Hideki Kametani

Acetyl-1-carnitine 2: Effects on learning and memory performance of aged rats in simple and complex mazes

Acetyl-1-carnitine (AC) was administered via drinking water for six months to one group (OLD-AC) of male F-344 rats beginning at 16 months of age, while another group (OLD-CON) of rats was given water only during that period. The rats were maintained on this treatment throughout behavioral testing, which began at 22 months of age. Performance of the OLD-AC and OLD-CON rats was compared to that of young control (YG-CON) rats on the following set of tasks: spontaneous alternation in the arms of a T-maze, two-choice simultaneous discrimination in the stem of a T-maze, rewarded alternation in the arms of a T-maze, spatial discrimination and reversal on a circular platform, spatial working memory in the radial 8-arm maze, long-term memory in the 14-unit T-maze, and for preference of the light or dark chamber of a two-compartment box. AC improved the long-term memory performance in the split-stem T-maze and on the circular platform but had no discernable effects on performance of aged rats in the other tasks. Possible reasons for the selectivity of this agents action on behavior are suggested.

Acetyl-l-carnitine 1: Effects on mortality, pathology and sensory-motor performance in aging rats

Three different test sites assessed the effects of acetyl-1-carnitine (AC) on age-related changes in general health, sensory-motor skills, learning, and memory. Two groups of rats began the experiments at 16 months of age. One group (OLD-AC) was given AC, 75 mg/kg/day, beginning at 16 months. The other group (OLD-CON) was treated identically except it was not given the drug. Beginning at 22 months of age, these rats and a group of young (3-4 months old) rats (YG-CON) were given a series of sensory-motor tasks. AC decreased mortality, and had no reliable effect on body weight, fluid intake, or the general health of the rats. These data indicate that a chronic dose of AC does not interfere with food and water intake, and may increase longevity. An age-related decline of performance occurred in most of the sensory-motor tasks; locomotor activity was reduced in a novel environment and in a runwheel, and the ability to prevent falling was reduced in tests on a taut wire, rotorod, inclined screen, and several types of elevated bridges. An age-related decline of performance did not occur in grooming, or in the latency to initiate several different behaviors. AC had no effect on performance in any sensory-motor task. These data indicate that the improvements produced by AC in some tests of spatial memory may be due to the effects of AC on cognitive abilities rather than on sensory-motor skills.

In Vivo Assessment of Striatal Dopamine Release in the Aged Male Fischer 344 Rat

A microdialysis probe was implanted into the striatum of young (4- to 5-month-old) and aged (26- to 27-month-old) Fischer 344 male rats to assess age-related alterations in striatal dopamine (DA) release. Basal levels of DA and the magnitude of DA response evoked by 50 mM and 100 mM high potassium (K+) in aged rats were similar to those in young rats. Furthermore, K(+)-evoked DA release did not correlate with motor performance within either age group. In contrast, amphetamine (250 microM) evoked-DA release of aged rats was significantly lower than that of young rats. Moreover, the enhancement of K(+)-evoked DA release by oxotremorine (500 microM) was significantly attenuated in aged rats. These results indicate that a putative DA release mechanism and its cholinergic modulation of the aged striatum are impaired.

The reversal effect of antidepressants on the escape deficit induced by inescapable shock in rats

This experiment investigated the effect of antidepressants on the escape deficit induced by inescapable shock. Following exposure te escapable shock, rats received a single injection of either tricyclic antidepressants (imipramine, desipramine), and atypical antidepressant (nomifensine), or saline. In a subsequent two-way shuttle test, treatments with these antidepressants reversed the escape deficit of the “inescapable-shock” groups without affecting performance of the “escapable-shock” groups. It is suggested that catecholamine re-uptake inhibition of the acute actions of antidepressants contributed to this reversal effect. The findings are discussed in relation to the neurochemical hypothesis of the escape deficit induced by inescapable shock and to an animal model of depression.

