Presynaptic effects

At low doses, both psychostimulants could theoretically stimulate tonic, extracellular levels of monoamines, and the small increase in steady state levels would produce feedback inhibition of further release by stimulating presynaptic autoreceptors. While this mechanism is clearly an important one for the normal regulation of monoamine neurotransmission, there is no direct evidence to support the notion that the doses used clinically to treat ADHD are low enough to have primarily presynaptic effects. However, alterations in phasic dopamine release could produce net reductions in dopamine release under putatively altered tonic dopaminergic conditions that might occur in ADHD and that might explain the beneficial effects of methylphenidate in ADHD. 

Compared to a,-receptors, a2-receptors have only moderate distribution on the effector tissues however, they have important presynaptic effects. Alpha-one receptors are found on effector tissue cells at the neuroeffector junction the a2-receptors are found on the varicosities of the postganglionic neuron. Norepinephrine released from this neuron not only binds to the a.j-receptors on the effector tissue to cause some physiological effect but also binds to the a2-receptors on the neuron. Alpha-two receptor stimulation results in presynaptic inhibition" or in a decrease in the release of norepinephrine. In this way, norepinephrine inhibits its own release from the sympathetic postganglionic neuron and controls its own activity. Both ar and a2-receptors have equal affinity for norepinephrine released directly from sympathetic neurons as well as circulating epinephrine released from the adrenal medulla. 

The TCA drugs have lost their place as first-line therapy for depression because of their bothersome side effects (Table 33.2) at therapeutic doses and lethal effects in toxic doses. In addition to their presynaptic effects on the neuronal uptake of norepinephrine and serotonin, they block several postsynaptic receptors. They are potent cholinergic muscarinic receptor antagonists, resulting in symptoms such as dry mouth, constipation, tachycardia, blurred vision and urinary retention. Blockade of histamine receptors (Hi) often results in sedation and weight gain. Antagonism of aj-adrenoceptors in the vasculature can cause orthostatic hypotension. 

Gothert M Presynaptic effects of 5-HT, in Aspects of Synaptic Transmission LTP, Galanin, Opioids, Autonomic and 5-HT. Edited by Stone TW. New York, Taylor Francis, 1991, pp 314-329... 

Concentration-dependent presynaptic effects of 2-PAM on the release of acetylcholine from terminals of nerves innervating the rat diaphragm muscle were seen at concentrations of 10- -l0" 3 m 2-PAM stimulated the release of acetylcholine higher concentrations led to a total block of the evoked release of acetylcholine.30> 0... 

GABA (7- aminobutyric acid) May have presynaptic effects on excitatory ENS nerve terminals. Has some relaxant effect on the gut. Probably not a major transmitter in the ENS. 

In myocardial ischemia, several of the mechanisms presented above come into play. First, neuropeptides such as CGRP are released from cardiac sensory C fibers and subsequently release histamine from mast cells as just mentioned. Histamine then can act at least at two presynaptic H3 heteroreceptors on the C fibers to attenuate further neuropeptide release (Section 3.9), and on postganglionic sympathetic fibers to attenuate exocytotic as well as carrier-mediated noradrenaline release (Section 3.3). Both presynaptic effects are potentially beneficial. The H3 receptors are unique in this pattern of effects. Presynaptic adenosine Ai receptors, when activated, also inhibit both exocytotic and carrier-mediated noradrenaline release, but cardiac Ai receptors in addition mediate negative chronotropic and dro-motropic effects. Presynaptic 0C2-adrenoceptors, when activated, reduce exocytotic noradrenaline release but enhance carrier-mediated noradrenaline release (due to stimulation of the Na+/H+ exchanger, Imamura et al. 1996b), which is the major mode of noradrenaline release and the major arrhythmogenic risk in protracted myocardial ischemia (see Levi and Smith 2000 Koyama et al. 2003). 

Ronde P, Nichols RA (1998) High calcium permeability of serotonin 5-HT3 receptors on presynaptic nerve terminals from rat striatum. J Neurochem 70 1094-1103 Rosenstein RE, Chuluyan HE, Cardinali DP (1990) Presynaptic effects of gamma-aminobutyric acid on norepinephrine release and uptake in rat pineal gland. J Neural Transm 82 131—40 Rousseau SJ, Jones IW, Pullar IA, Wonnacott S (2005) Presynaptic [alpha]7 and non-[alpha]7 nicotinic acetylcholine receptors modulate [3H]d-aspartate release from rat frontal cortex in vitro. Neuropharmacology 49 59... 

In some cases, the discovery and characterization of presynaptic receptors established the existence of anew receptor subtype, like the 0C2 adrenoceptor (Dubocovich and Langer 1974 Langer 1974) and histamine H3 receptor (Arrang et al. 1987). It should be noted, however, that the receptor subtypes located presynaptically are also located postsynaptically. The latter should be taken into account in the strategy of discovery and development of new drugs with preferential presynaptic effects. 

Ogura, M., and Kita, H. (2000). Dynorphin exerts both postsynaptic and presynaptic effects in the... 

Another facet of striatal LTP is that potentiation is reliably induced by HFS in the presence of the potassium-channel blocker, tetra-ethyl ammonium (Walsh, 1991 Wickens et al., 1998). By analogy with other systems, this result might be interpreted as an increased influx of calcium into the postsynaptic neuron. However, this does not appear to be the case. Intracellular application of potassium-channel blockers does not facilitate LTP (Wickens et al., 1998), as would be predicted, if these effects were mediated by greater depolarization of the postsynaptic neuron. The facilitation of LTP by extracellular potassium-channel blockers is therefore more likely to be due to presynaptic effects, such as facilitation of dopamine release by prolongation of the action potential in dopaminergic axon terminals. 

Barstad, J.A.B., 1962 Presynaptic effect of the neuro-musclular transmitter. Experlentla 18 579-580. 

Furosemide (40-80 mg) has been reported to enhance and prolong D-tubocurarine-induced block in anephric patients (63). In animals low doses potentiated D-tubocur-arine (and suxamethonium) probably via presynaptic effects, while high doses (1-40 mg/kg in cats) reversed the neuromuscular actions of these relaxants (64). The effects of high doses were similar to those of theophylline. 

Presynaptic effect of morphine and haloperidol on dopamine synthesis Shyu, Bai-Chuang Chiang, Yi Wang, Wei-Kung... 

Ipratropium bromide (ATROVENT, others) is a quaternary ammonium derivative of atropine. Oxitropium bromide is a quaternary derivative of scopolamine. Ipratropium blocks all subtypes of muscarinic receptors and thus blocks presynaptic muscarinic inhibition of ACh release. The most recently developed and bronchoselective member of this family, tiotropium bromide (spiriva), has a longer duration of action and shows some selectivity for Mj and M3 receptors, with lower affinity for receptors, and thus less presynaptic effect on ACh release. 

As in the dorsal striatum, both the acute presynaptic effects of cannabinoids (Hoffman and Lupica, 2001 Robbe et al, 2001) and LTD of excitatory afferents to the nucleus acciunbens (NAc) (Kombian and Malenka, 1994 Robbe, 2002a) have been described. Therefore, it was of considerable interest to determine whether LTD in the NAc was similar to that described in the dorsal striatum, in terms of its dependence upon endocannabinoids. Similar to the dorsal striatum, LTD in the NAc was... 

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