Postsynaptic autoreceptors

Additional neuropharmacological changes that may contribute to the clinical effects of tricyclic antidepressants include indirect facihtation of 5-HT (and perhaps DA) neurotransmission through excitatory heteroreceptors on other monoaminergic neurons, or desensitized, inhibitory autoreceptors, as well as D autoreceptors. Activated release of 5-HT and DA may, in turn, lead to secondary down-regulation of 5-HTj autoreceptors, postsynaptic S-HT receptors, and perhaps D autoreceptors and postsynaptic Dj receptors. 

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. 

Reduce destruction. This may be achieved by blocking the neuronal or glial uptake (3a) of the NT or its extra- (3b) or intraneuronal metabolism (3c). Its success depends on there still being an adequate, even if reduced, release of the NT, and the protected NT being able to work postsynaptically and not stimulate autoreceptors to reduce the synaptic release of the endogenous NT even further. If the uptake sites are outside the synapse then the protected NT may not easily gain access to the receptors located postsynaptically. 

Figure 17.4 The effect of neuroleptics on the activity of DA neurons. Although neuroleptics (DA antagonists) are used primarily to inhibit the postsynaptic effects of released DA they also increase the activity of the DA neuron itself since they (1) inhibit the effect of synaptic DA on nerve terminal autoreceptors and so increase DA release (2) block inhibitory DA autoreceptors on the soma of the DA neuron so that they cannot be stimulated by endogenous DA, possibly released from the neuron s own dendrites and (3) facilitate feedback excitation to the DA neuron from those neurons normally inhibited by distally released DA. All the DA receptors involved are D2 (or possibly D3). — Blocked by D2 antagonists (neuroleptics)...

Histamine produces its pharmacological actions by three subtypes of receptors the postsynaptic Hi and H2 receptors and the presynaptic H3 receptor. The H3 receptor is mainly located in the central nervous system (CNS), where it acts as an inhibitory autoreceptor in the central histaminergic neuronal pathways [176]. A number of therapeutic applications have been proposed for selective H3 receptor antagonists, including several CNS disorders such as Alzheimer s disease. Attention Deficit Hyperactivity Disorder, Schizophrenia, or for enhancing memory or obesity control. 

Markstein, R., and Lahaye, D. In vitro effect of the racemic mixture and the (-)enantiomer of N-n-propyl-3(3-hydroxyphenyl)-piperidine (3-PPP) on postsynaptic dopamine receptors and on a presynaptic dopamine autoreceptor. J. Neural Transm 58 43-53, 1983. 

Mulder, A.H. Draper, R. Sminia, P. Schoffelmeer, A.N.M. and Stoof, J.C. Agonist and antagonist effects of 3-PPP enantiomers on functional dopamine autoreceptors and postsynaptic dopamine receptors in vitro. jji J. Pharmacol 107 291 -297, 1985. 

The 5-HTia receptor is located on the soma and the dendrites (somatodendritic autoreceptor) of 5-HT neurons, and at postsynaptic sites. Wang Aghajanian (1977), and Aghajanian Lakoski (1984) have shown that the somatodendritic autoreceptor mediates collateral inhibition, and that the ionic basis... 

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. 

The postsynaptic receptors on any given neuron receive information from transmitters released from another neuron. Typically, postsynaptic receptors are located on dendrites or cell bodies of neurons, but may also occur on axons or nerve terminals in the latter case, an axoaxonic synaptic relationship may cause increases or decreases in transmitter release. In contrast, autoreceptors are found on certain neurons and respond to transmitter molecules released from the same neuron. Autoreceptors may be widely distributed on the surface of the neuron. At the nerve terminal, they respond to transmitter molecules released into the synaptic cleft on the cell body, they may respond to transmitter molecules released by dendrites. Functionally, most autoreceptors appear to decrease further transmitter release in a kind of negative feedback loop. Autoreceptors have been identified for all the catecholamines, as well as for several other neurotransmitters. a2-adrenergic receptors are often found on noradrenergic nerve terminals of postganglionic sympathetic nerves, as well as on noradrenergic neurons in the CNS [36], and activation of these receptors decreases further norepinephrine release. Dopamine autoreceptors,... 

---