Parietal cortex lesions do not impair retention performance of rats in a 14-unit T-maze unless hippocampal damage is present

Young male F-344 rats, pretrained in a straight runway to avoid shock, were then trained in a shock-motivated 14-unit T-maze. One day after maze acquisition, extensive parietal cortex lesions (PC) or sham operations (CON) were performed to assess possible involvement of parietal cortex in the age-related impairment previously observed in this task. Twelve days after surgery, a first 10-trial retention session in the 14-unit T-maze was conducted. One day later the vibrissae of half the rats in each group were clipped to examine involvement of the damaged barrel cortex field in maze performance of rats with PC lesions. The following day a second 10-trial retention session occurred. Finally, retention of the straight runway avoidance response was tested. Histological verification revealed a group with consistent parietal damage but also a subgroup with relatively small lesions to dorsal or lateral hippocampus in addition to parietal damage (PC + HIP). Behavioral results revealed virtually perfect maze retention for CON and PC rats. In contrast, PC + HIP rats were severely impaired in maze retention performance. Retention of the straight runway avoidance response was perfect in CON and PC rats but was impaired in PC + HIP rats. Vibrissae clipping did not affect error performance in the maze but led to a transitory increase in runtime. Overall, the results indicate that parietal lobe damage shortly after acquisition does not impair retention performance of young rats in the 14-unit T-maze, unless hippocampal damage is also evident. Thus, parietal lobe dysfunction alone would not appear to be involved in the age-related retention impairment previously observed in this task.

Intracerebroventricular injection of Nω-nitro-l-arginine in rats impairs learning in a 14-unit T-maze

We investigated whether intracerebroventricular (i.c.v.) infusion of the nitric oxide synthase inhibitor, Nomega-nitro-L-arginine (N-Arg), impairs learning in male Sprague-Dawley rats (2-3 months old) in a 14-unit T-maze. Rats were pretrained in one-way active avoidance to a criterion of 13/15 avoidances of foot shock in a straight runway. The next day, rats received i.c.v. injections of either artificial cerebrospinal fluid (aCSF) as controls or N-Arg (12 microg or 15 microg) 30 min before training in the 14-unit T-maze. The learning contingency was to negotiate each of 5 segments within 10 s to avoid footshock during 15 trials. Performance variables included errors (deviations from the correct pathway), runtime from start to goal, and shock frequency and duration. Compared to controls, the number of errors over the last 10 trials was higher in rats receiving 15 microg N-Arg and over the last 5 trials for those given 12 microg. Runtime, shock frequency and duration were increased in both N-Arg groups. The N-Arg-induced (15 microg i.c.v.) impairment could be attenuated when the nitric oxide donor, sodium nitroprusside (1 mg/kg), was administered intraperitoneally 1 min prior to maze learning. In a retention test, rats were treated with either aCSF or 15 microg N-Arg i.c.v. 30 min before being retested in the maze 7-10 d following acquisition training. Under these conditions, maze performance was not significantly affected. These results confirmed previous findings that inhibition of nitric oxide synthase impairs acquisition but not retention. Moreover, the N-Arg-induced learning impairment does not appear to be related to noncognitive aspects of performance.

Comparison of retention performance between young rats with fimbria-fornix lesions and aged rats in a 14-unit T-maze

Young (3-months) and aged (24-months) male F-344 rats were pretrained in one-way active avoidance in a straight runway for 3 days. Then two 10-trial daily sessions were given in a 14-unit T-maze in which the response requirement was to negotiate each of 5 maze segments within 10 s to avoid footshock. One day or one week after acquisition, bilateral electrolytic lesions were made in the fimbria-fornix of young rats (1-day lesion or 1-week lesion). Corresponding sham operations were made for remaining young rats (1-day sham or 1-week sham). Aged animals did not receive any surgical treatment. One week after surgery, a 10-trial retention test was conducted to assess the lesion effects on retention and to manipulate the interval between acquisition and lesions. Aged animals were tested in the maze 1 week after acquisition. Results revealed that rats with fimbria-fornix lesions exhibited significant impairment compared to sham-operated groups on all retention performance measures including errors, runtime, number of shocks, duration of shock, and alternation errors. The number of errors and alternation errors of lesioned animals were still higher than those of sham-operated animals at the second half of the retention test, whereas other non-cognitive measures for lesioned animals recovered to control levels. The interval between acquisition training and lesions had no influence on retention performance. Although performance of aged rats during acquisition and retention trials was significantly worse than that of young controls and lesioned animals, a similar recovery pattern during retention testing was found for young rats with fimbria-fornix lesions and aged rats, i.e. both groups showed significant declines in non-cognitive measures with less decline in cognitive measures. These results suggest that the fimbria-fornix is partially involved in retention of 14-unit T-maze performance and that the age-related retention deficit observed in this task may be related to impaired transmission through this pathway.

