NSC 243 Serotonin

B6 and B7 comprise dorsal raphe nuclei B8 and B5 are the median raphe nuclei B1-4 project to brainstem and cerebellum and spinal cord 95% of body’s 5-HT is found in the periphery in the enteric NS, about 100 million neurons. 5-HT is a major regulator of GI function—causes constriction of gastric smooth muscle

5-HT staining of dorsal and median raphe nuclei Rat midbrain

Very dense neo-cortical innervation; > NE Proposed “harmonizer” activity, generally inhibitory, simultaneously affect activity throughout the brain; however, the m and d systems are distinct in several ways: electrophysiology, morhphology, and innervation. Generally increasing or decreasing 5-HT all over may not accomplish the goal. May need to be more regionally selective. No system seems to absolutely require 5-HT Raphe receive input from DA neurons in SN and VTA, and NE from LC; also reciprocal dorsal-median connections and afferents from amygdala, cortex, and hypothalamus M system: coarse, large spherical varicosities D system: fine, small varicosities, more sensitive to neurotoxic amphetamine derivatives like ecstasy

Very regular firing rate, regulated by Ca dependent K current, somatodendritic autoreceptors (5-HT1A), and heterosynaptic input. Largely independent of stressors or environment

Functional Roles of 5-HT General tone of NS Repetitive activities like grooming activate 5-HT neurons 5-HT stimulates CRH (corticotropin-releasing hormone) release from hypothalamus 5-HT has negative effects on the ability of light to reset the circadian clock 5-HT activation decreases food consumption and drugs that inhibit 5-HT stimulate food intake Effect on satiety

Serotonin synthesis Quite analogous to DA production

Synthesis takes place in the terminal

Stimulation induced regulation of 5-HT production This increase is Ca dependent, probably linked to phosphorylation, like TH. Kinetic changes not known (Km or Vmax)

Increasing tryptophan increases 5-HT release Tryptophan availability is the limiting factor

Effect of egg protein diet on tryptophan:LNAA ratio After different concentrations of hydrolyzed egg protein diet. This effect is mimicked by high carb diets, but not all protein diets, which are expected to increase all LNAA (large neutral amino acids) British Journal of Nutrition (2011), 105, 611–617

Inactivation of 5-HT signal SERT

Serotonin inactivation is a target of many pharmaceuticals Inhibitors of 5-HT uptake and degradation are among the most common pharmaceuticals Solid lines are agonists, dashed are inhibitors or antagonists * *

Serotonin transporters Fenfluramine disrupts the proton gradient, blocks uptake of serotonin into vesicles, and also inhibits SERT uptake of 5-HT. Also makes SERT run in reverse—build up of 5-HT inside the cell favors export of 5-HT via SERT into the synapse. Chronic inhibition of SERT (cocaine) causes its downregulation. SERT activity regulated by activity in both directions

Inhibition of SERT Tricyclic antidepressants like imipramine, SSRI’s like prozac Inhibit SERT, increase 5-HT levels Effects take weeks to develop Compensatory changes?

Transient regulation of monoamine transporters

Regulation of 5-HT release Tryptophan availability Firing rate of neuron (pretty constant) Autoreceptors Somatodendritic Terminal

Effect of 5-HT autoreceptors * *

Regulation of 5-HT release Autoreceptors Somatodendritic “activity modulating” Terminal “release modulating” Drug effects: tryptophan, SSRI, MAO inhibitors Meant to increase 5-HT; actually can inhibit raphe firing via autoreceptors!

Regulation of 5-HT release Effects of Drugs: Amph, Ecstasy (MDMA), and fenfluramine Reverse SERT, block vesicular transport Destroy dorsal raphe terminals (not median) Tax energy: disrupt ion gradients Non-exocytotic, non-Ca2+ dependent release

Toxic effects of MDMA

Activity of pre-synaptic autoreceptor 5HT1A on firing In the absence of NK-1 (the substance P receptor), ipsapirone (the 5-HT1A agonist) is unable to inhibit 5-HT firing (IC50 is one order of magnitude higher). NK1 antagonists are useful antidepressants;  the constitutive lack of NK1 receptors appears to be associated with a downregulation/functional desensitization of 5-HT1Aautoreceptors resembling that induced by chronic treatment with SSRI antidepressants. (5HT1A agonist) Froger et al 2001

Release of CA Ca2+ dependent exocytosis Release at varicosities

Volume transmission

Sites of preferential volume release of 5-HT Dorsal Raphe SN? Protected by glial sheaths surrounding synapses, so not in practice SERT located far from synapses in these regions, allows for distance transmission Explains why receptors are often non-junctional