Vimala H. Sethy

CHOLINE: SELECTIVE ACCUMULATION BY CENTRAL CHOLINERGIC NEURONS

Abstract— Most of the cholinergic input to the hippocampus was destroyed by placement of lesions in the medial septal area. In animals with such lesions we found that hippocampal ChAc activity was reduced by 85–90% and endogenous acetylcholine levels were reduced by more than 80 %. When hippocampal synaptosomes from animals with lesions were incubated with [3H]choline at concentrations of 7.5 nm, 1 μm and 10 μm there was approximately a 60 % reduction in the uptake of [3H]choline, suggesting that cholinergic nerve endings were mainly responsible for [3H]choline uptake. At 0.1 mm concentrations of [3H]choline, there was only a 25 % reduction of choline uptake, suggesting that at higher concentrations of choline there was more nonspecific uptake. The uptake of radiolabelled tryptophan, glutamate and GABA were only slightly or not at all affected by the lesions. There was a significant reduction of uptake of radiolabelled serotonin and norepinephrine, since known monoaminergic tracts were disrupted. Choline uptake was reduced only in brain regions in which cholinergic input was interrupted (i.e. the cerebral cortex and hippocampus) and remained unchanged in other regions (i.e. the cerebellum and striatum). The time course of the reduction in choline uptake was similar to that of the reductions in ChAc activity and endogenous ACh levels; there was no decrease at 1 day, a significant decrease at 2 days, and the maximal decrease at 4 days postlesion. There was a close correlation among choline uptake, ChAc activity and ACh levels in the four brain regions examined (i.e. the striatum, cerebral cortex, hippocampus and cerebellum). Our results suggest that when hippocampal synaptosomes (and perhaps synaptosomes from other brain areas as well) are incubated in the presence of choline, at concentrations of 10 μm m or lower, then cholinergic nerve endings are responsible for the bulk of the choline accumulated by the tissue.

Therapy of intention myoclonus with L‐5‐hydroxytryptophan and a peripheral decarboxylase inhibitor, MK 486

Three patients with postanoxic intention myoclonus, two patients with intention tremor, and one patient with cerebral palsy were administered L-5-hydroxytryptophan (L-5HTP), the precursor of serotonin, in combination with MK 486, a peripheral amino acid decarboxylase inhibitor. L-5HTP combined with MK 486 were potent long-term therapeutic agents for postanoxic intention myoclonus, but had no effect on intention tremor or cerebral palsy. These drugs were well-tolerated by the patients and more effective than any other known therapy for intention myoclonus. Cerebrospinal fluid concentration of 5-hydroxyindoleacetic acid, the main catabolite of serotonin, appeared low in two patients with intention myoclonus and increased markedly during drug therapy. Postanoxic intention myoclonus may be causally related to a deficiency of brain serotonin.

Choline and acetylcholine: Regional distribution and effect of degeneration of cholinergic nerve terminals in the rat hippocampus

Abstract The regional distribution of choline and acetylcholine was examined in rat brain. Choline was found to have a distribution similar to that of acetylcholine. With the exception of the cerebellum the ratio of choline to acetylcholine in different brain regions ranged between 2.5 and 3.6. When the majority of the cholinergic nerve endings in the hippocampus were destroyed by placement of a lesion in the medial septal area the concentrations of acetylcholine and choline in the hippocampus were reduced by 70–74 and 20–32 %, respectively. These results suggest that a significant portion of the free choline in brain is associated with cholinergic neurones.

Neuroprotective effects of the dopamine agonists pramipexole and bromocriptine in 3-acetylpyridine-treated rats

The neuroprotective effects of pramipexole, a dopamine agonist, were investigated in 3-acetylpyridine (3-AP)-treated Wistar rats. Bromocriptine was used as a reference compound to compare the results obtained with pramipexole. A significant reduction (P < 0.01) in cerebellar cGMP and ATP was observed 96 h after treatment with 3-AP (500 micromol/kg, i.p.). Both pramipexole and bromocriptine significantly attenuated 3-AP-induced reduction in cerebellar cGMP and ATP. Consistent with the neurochemical effect, both pramipexole and bromocriptine prevented 3-AP-induced loss of motor coordination. 3-Acetylpyridine produced a significant (P < 0.01) loss of neurons in the inferior olivary nucleus. Treatment with pramipexole and bromocriptine partially, but significantly (P < 0.01), prevented the loss of inferior olivary neurons. There was no reduction in the temperature of the animals, indicating that hypothermia was not responsible for neuroprotection.

Antimuscarinic drugs—Effect on brain acetylcholine and tremors in rats

Abstract The effect of cholinergic and antimuscarinic drugs on rat brain acetylcholine (ACh) concentration and on tremors has been studied. The cholinergic drugs (physotigmine and oxotremorine) increased brain ACh concentration and produced tremors. Antimuscarinic drugs (atropine, benztropine and trihexyphenidyl) decreased brain ACh concentration, blocked oxotremorine-induced tremors and prevented the oxotremorine- induced increase in brain ACh. Physostigmine-induced tremors and elevation in brain ACh concentration were not altered by pretreatment with benztropine and trihexyphenidyl. However, atropine reduced physostigmine-induced tremors and prevented the increase in brain ACh concentration. The results suggest that oxotremorine- and physostigmine-induced tremors are causally related to an increase in brain ACh concentration.

