Autoreceptors

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. 

Dopaminergic mechanisms within the ventral striatum (i.e., nucleus accumbens) subserve the ability of amphetamine and methylphenidate in low to moderate doses to increase locomotor activity. In contrast, very low dosages in animals seem to cause hypoactivity presumably by stimulation of autoreceptors, a finding that would be compatible with the clinical impression that methylphenidate might be usefiil in some patients with mania. 

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. 

Thermos K, Bagnoli P, Epelbaum J et al (2006) The somatostatin sstl receptor an autoreceptor for somatostatin in brain and retina Pharmacol Ther 110(3) 455-464... 

Fig. 8.3 Chemokines are neuromodulators. Some chemokines can be synthesized, as their own receptor, by the same neuron (a). A chemokine released by exocytosis can modulate the electrical activity of neurons after binding to its own presynaptic receptor (autoreceptor). Chemokines can also act on other neurons and glial cells (astrocytes and microgha) which express chemokine receptors (b). (Adapted from Rostene and Melik-Parsadaniantz, Pour la Science 2008, 369 66-72)...

Evidence suggests that co-transmitters in a terminal have their own autoreceptors and, in some cases, activation of their own presynaptic receptor can influence the release of the co-stored, classical transmitter. For instance, activation of P2Y-autoreceptors by ATP is thought to affect the release of noradrenaline from sympathetic neurons. However, in other cases, feedback modulation of release of classical and their associated co-transmitters seems to have separate control mechanisms. This would suggest that either the two types of transmitter are concentrated in different nerve terminals or that mechanisms for regulating release target different vesicles located in different zones of the terminal (Burnstock 1990). 

Taking ai-adrenoceptors as an example, several possible mechanisms have been suggested (see Starke 1987). The first rests on evidence that these autoreceptors are coupled to a Gi (like) protein so that binding of an a2-adrenoceptor agonist to the receptor inhibits the activity of adenylyl cyclase. This leads to a fall in the synthesis of the second messenger, cAMP, which is known to be a vital factor in many processes involved in exocytosis. In this way, activation of presynaptic a2-adrenoceptors could well affect processes ranging from the docking of vesicles at the active zone to the actual release process itself... 

Pali), P and Stamford, JA (1993) Real-time monitoring of endogenous noradrenaline release in rat brain slices using fast cyclic voltammetry. 2. Operational characteristics of the alpha2 autoreceptors in the bed nucleus of the stria terminalis, pars ventralis. Brain Res. 608 134-140. 

Starke, K (1987) Presynaptic a-autoreceptors. Rev. Physiol. Biochem. Pharmacol. 107 73-146. 

While there is no active neuronal uptake of ACh itself, cholinergic nerve terminals do possess autoreceptors. Since these are stimulated by ACh rather than by the choline, to which ACh is normally rapidly broken down, it is unlikely that they would be activated unless the synaptic release of ACh was so great that it had not been adequately hydrolysed by cholinesterase. 

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). 

RELEASE AND TURNOVER Short-term control (autoreceptors)... 

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. 

D3 Much less abundant than D2. Mainly in limbic regions (nucleus accumbens and olfactory tubercle) but also in hypothalamus. Some in caudate and cortex and also expressed on DA neurons in substantia nigra, presumably as autoreceptors. No effect on adenylate cyclase but inhibits Ca + entry (autoreceptor role). High affinity for DA (Ali 25nM). 

Starke, K (1987) Presynaptic a-autoreceptors. Rev. Physiol. Biochem. Pharmacol. 107 73-146. Zhong, H and Minneman, KP (1999) i-Adrenoceptor subtypes Eur. J. Pharmacol. 375 261-276. Zigmond, RE, Schwarzschild, MA and Rittenhouse, AR (1989) Acute regulation of tyrosine hydroxylase by nerve activity and by neurotransmitters via phosphorylation. Ann. Rev. Neurosci. 12 451-461. 

The apparent reliance of enzyme activation on phosphorylation and intracellular Ca + gives a clue as to how the rate of 5-HT synthesis might be coupled to its impulse-evoked release. Certainly, the impulse-induced increase in intracellular Ca +, and/or activation of the G protein-coupled receptors that govern synthesis of cAMP, could modify the activity of tryptophan hydroxylase. Indeed, this could explain why activation of either somal 5-HTia autoreceptors in the Raphe nuclei (which depress the firing rate of 5-HT neurons) or terminal 5-HTib autoreceptors (which depress 5-HT release) can reduce the production of cAMP and attenuate 5-HT synthesis. 

Impulse-evoked release of 5-HT, like that of noradrenaline, is subject to fine control by a system of autoreceptors, in particular 5-HTia receptors on the cell bodies of neurons in the Raphe nuclei and 5-HTib/id receptors on their terminals. Because these are all G /o protein-coupled receptors, their activation reduces the synthesis of cAMP so that 5-HTia agonists (or 5-HT itself) decrease neuronal excitability and the firing of Raphe neurons whereas activation of 5-HTib/id receptors seems to disrupt the molecular cascade that links the receptor with transmitter release (see Chapter 4). 

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. 

---