Somatodendritic autoreceptors

Figure 20.6 Schematic representation of the effects of 5-HT reuptake inhibitors on serotonergic neurons, (a) 5-HT is released at the somatodendritic level and by proximal segments of serotonergic axons within the Raphe nuclei and taken up by the 5-HT transporter. In these conditions there is little tonic activation of somatodendritic 5-HTia autoreceptors. At nerve terminals 5-HTib receptors control the 5-HT synthesis and release in a local manner, (b) The blockade of the 5-HT transporter at the level of the Raphe nuclei elevates the concentration of extraneuronal 5-HT to an extent that activates somatodendritic autoreceptors (5-HTia). This leads to neuronal hyperpolarisation, reduction of the discharge rate and reduction of 5-HT release by forebrain terminals, (c) The exposure to an enhanced extracellular 5-HT concentration produced by continuous treatment with SSRIs desensitises Raphe 5-HTia autoreceptors. The reduced 5-HTia function enables serotonergic neurons to recover cell firing and terminal release. Under these conditions, the SSRI-induced blockade of the 5-HT transporter in forebrain nerve terminals results in extracellular 5-HT increases larger than those observed after a single treatment with SSRIs. (Figure and legend taken from Hervas et al. 1999 with permission)...

The inhibition of firing of catecholamine neurons resulting from amphetamine administration is likely due to activation of somatodendritic autoreceptors. This causes a hyperpolarization of the somatodendritic membrane of both locus coeruleus noradrenergic and substantia nigra dopamine neurons, probably as a consequence of an increase in potassium conductance (Lacey et al. 1987 Williams et al. 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... 

Serotonin 5-HT1A Human cDNA Alzheimer s disease, anxiety, depression, schizophrenia, hypertension, inflammation, pain, migraine, spasticity ulcers, obesity glaucoma Somatodendritic autoreceptor in hippocampus and raphe nuclei, circadian rhythm, somatodendritic heteroreceptor at cholinergic terminals of myenteric plexus... 

FIGURE 5—37. Presynaptic 5HT1A receptors are autoreceptors, are located on the cell body and dendrites, and are therefore called somatodendritic autoreceptors. 

FIGURE 5-38. The 5HT1A somatodendritic autoreceptors depicted in Figure 5-37 act by detecting the presence of 5HT and causing a shutdown of 5HT neuronal impulse flow, depicted here as decreased electrical activity and a reduction in the color of the neuron. 

Once the 5HT1A somatodendritic autoreceptors are desensitized, 5HT can no longer effectively inhibit its own release, and the serotonin neuron is therefore dis-inhibited. This results in a flurry of >HT release from axons due to an increase in neuronal impulse flow (Fig. 6—38). This is just another way of saying that the serotonin release is turned on at the axon terminals. The serotonin that now pours out of the various projections of serotonin pathways in the brain theoretically mediates the various therapeutic actions of the SSRls. 

FIGURE 7—33. Mechanism of action of buspirone augmentation—pact 3. Shown here is how buspirone potentiates ineffective SSRI action at 5HT1A somatodendritic autoreceptors, resulting in the desired disinhibition of the 5HT neuron. This combination of 5HT1A agonists plus SSRIs may be more effective, not only in depression but also in other disorders treated by SSRIs, such as obsessive-compulsive disorder and panic. 

FIGURE 8—11. Serotonin 1A partial agonists such as buspirone may reduce anxiety by actions both at presynaptic somatodendritic autoreceptors (left) and at postsynaptic receptors (right). Presynaptic actions are more likely related to anxiolytic actions, and postsynaptic actions are perhaps more likely linked to side effects such as nausea and dizziness. 

Hallucinogens have rather complex interactions at neurotransmitter systems, but one of the most prominent is a common action as agonists at serotonin 2A (5HT2A) receptor sites (Fig. 13—10). Hallucinogens certainly have additional effects at other 5HT receptors (especially 3HT1A somatodendritic autoreceptors) and also at other neurotransmitter systems, especially norepinephrine and dopamine, but the relative importance of these other actions are less well known. Also, MDMA appears to be a powerful releaser of serotonin and it and several drugs structurally related to it... 

