Serotonergic neurons

In addition to central dopaminergic and cholinergic neurons, serotonergic neurons are also affected by FKBP ligands. Rats treated with the neurotoxin para-chloroamphetamine (PCA) suffer destruction of neurons which use serotonin as a neurotransmitter. Rats treated with GPI 1046, administered at the time of PCA lesioning and for 14 days thereafter, were compared with rats receiving PCA or vehicle alone. PCA... 

Unlike aniracetam, pramiracetam does not appear to interact with dopaminergic, serotonergic, or adrenergic neurotransmission (72). The agent inhibits prolylendopeptidase in certain brain areas, but its inhibition constant, iC, is only 11 ]lM (69). The absence or weak activity of this compound with various neuronal systems appears to make it less likely to be of significant therapeutic value than other members of this class of agents. 

SERT, 5HTT (SLC6A4) 5HT = serotonin -1 CNS serotonergic neurons (emanate from raphe nuclei) platelets, smooth muscle, intestine ... 

DAT is predominantly expressed by dopaminergic brain neurons, NET by noradrenergic neurons in the central and peripheral nervous system, and SERT is restricted to the axons of serotonergic neurons, which originate in the raphe nuclei and innervate numerous higher brain regions therefore SERT is widely distributed in the brain. Outside the brain, 5HT transport can be measured on non-neuronal cells (e.g. platelets, lympho-blastoid cells and smooth muscle cells) most of the 5HT appearing in the circulation is taken up by platelets. 

As a result of the neurochemical changes caused by MDMA, there is significant, observable functional impairment as well. These impairments occur in areas of the brain that have high concentrations of serotonergic neurons. Most notably affected are cognition and memory. Studies have shown decreases... 

Reich DL, Silvay G Ketamine an update on the first twenty-five years of clinical experience. Can J Anaesth 36 186—197, 1989 Ricaurte GA, Forno LS, Wilson MA, et al (+/-)3,4-Methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates. JAMA 260 51-55, 1988... 

Jacobs, BL and Fomal, CA (1999) Activity of serotonergic neurons in behaving animals. Neuropsychopharmacology 21 9S-15S. 

Lowry, CA, Odda, JE, Lightman, SL and Ingram, CD (2000) Corticotropin-releasing factor (CRF) increases the in vitro firing rates of serotonergic neurones in the rat dorsal raphe nucleus evidence for selective activation of a topographically organised mesolimbocortical system. J. Psychopharmacol. 14 (Suppl 2) All. 

Vahabzadeh, A. Boutelle, MG and Fillenz, M (1995) Effects of changes in rat brain glucose on serotonergic and noradrenergic neurons. Eur. J. Neurosci. 7 175-179. 

The main problems with early, irreversible MAOIs were adverse interactions with other drugs (notably sympathomimetics, such as ephedrine, phenylpropanolamine and tricyclic antidepressants) and the infamous "cheese reaction". The cheese reaction is a consequence of accumulation of the dietary and trace amine, tyramine, in noradrenergic neurons when MAO is inhibited. Tyramine, which is found in cheese and certain other foods (particularly fermented food products and dried meats), is normally metabolised by MAO in the gut wall and liver and so little ever reaches the systemic circulation. MAOIs, by inactivating this enzymic shield, enable tyramine to reach the bloodstream and eventually to be taken up by the monoamine transporters on serotonergic and noradrenergic neurons. Fike amphetamine, tyramine reduces the pH gradient across the vesicle membrane which, in turn, causes the vesicular transporter to fail. Transmitter that leaks out of the vesicles into the neuronal cytosol cannot be metabolised because... 

Both these predictions are borne out by clinical experience despite the snag that only MAOb is found in serotonergic neurons (Saura et al. 1996). So far, there is no explanation for this anomaly. However, the lack of a tyramine-induced pressor effect with moclobemide probably owes more to the fact that it acts as a reversible inhibitor of MAOa (RIMA) than to its isoenzyme selectivity. Its reversible inhibition of MAOa means that, should tyramine ever accumulate in the periphery, it will displace... 

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)...

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