Brain presynaptic effects

Aschner M, Clarkson TW (1989) Methylmercury uptake across bovine brain capillary endothelial cells in vitro the role of amino acid. Pharmacol Toxicol 64 293-297 Atchison WD, Narahashi T (1982) Methylmercury-induced depression of neuromuscular transmission in the rat. Neurotoxicology 3 37-50 Atchison WD, Clark AW, Narahashi T (1984) Presynaptic effects of methylmercury at the mammalian neuromuscular junction. In Narahashi T (ed) Cell and mol neurotoxicol. Raven, New York, pp 23-43 Ballatori N, Clarkson TW (1983) Biliary transport of glutathione and methylmercury. Am J Physiol 244 G435-G441... 

Brain slices provide an excellent environment in which to study presynaptic effects. The slicing procedure conserves most of the structural integrity within the slice but removes all extrinsic interaction, i.e., postsynaptic effects. This allows all alteration of neurotransmission to be attributed solely to presynaptic effects. This is especially important when studying autoreceptors, as D2 and Dj receptors are found both as presynaptic autoreceptors and post-synaptic receptors. Therefore any agonist that stimulates these receptors may have both presynaptic and postsynaptic effects in the intact animal. 

It is possible to deplete the brain of both DA and NA by inhibiting tyrosine hydroxylase but while NA may be reduced independently by inhibiting dopamine jS-hydroxylase, the enzyme that converts DA to NA, there is no way of specifically losing DA other than by destruction of its neurons (see below). In contrast, it is easier to augment DA than NA by giving the precursor dopa because of its rapid conversion to DA and the limit imposed on its further synthesis to NA by the restriction of dopamine S-hydroxylase to the vesicles of NA terminals. The activity of the rate-limiting enzyme tyrosine hydroxylase is controlled by the cytoplasmic concentration of DA (normal end-product inhibition), presynaptic dopamine autoreceptors (in addition to their effect on release) and impulse flow, which appears to increase the affinity of tyrosine hydroxylase for its tetrahydropteridine co-factor (see below). 

In addition to its relatively high affinity at postsynaptic 5-HT receptors, MDMA exhibited high affinity for 5-HT uptake sites and has been shown to increase the release of [ H]5-HT and block [ H]5-HT uptake in vitro. These data suggest that some of the actions of MDMA may be mediated at presynaptic binding sites. With respect to [ H]5-HT release, MDMA has been reported to increase the release of [ H]5-HT from brain synaptosomes (Nichols et al. 1982) and hippocampal slices (Johnson et al. 1986). With respect to uptake blockade, MDMA has been reported to competitively inhibit H-5-HT uptake in vitro (Shulgin 1986). Furthermore, the neurotoxic effects of in vivo administration of MDMA on serotonin terminals can be blocked by concomitant administration of the 5-HT uptake blocker citalo-pram (Battaglia et al. 1988b Schmidt and Taylor 1987). Additional evidence in support of the hypothesis that MDMA produces some of its... 

Selegiline (Eldepryl ) Blocks MAOB metabolism and presynaptic reuptake of DA in the brain Start with 5 mg in the morning if symptoms continue, add 5 mg at noon 5 mg daily may be as clinically effective as 10 mg daily with fewer side effects... 

Against this backdrop, researchers reported evidence that iproniazid, the antitubercular drug that was to become the first antidepressant, might increase norepinephrine and serotonin levels in the brain. How did it have this effect Recall that some of the neurotransmitter molecules released by a neuron are destroyed by enzymes in the synaptic cleft between the sending presynaptic neuron and the receiving postsynaptic neuron. When the neurotransmitter is a monoamine - like norepinephrine and serotonin - this process is called monoamine oxidase (MAO). As early as 1952 researchers at the Northwestern University Medical School in Chicago reported that iproniazid inhibited the oxidation of monoamines. This meant that iproniazid was a... 

The acute CNS effects of MDMA administration are mediated by the release of monoamine transmitters, with the subsequent activation of presynaptic and postsynaptic receptor sites.40 As specific examples in rats, MDMA suppresses 5-HT cell firing, evokes neuroendocrine secretion, and stimulates locomotor activity. MDMA-induced suppression of 5-HT cell firing in the dorsal and median raphe involves activation of presynaptic 5-HT1A autoreceptors by endogenous 5-HT.4142 Neuroendocrine effects of MDMA include secretion of prolactin from the anterior pituitary and corticosterone from the adrenal glands 43 Evidence supports the notion that these MDMA-induced hormonal effects are mediated via postsynaptic 5-HT2 receptors in the hypothalamus, which are activated by released 5-HT. MDMA elicits a unique profile of locomotor effects characterized by forward locomotion and elements of the 5-HT behavioral syndrome such as flattened body posture, Straub tail, and forepaw treading.44 6 The complex motor effects of MDMA are dependent on monoamine release followed by activation of multiple postsynaptic 5-HT and DA receptor subtypes in the brain,47 but the precise role of specific receptor subtypes is still under investigation. 

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