Romero L, Artigas F. Preferential potentiation of the effects of serotonin uptake inhibitors by 5-HT1A receptor antagonists in the dorsal raphe pathway role of somatodendritic autoreceptors. JNeurochem 1997 68 2593-2603. 

HTlA receptors are expressed at both postsynaptic locations in 5-HT target areas (including the amygdala, hippocampus, and cortex) and presynaptic sites on 5-HT neurons in the raphe nuclei as somatodendritic autoreceptors. Because autoreceptors control neuronal firing and consequently 5-HT release, and because an increase in extracellular 5-HT levels during development (see previous section) has been implicated in anxiety, it initially was believed that the anxiety-like phenotype of 5-HTia receptor-deficient mice was because of increased 5-HT release. However, basal 5-HT levels are not altered, as measured by in vivo microdialysis, in 5-HTia receptor-deficient mice, presumably because of the compensatory action of presynaptic 5-HTib... 

Figure 1.6 The nomenclature used to describe receptor location on neurones. Starting with Neurone A , neurotransmitter released at the terminals will interact with POSTSYNAPTIC receptors on Neurone B Similarly, neurotransmitter releasedfrom Neurone D will interact with postsynaptic receptor on Neurone A Neurotransmitter releasedfrom Neurone A will also regulate its own release by interacting with the TERMINAL A UTORECEPTOR or affect neuronal firing by interacting with the SOMATODENDRITIC AUTORECEPTOR Release of neurotransmitter from Neurone A can also be regulated by activation of PRESYNAPTIC HETEROCEPTORS on the terminals, which are postsynaptic receptors activated by neurotransmitter from Neurone C...

The DA autoreceptor at both sites is the D2 receptor similarly, the NA autoreceptor is the 0(2 receptor. With 5-HT neurones the 5-HTia receptor acts as the main somatodendritic autoreceptor but the 5-HTib/id receptor is the terminal autoreceptor. 

Fig. 14.4. Typical nerve ending showing the cell body (i.e., somatodendritic) autoreceptors (B) and the terminal autoreceptors (C). Neurotransmitter molecules also are shown (A). Neurotransmitters can interact with cell body autoreceptors (B) to regulate synthesis and with terminal autoreceptors (C) to regulate release. Shown above is a drug molecule blocking the cell body autoreceptor and preventing an interaction with the neurotransmitter.

The majority of these compounds are agonists or partial agonists. Pure antagonists, devoid of any agonistic activity at presynaptic receptors (somatodendritic autoreceptors) or postsynaptic receptors were identified only very recently (for details of the definition of agonists, partial agonists and antagonists, see [6]). 

An example of a flexible aryloxyalkylamine is S14063, claimed as a potent 5-HT1A antagonist devoid of P-adrenoceptor blocking activity [65] (Table 13). The activity of S14063 on somatodendritic autoreceptors is not yet published. 

Extensive studies on the pharmacological and biochemical properties of 5-HT,a receptors in various brain regions revealed no real differences between somatodendritic autoreceptors within the dorsal raphe nucleus and the postsynaptic receptors in the septum and hippocampus [24]. 5-HT, receptors from different species, including man, have been cloned, and foimd to be so similar that until now it is generally accepted that 5-HT, receptors, at least 5-HT,a binding sites, are identical [25]. 

Studies on the site of action strongly suggest an effect mediated via the somatodendritic autoreceptor. Direct iiyection of 8-OH-DPAT into the dorsal and medial raphe nucleus enhanced feeding [13,14,15]. Similarly 5-HT depletion by PCPA antagonized 8-OH-DPAT effects on feeding, pointing to the autoreceptor as the site of action [16]. 

Local application of 8-OH-DPAT in the raph4 nuclei reduces the firing rate of serotonergic neurons by acting on the somatodendritic autoreceptor. This in turn leads to a reduction of the serotonergic neurotransmission, i.e. less serotonin is released in the synaptic cleft. It is not known which of the postsynaptic receptors is critically involved in the mediation of LLR. As far as we know, no local application studies have been performed in the major projection areas of the serotonin system. 

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