Presynaptic autoreceptor

Starke K (2001) Presynaptic autoreceptors in the third decade focus on a2-adrenoceptors. J Neurochem 78 685-693... 

Methylphenidate like cocaine largely acts by blocking reuptake of monoamines into the presynaptic terminal. Methylphenidate administration produces an increase in the steady-state (tonic) levels of monoamines within the synaptic cleft. Thus, DAT inhibitors, such as methylphenidate, increase extracellular levels of monoamines. In contrast, they decrease the concentrations of the monoamine metabolites that depend upon monoamine oxidase (MAO), that is, HVA, but not catecholamine-o-methyltransferase (COMT), because reuptake by the transporter is required for the formation of these metabolites. By stimulating presynaptic autoreceptors, methylphenidate induced increase in dopamine transmission can also reduce monoamine synthesis, inhibit monoamine neuron firing and reduce subsequent phasic dopamine release. 

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. 

As with many neurons (e.g. NA) there are presynaptic autoreceptors on the terminals of dopamine neurons whose activation attenuate DA release. Although most of these receptors appear to be of the D2 type, as found postsynaptically, D3 receptors are also found. It is possible that in addition to the short-term control of transmitter release they may also be linked directly to the control of the synthesising enzyme tyrosine hydroxylase. It seems that autoreceptors are more common on the terminals of nerves in the nigrostriatal (and possibly mesolimbic) than mesocortical pathway. 

D2 Mostly in striatum, nucleus accumbens and olfactory tubercle but also on neuron cell bodies in substantia nigra and ventral tegmentum where they are the autoreceptors for locally (dendritic) released DA. The loss of specific D2 antagonist binding in the striatum after lesions of the afferent nigro-striatal tract indicates their presynaptic autoreceptor role on terminals there. Other lesion studies have also established D2 receptors on other inputs such as the cortico striatal tract. 

Unlike other transmitter systems, there are no obvious meehanisms for dampening glutamate release. Presynaptic autoreceptors for glutamate are mostly of the kainate type (see below) and appear to act as positive rather than negative influenees on further release of the amino acid. Although poorly characterised at present, inhibitory autoreceptors of the metabotropic type of receptors may act to inhibit release of glutamate. 

Reduce release. This is most likely to be achieved by stimulating inhibitory presynaptic autoreceptors (2a). Some drugs may reduce storage (2b) and hence release, although it is unlikely that this can be targeted at just one NT. 

Figure 20.1 Schematic diagram illustrating how antidepressants increase the concentration of extraneuronal neurotransmitter (noradrenaline and/or 5-HT). In the absence of drug (b), monoamine oxidase on the outer membrane of mitochondria metabolises cytoplasmic neurotransmitter and limits its concentration. Also, transmitter released by exocytosis is sequestered from the extracellular space by the membrane-bound transporters which limit the concentration of extraneuronal transmitter. In the presence of a MAO inhibitor (a), the concentration of cytoplasmic transmitter increases, causing a secondary increase in the vesicular pool of transmitter (illustrated by the increase in the size of the vesicle core). As a consequence, exocytotic release of transmitter is increased. Blocking the inhibitory presynaptic autoreceptors would also increase transmitter release, as shown by the absence of this receptor in the figure. In the presence of a neuronal reuptake inhibitor (c), the membrane-bound transporter is inactivated and the clearance of transmitter from the synapse is diminished...

The activation of presynaptic autoreceptors, as revealed by changes in terminal excitability, suggests that amphetamine releases dopamine at every tested dose. This observation is consistent with recent direct demonstrations using... 

Schwartz, J.C.,Arrang, J. M., Garbarg, M., Gulat-Marnay, C. and Pollard, H. Modulation of histamine synthesis and release in brain via presynaptic autoreceptors and heteroreceptors. Ann. N.Y.Acad. Sci. 604 40-54,1990. 

The idea that indole hallucinogens might increase startle by interacting with presynaptic autoreceptors has received some experimental support. Davis and Sheard (49) found that lesions of the dorsal and median raphe nuclei blocked the usual excitatory effect of a low dose (40 jtg/kg) of LSD on acoustic startle. Moreover, other treatments that decreased raphe cell firing rates also blocked the excitatory effects of LSD on startle. For example, pretreatment with chlor-imipramine (CIMI), which decreases raphe cell firing indirectly by blocking 5-HT reuptake (153), blocked the usual excitatory effect of LSD on startle without preventing the entry of LSD into the brain (47). These data were consistent with the disinhibition hypothesis. 

The chief direct mechanism of the methyixanthines is the antagonism of adenosine receptors (Snyder and Sklar 1984). Adenosine is an inhibitory neurotransmitter, acting at inhibitory presynaptic autoreceptors. At... 

Starke K, Gothert M, Kilbinger H. Modulation of neurotransmitter release by presynaptic autoreceptors. Physiol Rev 1989 69 864-989. 

These drugs increase synaptic serotonin by selectively blocking the serotonin reuptake transporter. In preclinical and human studies acute doses tend to be anxiogenic (Bell and Nutt 1998) but chronic administration has anxiolytic effects, possibly due to downregulation of presynaptic autoreceptors (Blier et al. 1990). There are five SSRIs widely available citalopram, fluoxetine, fluvoxam-ine, paroxetine and sertraline. Escitalopram, the S-enantiomer of citalopram. 

By activating presynaptic autoreceptors in brain stem locus ceruleus neurons (where most noradrenergic fibers have their origin), clonidine reduces norepine-pherine release and turnover. This inhibitory effect on noradrenergic locus ceruleus neurons, as well as direct effects on thalamic receptors, are most likely responsible for the sedative effects of clonidine (Berridge and Foote, 1991 Buzsaki et ah, 1991). 

Lithium may facilitate the release of 5-HT, perhaps by increasing tryptophan uptake, enhancing 5-HT release through presynaptic autoreceptors, and/or by increasing activity at postsynaptic 5-HT receptors (i.e., act as a 5-HT agonist). Some data, however, question the long-term effect of lithium on 5-HT enhancement when studied in patients, as opposed to healthy control subjects ( 27). Similar to lithium, clonazepam can increase 5-HT synthesis and cerebrospinal fluid (CSF) levels of its major metabolite, 5-hydroxyindoleacetic acid. Other agents known to enhance 5-HT activity by different mechanisms have also shown initial promise as potential antimanic treatments (e.g., L-tryptophan, a 5-HT precursor). 

As previously noted, all currently available antidepressants enhance monoamine neurotransmission by one of several mechanisms. The most common mechanism is inhibition of the activity of SERT, NET, or both monoamine transporters (Table 30-2). Antidepressants that inhibit SERT, NET, or both include the SSRIs and SNRIs (by definition), and the TCAs. Another mechanism for increasing the availability of monoamines is inhibition of their enzymatic degradation (the MAOIs). Additional strategies for enhancing monoamine tone include binding presynaptic autoreceptors (mirtazapine) or specific postsynaptic receptors (5-HT antagonists and mirtazapine). Ultimately, the increased availability of monoamines for... 

FIGURE 6-35. Mechanism of action of serotonin selective reuptake inhibitors (SSRIs)—part 1. Depicted here is a serotonin neuron in a depressed patient. In depression, the serotonin neuron is conceptualized as having a relative deficiency of the neurotransmitter serotonin. Also, the number of serotonin receptors is up-regulated, or increased, including presynaptic autoreceptors as well as postsynaptic receptors. 

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