Effect Of Nicotinic Receptor Stimulation Research Articles

P4-266: Protective effects of nicotinic receptor stimulation with nicotine or acetylcholinesterase inhibitors against beta amyloid- or glutamate-induced neuronal death

P4-266: Protective effects of nicotinic receptor stimulation with nicotine or acetylcholinesterase inhibitors against beta amyloid- or glutamate-induced neuronal death

Investigation of endogenous neurotransmitters of guinea pig gallbladder using nicotinic agonist stimulation.

Gallbladder motility is modulated by intrinsic nerves, the identities of which are not well established. The aim of this study was to determine the effect of nicotinic receptor stimulation of intrinsic nerves on gallbladder muscle contractility. Guinea pig gallbladder muscle strips were studied in vitro. Histamine 1 microM was used to increase baseline tone. The nicotinic receptor agonist, 1,1-dimethyl-4-phenylpiperazinium (DMPP), produced a biphasic response characterized by an initial transient contraction followed by a sustained relaxation. The initial contraction was inhibited by the neural blocker tetrodotoxin, the nicotinic antagonist hexamethonium, and the muscarinic antagonist atropine, but not by a substance P receptor antagonist or a bombesin receptor antagonist. The relaxation response to DMPP was not affected by tetrodotoxin, but was reduced by hexamethonium and omega-conotoxin GVIA, an inhibitor of neurotransmitter release. The relaxation response was reduced by the nitric oxide synthase inhibitor L-NAME, but not by a vasoactive intestinal peptide antagonist or propranolol. DMPP produces a biphasic response in the guinea pig gallbladder. The initial contractile response is mediated by nicotinic receptors on the cell body or axon of cholinergic nerves. The relaxation response appears to result, in part, from activation of nicotinic receptors on nerve terminals of nitric oxide-releasing nerves. These results suggest nicotinic receptors have heterogeneity in location depending on excitatory or inhibitory neuronal function.

Effect of nicotine on dopaminergic-cholinergic interaction in the striatum

We have investigated the effect of nicotinic receptor stimulation on acetylcholine (ACh) release measured by radioassay in rat striatal slices. Since the release of ACh in the striatum is tonically inhibited by endogenous dopamine and nicotine enhances the release of dopamine, we studied the release of ACh when the dopaminergic input was impaired. We used chemical denervation (6-hydroxydopamine pretreatment) or D 2-receptor-blockade by sulpiride to remove the dopaminergic control of the cholinergic neurons. In our experiments nicotine failed to increase ACh release from striatal slices taken from rats whose dopaminergic-cholinergic interaction was not impaired but it enhanced the release of ACh from slices dissected from 6-hydroxydopamine pretreated rats or in the presence of sulpiride. Our results provide neurochemical evidence for the existence of nicotinic receptors on striatal cholinergic interneurons. Since the spontaneous release of ACh enhanced by nicotine was inhibited by tetrodotoxin it seems very likely that (−)-nicotine acts on the somatodendritic part of cholinergic interneurons.

Pharmacology of nicotinic receptor‐mediated inhibition in rat dorsolateral septal neurones.

1. Intracellular electrophysiological techniques were employed to investigate the effects of nicotinic receptor stimulation on rat dorsolateral septal nucleus (DLSN) neurones in a submerged rat brain slice preparation. 2. Acetylcholine (in the presence of the muscarinic antagonist, atropine), nicotine or dimethylphenylpiperazinium (DMPP), applied either by pressure ejection or superfusion, produced predominantly a membrane potential hyperpolarization. 3. Following concentration-response comparisons, DMPP appeared to exhibit fewer desensitizing properties and greater efficacy than nicotine with half-maximal hyperpolarizing responses attainable at 3 and 10 microM, respectively. 4. Pharmacological analyses revealed that the agonist-induced membrane hyperpolarization was sensitive to antagonism by mecamylamine (50-100 microM) and neuronal bungarotoxin (0.2-0.3 microM), but not alpha-bungarotoxin (0.5-1.0 microM), curare (10-50 microM) or dihydro-beta-erythroidine (50-100 microM). 5. Hyperpolarizing responses to DMPP were found to reverse near the equilibrium potential for potassium and were sensitive to changes in extracellular potassium concentration as predicted by the Nernst equation. Under single-electrode voltage clamp, application of DMPP produced an outward current (75-100 pA) which approached reversal at around -88 mV. These findings indicated that the hyperpolarizing response to nicotinic receptor stimulation was mediated by changes in membrane permeability to potassium. 6. DMPP-induced membrane hyperpolarization resulted from a direct action on postsynaptic DLSN neurones since the response persisted under conditions of superfusion with calcium-free/high-magnesium media or tetrodotoxin; both conditions blocked orthodromically induced neurotransmission. The hyperpolarizing response remained unaltered in TTX but was diminished in calcium-free/high-magnesium media. Further studies revealed blockade of the DMPP response following intracellular injection of EGTA. This response was also sensitive to antagonism by various calcium-dependent potassium channel blockers including apamin, barium and tetraethylammonium. 7. Our studies reveal a novel class of CNS nicotinic receptor whose action upon stimulation by an agonist results in a membrane hyperpolarization via a calcium-dependent increase in potassium ion conductance.