Effect of anesthetic doses of γ-hydroxybutyrate on the acetylcholine content of rat brain

SummaryGamma-hydroxybutyrate administered in anesthetic doses produces a time dependent increase in the levels of rat brain acetylcholine. A maximal increase in whole brain and subcortical levels of acetylcholine is observed about 15 min after administration of the lactone form of the drug. A similar GHB-induced increase in acetylcholine is observed in the striatum and a 75% increase in the hippocampus 15 min after administration of the drug. A good temporal correlation was not obtained between the increase in acetylcholine and the depth of anesthesia produced by the drug. Gamma-hydroxybutyrate did not cause a significant change in the striatal or hippocampal levels of choline. Possible mechanisms involved in the production of this increase in acetylcholine are discussed.

Effect of l-DOPA on brain acetylcholine and choline in rats

Abstract The effect of acute and chronic administration of l -DOPA on brain acetylcholine and choline was investigated in male rats. A single injection of l -DOPA had no effect on the concentration of acetylcholine in the brains of normal, oxotremorine and physostigmine treated animals. Chronic treatment with l -DOPA produced a small but significant increase in brain acetylcholine concentrations; however, brain choline concentrations were unchanged. The increase in brain acetylcholine may be due to an inhibitory effect of dopamine on central cholinergic neurons.

U-95666E: a potential anti-parkinsonian drug with anxiolytic activity.

1. U-95666E, a D2 selective dopamine agonist, was investigated for its effect on rat striatal acetylcholine (ACh) concentration and the results were compared with those obtained with pergolide, pramipexole and bromocriptine under similar conditions. 2. U-95666E, pergolide, pramipexole and bromocriptine dose-dependently increased striatal ACh concentration both in the non-reserpinized and reserpinized rats. 3. Intrinsic activity of U-95666E was similar to pergolide and pramipexole in non-reserpinized rats, but significantly lower in reserpinized rats. 4. The sensitivity of these dopamine agonists for increasing ACh levels in the denervated as compared to innervated striatum were significantly (p < 0.01) higher. 5. U-95666E also has anxiolytic activity in mice. 6. In conclusion, U-95666E may have potential for the treatment of Parkinsons Disease and associated anxiety.

BRAIN ACETYLCHOLINE AND CHOLINESTERASE: EFFECT OF PHENOTHIAZINES AND PHYSOSTIGMINE INTERACTION IN RATS1

Abstract— The effect of phenothiazines either alone or in combination with physostigmine on whole brain acetylcholine concn and cholinesterase activity has been investigated in male rats. Phenothiazines (chlorpromazine, trifluperazine and thioridazine) when injected alone had no significant effect on brain acetylcholine concentration. Pretreatment with chlorpromazine and thioridazine significantly enhanced the physostigmine‐induced increase in brain acetylcholine concn and inhibition of cholinesterase activity. However, trifluperazine had no significant effect on the physostigmine‐induced increase in brain acetylcholine concentration and inhibition of cholinesterase activity. The potentiation of the physostigmine‐induced increase in brain acetylcholine concn by phenothiazines may be due to (1) increased acetylcholine turnover secondary to the blockade of dopamine receptors by neuroleptic drugs and.

Neuroprotective effects of the GABAA receptor partial agonist U-101017 in 3-acetylpyridine-treated rats

The neuroprotective effects of U-101017, [7-chloro-5-[cis-3,5-dimethylpiperazine)carbonyl]-imidazole[1,5a]quinoli ne-3-carboxylate], a GABA(A) receptor partial agonist, were investigated in 3-acetylpyridine (3-AP) treated Wistar rats. A significant (P < 0.01) reduction in both cGMP and ATP in the cerebellum was observed at 96 h after treatment with 3-AP (500 micromol/kg i.p.). Oral administration of U-101017 before and after treatment with 3-AP significantly attenuated 3-AP-induced decreases in cGMP and ATP, and this effect was dose related. Consistent with the neurochemical effect, U-101017 prevented 3-AP-induced loss of motor coordination. Treatment with U-101017 partially, but significantly (P < 0.01) prevented the loss of inferior olivary neurons. U-101017 had no significant effect on body temperature. Thus, hypothermia was not involved in neuroprotective effects of U-101017. Co-administration of flumazenil with each treatment of U-101017 blocked the neuroprotective effect of U-101017, indicating that it mediated neuroprotection via the benzodiazepine binding sites on the GABA(A) receptor complex. Delayed administration of U-101017 at various time intervals after treatment with 3-AP demonstrated a significant neuroprotective effect even at 8 h, suggesting that this drug has a wide therapeutic window.