Fimbria-fornix lesions in young rats impair acquisition in a 14-unit T-maze similar to prior observed performance deficits in aged rats

Bilateral electrolytic lesions were made in the fimbria-fornix of 3-month-old male Fischer-344 rats. One week after surgery, acquisition in a shock-motivated 14-unit T-maze was assessed in these experimental animals and compared with that of sham-operated and unoperated controls. All animals were pretrained to criterion in one-way active avoidance in a straight runway before receiving two 10-trial daily sessions in the complex maze task in which the response requirement was to negotiate each of five maze segments within 10 sec to avoid footshock. All groups showed high levels of performance in pretraining. In the complex maze, rats sustaining damage to the fimbria-fornix exhibited learning impairments compared with controls in all analyzed performance measures including errors, run time, number of shocks, duration of shock, and alternation errors. The latter measure, which reflected the rat’s tendency to maintain a strategy of alternating responses at the choice-points, showed no evidence of change with training among lesioned animals, whereas control animals demonstrated a dropout of this response strategy. The impairment in maze performance associated with the fimbria-fornix lesions appeared to parallel those previously observed in scopolamine-treated young rats and in aged rats.

Age difference of response strategy in radial maze performance of Fischer-344 rats

Age and sex differences in learning performance in an 8-arm radial maze were examined in Fischer-344 rats (aged: 22-27 months; young: 3-4 months). Results of total responses and initial correct responses showed impaired performance in aged rats. There was a sex difference only in initial correct responses of the aged group. In agreement with findings of previous studies, these results demonstrated deficits of spatial learning performance in aged rats. A response strategy was examined as a factor which may affect radial maze performance. Our results revealed that age groups utilized different response strategies to solve the task and appeared similar to reports of maze performance of young animals with experimentally impaired cholinergic function. The results suggest that age difference in a response strategy is due to deterioration of cholinergic system in aged rats, and factors which may have a relationship with the impaired performance in aged rats were discussed, including alteration of response strategy.

Impaired acquisition in a 14-unit T-maze following medial septal lesions in rats is correlated with lesion size and hippocampal acetylcholinesterase staining

Septohippocampal cholinergic system involvement in acquisition of an aversively motivated 14-unit T-maze was evaluated in 4-month-old male Fischer-344 rats. Each rat was assigned to one of two groups that received either a bilateral electrolytic lesion to the medial septal area (MSA) or a sham operation. One week after surgery, each rat began pretraining in one-way active avoidance (footshock = 0.8 mA) consisting of 10 trials per day on each of 3 consecutive days. Criterion for successful completion of pretraining was 8/10 avoidances on the third day. On the day following completion of pretraining, each rat received 10 trials in a shock-motivated 14-unit T-maze. The performance requirement was to move through each of five maze segments within 10 s to avoid footshock (0.8 mA). A second 10-trial session was provided 24 h later. Performance measures included errors, alternation errors, runtime, shock frequency, and duration. Following maze training, each rat was sacrificed, and formalin-fixed brains were frozen for histology, which included procedures for thionin Nissl and acetylcholinesterase (AChE) staining. MSA-lesioned rats were observed to be significantly impaired on all measures of maze performance compared to sham-operated controls. Densitometric analysis of hippocampal AChE staining revealed a 30% reduction in relative AChE staining of MSA-lesioned rats compared to sham-operated controls. Lesion size was observed to be highly positively correlated with maze errors. A negative correlation of mean error score with density of AChE staining was observed for MSA-lesioned rats, but not for sham-operated rats.(ABSTRACT TRUNCATED AT 250 WORDS)