Cortical High-affinity Choline Uptake Research Articles

Effects of S-8510, a novel benzodiazepine receptor partial inverse agonist, on basal forebrain lesioning-induced dysfunction in rats

We investigated the effects of a novel benzodiazepine partial inverse agonist, S-8510 (2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo [4,5-d] pyrano [4,3-b] pyridine monophosphate monohydrate), on the impairment of spatial memory, decreased high-affinity choline uptake and acetylcholine release in basal forebrain-lesioned rats. S-8510 (3 and 5 mg/kg, p.o. 30 min before each training session) significantly ameliorated the basal forebrain-lesion-induced impairment of spatial memory in water maze task. In vivo brain microdialysis studies showed that systemic administration of S-8510 at 3 and 10 mg/kg significantly increased the release of acetylcholine in the front-parietal cortex in basal forebrain-lesioned rats. Further, repeated administration of S-8510 (3 and 10 mg kg −1 day −1 for 5 days) reversed the decrease in cortical high-affinity choline uptake induced by basal forebrain lesion. Thus, S-8510 improved the spatial memory impairment induced by lesion of the basal forebrain in rats. In addition, it increased acetylcholine release and high-affinity choline uptake from the cortex, a region closely associated with memory, in basal forebrain-lesioned rats. These results indicate that S-8510 has cognition enhancing and cholinergic-activating effects in the basal forebrain-lesioned rats, suggesting that this agent may be useful for the treatment of mild to moderate senile dementia including Alzheimer's disease.

Repeated administration of tacrine to normal rats: Effects on cholinergic, glutamatergic, and GABAergic receptor subtypes in rat brain using receptor autoradiography

Tacrine, a potent acetylcholinesterae inhibitor, has been reported to improve cognitive function in patients with Alzheimer's disease. The present investigation was conducted to elucidate in vivo any interaction between tacrine-induced cortical cholinergic hyperactivity and glutamatergic and GABAergic neurotransmission, which might influence the therapeutic potential of tacrine. Seven days after a daily dosage of 10 mg/kg tacrine i.p. quantitative receptor autoradiography was performed in coronal sections throughout the brain. Repeated administration of tacrine resulted in decreased binding to high-affinity choline uptake, nicotinic and M 2-muscarinic acetylcholine receptor sites in a number of cortical regions, while reductions in M 1-muscarinic receptor binding were restricted to the cingulate and entorhinal cortex as well as caudate-putamen. Moreover, tacrine injections decreased cortical AMPA receptor binding throughout the brain, while NMDA, kainate, and GABA A receptor binding remained unchanged. Tacrine administration alters cortical AMPA receptor binding in the opposite direction to that observed in patients with Alzheimer's disease, suggesting that tacrine may exert a reversal in up/down-regulation of cortical glutamate receptor subtypes in Alzheimer patients. However, the drug-induced reductions in cortical high-affinity choline uptake sites as well as in nicotinic and in muscarinic acetylcholine receptor binding might partially counteract the cognition-enhancing effects of tacrine produced by acetylcholinesterase inhibition.

Opioid receptor subtypes mediating the noise-induced decreases in high-affinity choline uptake in the rat brain

Acute (20 min) exposure to 100-dB white noise elicits a naltrexone-sensitive decrease in sodium-dependent high-affinity choline uptake in the frontal cortex and hippocampus of the rat. In the present study, the subtypes of opioid receptors involved were investigated by pretreating rats with microinjection of specific opioid-receptor antagonists into the lateral cerebroventricle before noise exposure. We found that the noise-induced decrease in high-affinity choline uptake in the hippocampus was blocked by pretreatment with either μ-, δ-, or κ-opioid-receptor antagonists, whereas the effect of noise on frontal cortical high-affinity choline uptake was blocked by a μ- and δ- but not by a κ-antagonist. These data further confirm the role of endogenous opioids in mediating the effects of noise on central cholinergic activity and indicate that different neural mechanisms are involved in the effects of noise on the frontal cortical and hippocampal cholinergic systems.

Physical activity effects on hippocampal and parietal cortical cholinergic function and spatial learning in F344 rats

In the present investigation, the effects of physical activity on hippocampal cholinergic function, parietal cortical cholinergic function, and spatial memory were examined in F344 rats. Single bouts of physical activity elevated hippocampal and cortical high affinity choline uptake, whereas chronic physical activity significantly reduced only hippocampal high affinity choline uptake (HACU) and elevated muscarinic (QNB) receptor density. Three weeks prior to the end of the 14-week chronic treadmill running protocol, a group of chronic-run rats and their non-run controls were tested on a stringent version of Whishaw's place learning-set task. Chronic-run rats exhibited enhanced performance on the spatial task by significantly reduced second trial latencies and elevated first and second trial proximity ratio scores. Chronic-run spatial memory tested rats also showed enhanced hippocampal HACU and muscarinic receptor binding. These data indicate that chronic physical activity improves spatial learning performance. This improvement may be due, in part, to a chronic running-induced enhancement of hippocampal cholinergic functioning.

Unilateral and bilateral nucleus basalis lesions: Differences in neurochemical and behavioural recovery

The neurochemical and behavioural recovery following unilateral and bilateral lesions of the nucleus basalis was investigated in adult male Wistar rats 20 days and 6 months after surgery. The lesions were made by stereotaxic injections of ibotenic acid. Twenty days after surgery there was a statistically significant choline acetyltransferase decrease in the frontal and parietal ipsilateral cortex of the unilaterally lesioned rats and in the cortex of both hemispheres after bilateral lesions. Cortical high affinity choline uptake rate was significantly decreased 4 days after lesions but showed a rapid recovery within 20 days post-lesion in unilaterally and bilaterally lesioned rats. However, at this time both groups of lesioned rats showed a marked impairment in the acquisition of passive and active (shuttle-box) avoidance conditioned responses. Six months after surgery the decrease in choline acetyltransferase activity was smaller and statistically significant in the ipsilateral frontal cortex only in the unilaterally lesioned rats and in the frontal and parietal cortex of both hemispheres in the bilaterally lesioned rats. High affinity choline uptake was increased in the contralateral hemispheres of the unilaterally lesioned rats and was significantly larger than in the bilaterally lesioned rats. There was no difference in the acquisition of both passive and active avoidance conditioned responses between the sham operated and unilaterally lesioned rats, while the bilaterally lesioned rats could only negotiate the active avoidance conditioned response. In conclusion, our experiments demonstrate a remarkable neurochemical and behavioural recovery within 6 months in rats with a unilateral lesion of the nucleus basalis and only a limited recovery in the bilaterally lesioned rats.

Effect of quinolinic acid in the nucleus basalis magnocellularis on cortical high-affinity choline uptake.

A transient 45% increase in cortical high-affinity choline uptake (HACU) was observed after an injection of quinolinic acid (QUIN) into the nucleus basalis magnocellularis (nbM) of the rat. This was followed by a steady decline in choline uptake, which resulted in a 46% decrease by day 7. Specific [3H]hemicholinium-3 binding to coronal brain sections showed a similar pattern following injections of QUIN into the nbM. The increase in cortical HACU elicited by QUIN appeared to be dose dependent.