Raphe cell firing

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. 

Cox RF, Meller E, Waszczak BL Electrophysiological evidence for a large receptor reserve for inhibition of dorsal raphe cell firing by 5-HTlA agonists. Synapse 14 297-304, 1993... 

Sprouse JS, Aghajanian GK. (-)-Propranolol blocks the inhibition of serotonergic dorsal raphe cell firing by 5-HT1A selective agonists. Eur J Pharmacol 1986 128 295-298. 

Arborelius L, Hook BB, Hacksell U, Svensson TH. The 5-HT(lA) receptor antagonist (S)-UH-301 blocks the (R)-8-OH-DPAT-induced inhibition of serotonergic dorsal raphe cell firing in the rat. J Neural Transm Gen Sect 1994 96 179-186. 

FIGURE 11-2 Two classes of 5-HT autoreceptors with differential localizations. Somatodendritic 5-HTj autoreceptors decrease raphe cell firing when activated hy 5-HT released from axon collaterals of the same or adjacent neurons. The receptor subtype of the presynaptic autoreceptor on axon terminals in the human forebrain has different pharmacological properties and has heen classified as S-HTj this receptor modulates the release of 5-HT. Postsynaptic 5-HTj receptors are also indicated. 

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 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. 

Gartside, S.E., McQuade, R., and Sharp, T., Acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on 5-HT cell firing and release comparison between dorsal and median raphe 5-HT systems, Neuropharmacology 36(11-12), 1697-703, 1997. 

Once I got up, however, it wasn t all that difficult, and my balance was pretty good. Things seemed a little unreal, but I can t say just what kind of unreality it was. I saw no bizarre illusions or beautiful colors. Maybe that was because most of the time, especially while lying on my cot in the cubicle, I was visualizing the cells in my raphe nucleus firing messages to other parts of my brain. 

In the dorsal raphe nucleus GR agonists cause a reduction in the functional activity of 5-HTia auto receptor mediated inhibition of cell firing (Laaris et ah, 1995), an effect likely to be on receptor-effector coupling since there is no change in the number of 5-HTia receptors (Laaris et al, 1995). In vivo models of somatodendritic 5-HTia function, such as hypothermia in mice, are attenuated by corticosterone administration (McAllister-Williams et al., 2001), in agreement with this electrophysiological data. 

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). 

Both clinical and experimental studies have provided evidence that 5-HT can also regulate dopamine turnover. Thus several investigators have shown that a positive correlation exists in depressed patients between the homovaniUic acid (HVA), a major metabolite of dopamine, and 5-HIAA concentrations in the CSF. In experimental studies, stimulation of the 5-HT cell bodies in the median raphe causes reduced firing of the substantia nigra where dopamine is the main neurotransmitter. There is thus convincing evidence that 5-HT plays an important role in modulating dopaminergic... 

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