Action of agonists and antagonists at muscarinic receptors present on ileum and atria in vitro.

The action of 'selective' agonists and antagonists at muscarinic receptors mediating ileal contractions, and the rate and force of atrial contractions has been assessed. The effect of nicotinic receptor stimulation, catecholamine release and acetylcholinesterase (AChE) action on muscarinic activity has also been assessed. The nicotinic actions of carbachol did not affect its agonist potency nor the antagonist affinity data obtained when this agonist was used in atrial and ileal preparations. Antagonist data indicated that muscarinic receptors mediating the rate and force of atrial contractions did not differ. Differences in agonist potencies at these two muscarinic receptors were attributable to either differences in intrinsic efficacy or susceptibility to the action of acetylcholinesterase. The small differences in agonist potency observed between atrial and ileal muscarinic receptors were considered not sufficient to indicate receptor heterogeneity. The pirenzepine affinity data indicated that all three receptors are of the M2 type. Affinity data using secoverine and 4-diphenyl-acetoxy-N-methyl piperidine methiodide indicated that ileal and atrial muscarinic receptors differ. Data obtained using gallamine, pancuronium and stercuronium cannot be regarded as indicative of receptor affinity since the antagonism is not competitive; it did nonetheless corroborate the conclusion that ileal and atrial muscarinic receptors are different.

Nicotinic receptor stimulation activates enkephalin release and biosynthesis in adrenal chromaffin cells.

Neuroendocrine cells release a portion of their stored secretory hormone content when exposed to tissue-specific secretagogues. In the case of the adrenal medulla, catecholamines and enkephalin peptides, as well as other secretory proteins, are secreted in response to acetylcholine, which is released onto cholinergic receptors on chromaffin cells upon splanchnic nerve stimulation in vivo. Secretagogue stimulation thus depletes intracellular stores of exportable hormone. We were interested to know whether the signal for exportable hormone release might also function as a signal for compensatory hormone repletion by enhancing the biosynthesis of the released hormone(s). Accordingly, we have investigated the effect of nicotinic receptor stimulation on Met-enkephalin peptide biosynthesis and expression of proenkephalin messenger RNA in primary cultures of bovine chromaffin cells. Our results, reported here, suggest a model for stimulus-secretion-synthesis coupling in which nicotinic receptor occupancy activates two pathways. One pathway, dependent on calcium and not mimicked by increased intracellular cyclic AMP, leads to exocytotic hormone release; the other, probably via a calcium-dependent increase in intracellular cyclic AMP, leads to a compensatory increase in intracellular enkephalin through activation of transcription of the proenkephalin structural gene.

Regulation of Gastrin and Somatostatin Secretion, by Intramural Neurons: Effect of Nicotinic Receptor Stimulation With Dimethyl-Phenylpiperazinium

The nicotinic receptor agonist, 1,1-dimethyl-4-phenylpiperazinium was used to examine the intramural neural regulation and the functional linkage of gastrin and somatostatin the isolated vascularly perfused rat stomach. 1,1-Dimethyl-4-phenylpiperazinium (10(-5) to 10(-4) M) caused a biphasic dose-dependent increase in gastrin secretion. The gastrin response was abolished by hexamethonium but only partly inhibited (35% at the higher dose of 1,1-dimethyl-4-phenylpiperazinium) by atropine. The same dose of atropine inhibited the maximal gastrin response to the muscarinic agonist, methacholine, by 80%. From this it was concluded that 1,1-dimethyl-4-phenylpiperazinium activates intramural cholinergic and noncholinergic neurons to cause gastrin secretion, 1,1-dimethyl-4-phenylpiperazinium also caused a biphasic, dose-dependent increase in somatostatin secretion. The somatostatin response was completely inhibited by atropine and hexamethonium. Since muscarinic cholinergic agonists cause inhibition of somatostatin secretion, the observed net increase in somatostatin suggests that 1,1 dimethyl-4-phenylpiperazinium activated predominantly a noncholinergic stimulatory neuron. It is hypothesized that this neuron is identical to the gastrin-stimulating noncholinergic neurons and that it releases bombesin, a stimulant of gastrin and somatostatin secretion known to be present in gastric mucosal nerve terminals. The results of this study are consistent with a previously proposed model according to which gastrin secretion is regulated by the activity of two interdependent intramural neurons: a cholinergic neuron that causes gastrin secretion via inhibition of somatostatin and a noncholinergic neuron that releases a synergistic, direct stimulant of gastrin secretion, most likely bombesin.