Abstract: N ‐Methyl‐ d ‐aspartate (NMDA) receptors regulating the release of [ 3 H]noradrenaline ([ 3 H]NA) and d ‐[ 3 H]aspartate ( d ‐[ 3 H]Asp) were investigated in superfused slices of rat hippocampus in the presence and absence of nitrergic drugs to examine a possible role for nitric oxide (NO) in the release process. In Mg 2+ ‐free Krebs‐Henseleit buffer, the NMDA‐evoked release of [ 3 H]NA and d ‐[ 3 H]Asp was Ca 2+ dependent and inhibited by the NMDA antagonist (±)‐3‐(2‐carboxypiperazin‐4‐yl)propenyl‐1‐phosphonic acid. NMDA‐stimulated release of [ 3 H]NA was tetrodotoxin (TTX; 0.1–2 µ M ) sensitive, whereas that for d ‐[ 3 H]Asp was TTX insensitive, indicating that the NMDA receptors involved are differentially localized; those for d ‐[ 3 H]Asp appear to be presynaptic, whereas those for [ 3 H]NA are extrasynaptic in location. l ‐Arginine (100 µ M ), the natural precursor of NO synthesis, enhanced NMDA‐evoked release of [ 3 H]NA (100%) and d ‐[ 3 H]Asp (700%). Exogenous NO donors—sodium nitroprusside, 3‐morpholinosyndnomine, and S ‐nitroso‐ N ‐acetylpenicillamine (all 100 µ M )—stimulated the NMDA‐evoked release. An exception was the inhibition by nitroprusside of NMDA‐evoked release of [ 3 H]NA, where the presence of antioxidants may influence channel activity. Inhibitors of NO synthase ( N G ‐nitro‐, N G ‐methyl‐, and N G ‐amino‐ l ‐arginine, all 100 µ M ) attenuated (50–80%) the NMDA‐stimulated release of [ 3 H]NA and d ‐[ 3 H]Asp, as did KN‐62 (10 µ M ), a specific inhibitor of calmodulin kinase II. Our data support roles for the NO transducing system subsequent to the activation of NMDA release‐regulating receptors as both an intraneuronal (presynaptically) and an extraneuronal messenger.
Summary: Local mechanisms that regulate transmitter release at autonomic neuroeffector junctions may be classified into four main types: (a) Automodulation, involving a feedback effect of the transmitter on receptors associated with the prejunctional terminals resulting in a restraint on the facilitation of release that occurs when a train of nerve impulses invades the terminals. Changes in the composition of the transmitter, such as the presence of adrenaline as a cotransmitter together with noradrenaline, can result in increased facilitation of transmission. (b) Transneuronal modulation involving an effect of the transmitter released from terminals of one type on adjacent terminals of another type; thus, noradrenaline release may be inhibited by acetylcholine released from cholinergic nerve terminals adjacent to the noradrenergic terminals. (c) Transjunctional modulation involving a feedback effect on the prejunctional nerve terminals of one or more factors released from effector cells. Such substances include adenyl compounds (adenosine and/or ATP) and metabolites of arachidonic acid. (d) Hormonal modulation involving the action of blood-borne hormones or locally generated hormone-like substances on prejunctional terminals. Some of the substances involved in modulation may act in more than one way; thus, opioids may function as cotransmitters or as hormones, and adenyl compounds may be cotransmitters or be released from effector cells. The effects of exogenous drugs on the substances involved in the modulation of transmission and on the prejunctional receptors for these substances account for many anomalous actions of drugs used or proposed for use in therapeutics.
There is no difference in the affinity and numbers of binding sites for [3H]-(−)-nicotine in homogenates of cerebral cortex from young adult (2–6 months) or aged (18–24 months) rats. Preliminary autoradiographic studies however indicate a greater degree of binding of [3H]-(−)-nicotine to coronal sections of aged rat whole brain. There is no difference in the affinity of d-tubocurarine in displacing [3H]-(−)-nicotine from its binding site in homogenates of rat cortex from young adult or aged rats. Activation of a presynaptic population of nicotine receptors on cortical cholinergic nerves by nicotine enhances [3H] acetylcholine release. At higher frequencies of stimulation, where activation of presynaptic nicotine receptors bv acetylcholine may be occurring, d-tubocurarine inhibits [3H]acetylcholine release.
