Yuji Nagawa

Age-related changes in learning and memory in the senescence-accelerated mouse (SAM)

Age-related changes in learning ability were studied in senescence-accelerated mice (SAM) reared under specific pathogen-free (SPF) conditions. SAM-P/8/Ta (SAM-P/8, senescence-prone substrain) showed an age-associated increase in spontaneous motor activity (SMA) compared with SAM-R/1/Ta (SAM-R/1, senescence-resistant substrain) in a novel environment when the activity was measured in the light period, although there was no significant difference in the dark period. In observations of the circadian rhythm of SMA, SAM-P/8 showed a significant increase in diurnal SMA. In SAM-P/8 mice, the acquisition of passive avoidance response was slightly but significantly impaired even at 2 months of age, compared with SAM-R/1 control; the impairment became obvious with aging. In a one-way active avoidance task, SAM-P/8 did not show any impairment in the acquisition of avoidance response at 2 and 4 months of age. However, significant impairment was observed in SAM-P/8 at 12 months of age. The impairments of avoidance tasks were not due to a decrease in shock sensitivity, as indicated by no significant change in the flinch-jump threshold. In a water-filled multiple T-maze task, there was no difference in the number of errors between the two groups. With regard to the performance time to reach the goal, however, SAM-P/8 showed a mild prolongation at 2 months of age, and the prolongation became marked with advancing age.(ABSTRACT TRUNCATED AT 250 WORDS)

Mesolimbic involvement in the locomotor stimulant action of thyrotropin-releasing hormone (TRH) in rats.

Thyrotropin-releasing hormone (TRH) injected i.p. in doses of 5 mg/kg and higher had a strong locomotor stimulant action with development of frequent rearing, mild sniffing, grooming, preening and other excitatory behaviours. The locomotor stimulation was also produced by bilateral injection of TRH and dopamine (DA) into the nucleus accumbens but not by bilateral injection of these substances into the caudate nucleus. Unilateral intracaudate injection of TRH provoked no behavioural changes in contrast to a distinct circling response to similarly injected DA. Either i.p. or bilateral intra-accumbens injection of haloperidol or pimozide on low doses effectively blocked the locomotor stimulant action of TRH. These results indicate that the DA system in the nucleus accumbens may be of importance in mediation of the locomotor stimulant action of TRH. Differential affinity of TRH to the two DA systems, the mesolimbic and nigrostriatal DA systems is also suggested.

Lesioning of the rat basal forebrain leads to memory impairments in passive and active avoidance tasks

Effects of the bilateral electrolytic lesioning of the basal forebrain (BF), including the ventral globus pallidus, on passive or active avoidance tasks, were studied in male Wistar rats. A severe deficit in acquisition of passive avoidance response was produced by the lesioning in the posterior level of BF. The retention of the passive avoidance response was markedly disrupted with post-training lesioning. Time-dependent but only slight recovery from the memory impairments was observed in the passive avoidance task given 4, 8 or 16 weeks after BF lesions. The acquisition of active avoidance response using a two-way shuttle box was also disturbed by BF lesioning. Retention of active avoidance response was clearly impaired by post-training lesions of the BF. The BF lesioned rats gradually acquired the passive avoidance performance when trained repeatedly at 24- or 48-h intervals, by giving a foot shock in case of avoidance failure. Extinction of the acquired passive avoidance response rapidly occurred in the BF lesioned rats. Furthermore, neurotoxic lesions of BF with kainic acid produced a significant impairment in acquisition of passive avoidance response. These results suggest that bilateral BF lesions impair the acquisition and retention of passive or active avoidance response, and that these impaired rats may be useful as an experimental model for Alzheimers disease and senile dementia.

γ-butyrolactone-γ-carbonyl-histidyl-prolinamide citrate (DN-1417) : A novel TRH analog with potent effects on the central nervous system

Abstract A novel TRH analog, γ-butyrolactone-γ-carbonyl-histidyl-prolinamide citrate (DN-1417) with very low TSH-releasing activity markedly increased motor activity in the mice, with and without reserpine administration. DN-1417 also promoted arousal from pentobarbital or ethanol sleep and from loss of consciousness induced by concussive head injury, and reversed hypothermia induced by pentobarbital and reserpine. Circling behavior was provoked by comparatively low doses of DN-1417 in mice with unilateral striatal lesion, and the effect was prevented by pimozide and α-methyl-p-tyrosine. The results indicate that DN-1417 is more potent and longer-acting than TRH in the CNS behavioral paradigms, and that some of the effects may be relevant to central monoaminergic systems.

TRH and its novel analog (DN-1417): antipentobarbital action and involvement of cholinergic mechanisms.

