (MS/VLDB), but not in nucleus accumbens, striatum or basal nucleus regions. These data suggest that: (1) intraventricular administration of AF64A can markedly impair working/episodic, as opposed to reference/skill memory, processes; (2) AF64A can be used to selectively alter presynaptic cholinergic indices within the hippocampus; and (3) the behavioral deficits resulting from AF64A administration are most likely a consequence of altered septohippocampal cholinergic function.

AF64A (ethylcholine aziridinium ion), a cholinergic neurotoxin, selectively impairs working memory in a multiple component T-maze task

The present study examined the nature of the cognitive deficits associated with a selective decrease of cholinergic activity in the hippocampus. Male Fischer rats were trained to perform a multiple component T-maze task which simultaneously assessed their ability to perform on the basis of trial-specific information (working memory) and trial-independent information (reference memory). Following 125 acquisition trials rats were bilaterally injected with AF64A (3 nmol/side) or artificial CSF into the lateral ventricles and allowed 14 days to recover before behavioral testing resumed. The controls rapidly returned to their preoperative level of performance on both components of the maze task. AF64A-treated animals were transiently impaired on the reference memory task. Their performance rapidly improved and they were performing at preoperative levels within 4 days of testing. In contrast, these animals exhibited a marked and long-lasting impairment in their performance of the working memory component. After behavioral testing was completed, neurochemical analysis revealed that AF64A produced a significant decrease in choline acetyltransferase (ChAT) activity in the hippocampus (43%) 42 days following surgery. This dosing regimen produced no alterations of striatal or cortical ChAT activity. These data suggest that alterations of hippocampal cholinergic activity severely impair an animals ability to perform working memory tasks.

Hemicholinium-3 prevents the working memory impairments and the cholinergic hypofunction induced by ethylcholine aziridinium ion (AF64A)

The present study examined whether intraventricular administration of the potent high affinity choline transport (HAChT) inhibitor hemicholinium-3 (HC-3) would attenuate the memory impairments and the neurochemical deficits induced by i.c.v. ethylcholine aziridinium ion (AF64A). Male Sprague-Dawley rats were trained to perform a delayed-non-match to sample radial arm maze (RAM) task in which a 1-h delay was imposed between the fourth and fifth arm selections. Following 30 acquisition trials, animals were bilaterally injected with AF64A (3 nmol/side) or AF64A preceded by HC-3 (20 micrograms/side) into the lateral ventricles and allowed 7 days to recover before behavioral testing resumed. Control animals received either artificial cerebrospinal fluid or HC-3. AF64A-treated rats were significantly impaired in their performance of the RAM task as evidenced by fewer correct choices following the delay and more total errors to complete the task. This behavioral deficit was associated with a significant (32%) decrease in HAChT in the hippocampus. In contrast, animals pretreated with HC-3 exhibited no significant decreases in HAChT or decrements in RAM performance. These findings indicate that the memory deficits resulting from intraventricular administration of AF64A are a consequence of the compounds cholinotoxic properties and in particular its interaction with the HAChT carrier. Furthermore they demonstrate that a select alteration of septohippocampal cholinergic activity is sufficient to disrupt working memory processes.

The use of the radial arm maze in neurotoxicology

The neurotoxicity of a variety of compounds may be uniquely expressed in their ability to disrupt cognitive function. The development of sophisticated behavioral tasks to assess cognitive and mnemonic function in rodents provides necessary tools for addressing these effects. The radial arm maze has been increasingly utilized to examine the psychological and neurobiological substrates of cognitive function. This paper critically examines the usefulness of this task in determining (1) the neurotoxicity of suspected neurotoxic compounds, (2) the neural systems which appear to be uniquely susceptible to a variety of toxicants and degenerative processes, and (3) the degree of behavioral and neural plasticity following neurotoxic insult. It is concluded that the radial arm maze provides an important tool that can be used to address several of the fundamental problems in neurotoxicology.

Dose- and delay-dependent working/episodic memory impairments following intraventricular administration of ethylcholine aziridinium ion (AF64A).

The present study examined the effects of intraventricular administration of the cholinergic neurotoxin ethylcholine aziridinium ion (AF64A) on performance of a radial arm maze task. Male Sprague-Dawley rats were trained to perform a delayed-nonmatch to sample radial arm maze task in which a 1-h delay was imposed between the fourth and fifth arm selections. Following acquisition, animals were injected bilaterally with AF64A (1.5 or 0.75 nmol/side) or artificial cerebrospinal fluid into the lateral cerebral ventricles and allowed 7 days to recover before behavioral testing resumed. Significant dose- and delay-dependent impairments in the radial maze performance were observed in AF64A-treated rats as evidenced by fewer correct choices following the delay and by more errors to complete the task. Long-term testing in this task revealed significant recovery of memory performance. These findings indicate dose-dependent impairments in memory following intraventricular administration of AF64A and spontaneous behavioral recovery following such insult.