Local mechanisms that regulate transmitter release at autonomic neuroeffector junctions may be classified into four main types: (a) Automodulation, involving a feedback effect of the transmitter on receptors associated with the prejunctional terminals resulting in a restraint on the facilitation of release that occurs when a train of nerve impulses invades the terminals. Changes in the composition of the transmitter, such as the presence of adrenaline as a cotransmitter together with noradrenaline, can result in increased facilitation of transmission. (b) Transneuronal modulation involving an effect of the transmitter released from terminals of one type on adjacent terminals of another type; thus, noradrenaline release may be inhibited by acetylcholine released from cholinergic nerve terminals adjacent to the noradrenergic terminals. (c) Transjunctional modulation involving a feedback effect on the prejunctional nerve terminals of one or more factors released from effector cells. Such substances include adenyl compounds (adenosine and/or ATP) and metabolites of arachidonic acid. (d) Hormonal modulation involving the action of blood-borne hormones or locally generated hormone-like substances on prejunctional terminals. Some of the substances involved in modulation may act in more than one way; thus, opioids may function as cotransmitters or as hormones, and adenyl compounds may be cotransmitters or be released from effector cells. The effects of exogenous drugs on the substances involved in the modulation of transmission and on the prejunctional receptors for these substances account for many anomalous actions of drugs used or proposed for use in therapeutics.
Abstract Acetylcholine (0·01–10 μmol litre−1) relaxed normal rings (endothelium-retained) of rabbit pulmonary artery precontracted with clonidine (10 μmol litre−1) while preparations with the endothelium removed responded with contraction only. Removal of the endothelium had no effect on contractions of the preparation to clonidine or field stimulation of the adventitial nerves (2 Hz, 10 s). Furthermore, the inhibitory effect of acetylcholine (0·3 and 1·0 μmol litre−1) on contractions induced by field stimulation was not influenced by the vascular endothelium.
The present study examined the effect of a range of doses of chronic nicotine (0.75, 1.5, 3.0 and 30.0 mg kg(-1) day(-1), s.c., 14 days) upon striatal dopaminergic nerve terminal survival following 6-hydroxydopamine (6-OHDA; 10 microg intrastriatal unilaterally) in rats; and the effects of acute nicotine (1 mg kg(-1), s.c.) pretreatment upon striatal neurodegeneration induced by methamphetamine (5 mg kg(-1), i.p., three doses at 2 h intervals) in wild-type and alpha4 nicotinic receptor (nAChR) subunit knockout mice. In both models of Parkinsonian-like damage, loss of striatal dopaminergic nerve terminals was assessed by [(3)H]-mazindol autoradiography. In rats, chronic nicotine infusion delivered by osmotic minipump implanted subcutaneously 7 days prior to intrastriatal 6-OHDA injection produced significant and dose-related protection against 6-OHDA-induced neurodegeneration. Low (0.75 and 1.5 mg kg(-1) day(-1)) but not high (3.0 and 30.0 mg kg(-1) day(-1)) nicotine doses significantly inhibited 6-OHDA-induced degeneration. In wild-type mice, acute nicotine treatment produced significant inhibition of methamphetamine-induced neurodegeneration. In alpha4 nAChR subunit knockout mice, acute nicotine treatment failed to inhibit methamphetamine-induced neurodegeneration. Nicotine is capable of protecting dopaminergic neurons against Parkinsonian-like neurodegeneration in vivo. In rats, this neuroprotective effect is critically dependent upon nicotine dose and is consistent with the activation of nAChRs, as high, desensitizing doses of nicotine fail to be neuroprotective. Further, neuroprotection is absent in alpha4 nAChR subunit knockout mice. The current results therefore suggest that activation of alpha4 subunit containing nAChRs constitutes a major component of the neuroprotective effect of nicotine upon Parkinsonian-like damage in vivo.
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