Possible neuroanatomical loci and the mode of action of thyrotropin-releasing hormone (TRH) or its analog, gamma-butyrolactone-gamma-carbonyl-histidyl-prolinamide citrate (DN-1417), in reducing the pentobarbital-induced sleeping time were investigated by using an intracerebral microinjection technique in rats. Intravenous, intraperitoneal or intracerebroventricular (ICV) injection of TRH or DN-1417 produced a dose-related reduction of the sleeping time induced by pentobarbital. TRH or DN-1417 given into the posterior hypothalamic regions including the dorsal premammillary nucleus, lateral hypothalamic area and posterior nucleus of hypothalamus had a significant pentobarbital sleep shortening action in low doses. Injection of these peptides into the dorsomedial nucleus of thalamus, mesencephalic reticular formation, medial septal nucleus or hippocampus was also effective, in comparatively low doses. However, higher doses were required to elicit the effect when the injections were made into the nucleus accumbens, lateral preoptic area or caudate nucleus. In this respect, the parietal cortex was insensitive to TRH or DN-1417. The pentobarbital sleep shortening action of TRH or DN-1417 injected peripherally or into the hypothalamic regions was markedly antagonized by ICV or intrahypothalamic pretreatment with atropine methyl bromide. On the contrary, ICV injection of atropine methyl bromide had a weak or no antagonizing action on the effect of TRH injected ICV or into the reticular formation, medial septal nucleus or hippocampus. These results suggest that possible neuroanatomical sites mediating the pentobarbital sleep shortening action of TRH or DN-1417 may be posterior hypothalamic regions, dorsomedial nucleus of thalamus, reticular formation, medial septal nucleus or hippocampus. A cholinergic mechanism may also be involved in the effect of TRH on the hypothalamus.

Thyrotropin-releasing hormone (TRH) and its analog (DN-1417): Interaction with pentobarbital in choline uptake and acetylcholine synthesis of rat brain slices

TRH or its analog DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-proliamide) given 15 min after intravenous (i.v.) administration of pentobarbital (30 mg/kg) markedly shortened the pentobarbital-induced sleeping time in rats. This effect was almost completely abolished by intracerebroventricular pretreatment with atropine methylbromide (20 micrograms/rat), thereby suggesting the involvement of cholinergic mechanism. The action mechanism was investigated using rat brain slices. TRH (10(-6)-10(-4)M) or DN-1417 (10(-7)-10(-5)M) caused significant increases in the uptake of [3H]-choline into striatal slices. TRH(10(-4)M) or DN-1417(10(-5)M) also stimulated the conversion of [3H]-choline to [3H]-acetylcholine in striatal slices. A 30% reduction of acetylcholine synthesis from [3H]-choline in hippocampal slices and a 40% reduction of [3H]-choline uptake in slices of cerebral cortex, hippocampus and hypothalamus were observed in rats pretreated with pentobarbital (60 mg/kg, i.v.). TRH or DN-1417 (20 mg/kg, i.v.) given 15 min after the administration of pentobarbital markedly reversed both of the pentobarbital effects. Direct application of pentobarbital (5 X 10(-4)M) to slices in vitro also caused a 20-40% reduction of [3H]-choline uptake of cerebral cortex, hippocampus and diencephalon. A concomitant application of TRH(10(-4)M) or DN-1417(10(-5)M) and pentobarbital abolished the pentobarbital effect. These results provide neurochemical evidence that the antagonistic effects of TRH and DN-1417 on pentobarbital-induced narcosis are closely related to alterations in the rat brain choline uptake and acetylcholine synthesis, which are considered to be measures of the activity of cholinergic neurons.

A TRH analog (DN-1417): Motor stimulation with rearing related to catecholaminergic mechanisms in rats

The effect of an analog of TRH, gamma-butyrolactone-gamma-carbonyl-histidyl-prolinamide citrate (DN-1417) on motor activity was studied in rats. Peripheral administration of DN-1417 (0.2-20 mg/kg, i.p.) caused a significant, dose-dependent increase in total spontaneous motor activity, with a definite increase in rearing behaviour. Both increases in spontaneous motor activity and rearing behaviour were markedly inhibited by pretreatment with chlorpromazine (1, 5 mg/kg, i.p.), haloperidol (0.1, 0.5 mg/kg, i.p.), pimozide (1 mg/kg, i.p.) or alpha-methyltyrosine (250 mg/kg, i.p.). Only stimulation of rearing behaviour was selectively attenuated by phenoxybenzamine (5 mg/kg, i.p.) or FLA-63 (25 mg/kg, i.p.) at doses producing no significant effect on spontaneous motor activity. Although propranolol (10 mg/kg, i.p.) and methysergide (10 mg/kg, i.p.) had no effect, atropine (10 mg/kg, i.p.) and mecamylamine (10 mg/kg, i.p.) respectively potentiated and counteracted the effects of DN-1417. Concerning the stimulation of spontaneous motor activity, the nucleus accumbens and lateral hypothalamic area were most sensitive to DN-1417, and the lateral hypothalamic area was the most sensitive site for the stimulation of rearing. Furthermore, DN-1417 (5 X 10(-5) M) significantly enhanced the spontaneous release of [3H]dopamine from the rat nucleus accumbens slices in vitro. These findings indicate that the motor stimulatory action of DN-1417 appears to be mediated primarily via a dopaminergic mechanism by enhancing the release of dopamine from nerve terminals, including the nucleus accumbens in the mesolimbic dopamine system, and, in turn, the rearing may be mediated via noradrenergic mechanism.

Cerebral embolization leads to memory impairment of several learning tasks in rats

The effects of cerebral embolization, produced by injecting microspheres into the left internal carotid artery, on passive and active avoidance tasks and water filled multiple T-maze task, were studied in male Wistar rats. The rats with cerebral embolization were markedly impaired acquisition and retention of the one-trial passive avoidance response. The impairment depended on the number of microspheres injected and continued for 2 weeks. The cerebral embolized rats were also impaired acquisition of two-way active avoidance response in a shuttle box. These impairments are not due to decrease in shock sensitivity, because there was no significant change in the flinch-jump threshold. The embolized rats also exhibited a significant disturbance in performance of water filled multiple T-maze learning. These results suggest that rats with cerebral embolization are impaired in three different types of learning tasks, and may be useful as an animal model for the vascular type of dementia.

Idebenone improves learning and memory impairment induced by cholinergic or serotonergic dysfunction in rats

The effects of idebenone, a cerebral metabolic enhancer, on learning and memory impairment in two rat models with central cholinergic or serotonergic dysfunction were investigated using positively reinforced learning tasks. A delayed alternation task using a T maze was employed to test the effect of idebenone on short-term memory impairment induced by a cholinergic antagonist, scopolamine. A correct response, defined as a turn toward the arm opposite to that in the forced run, was rewarded with food pellets. Scopolamine (0.2 and 0.5 mg/kg, i.p.) significantly decreased the correct responses to the chance level in the 60-s-delayed alternation task. The scopolamine (0.2 mg/kg, i.p.)-induced impairment of short-term memory was improved by idebenone (3-30 mg/kg, i.p.) or an acetylcholinesterase inhibitor, physostigmine (0.1 and 0.2 mg/kg, i.p.), administered simultaneously. The central serotonergic dysfunction model was produced by giving rats a diet deficient in tryptophan, a precursor of serotonin. The rats fed on a tryptophan-deficient diet (TDD) showed a slower learning process in the operant brightness discrimination task (mult V115 EXT) than did rats fed on a normal diet. Idebenone (60 mg/kg/day) admixed with the TDD decreased the number of lever-pressing responses emitted during the extinction periods. The percentage of correct responses was significantly higher in the idebenone-treated group than in the control TDD group. These results suggest that idebenone may improve both the impairment of short-term memory induced by a decreased cholinergic activity and the retardation of discrimination learning induced by central serotonergic dysfunction.

Effects of idebenone on memory impairment induced in ischemic and embolization models of cerebrovascular disturbance in rats

Two rat models of memory impairment in passive avoidance learning induced by cerebrovascular disturbance, were established to estimate the effects of a cerebral metabolic enhancer, idebenone. Transient and global cerebral ischemia in rats, produced by 4-vessel occlusion for 200 s immediately after the acquisition trial of passive avoidance learning, shortened the latencies in the retention test trial performed 24 h later. This retrograde amnesia was reversed significantly by idebenone administered orally or intraperitoneally at the doses of 10 and 30 mg/kg before the retention test trial. Idebenone at a dose of 10 mg/kg, given intraperitoneally before or immediately after the ischemia, also markedly inhibited the appearance of amnesia. In the second model, permanent and cerebral hemisphere embolization produced by injecting 2,000 microspheres into the internal carotid artery, significantly impaired passive avoidance learning performed 7 days later. The repeated administration of idebenone (30 mg/kg, i.p.). once a day after the embolization, significantly improved the impairment of passive avoidance learning in the embolized rats. Furthermore, physostigmine and arginine-vasopressin as reference compounds improved the impairment of passive avoidance learning in these models. These findings suggest that idebenone ameliorates memory impairment induced by cerebral vascular disturbance in rats.