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A PRESENTATION ON

AN OVERVIEW ON THE INVOLVMENT OF SEROTONIN (5-HT) IN CENTRALLY AND PERIPHERALLY MEDIATED PHYISIOLOGICAL FUNCTIONS

BY JOSHUA K NWEKEAMINU ABUBAKAR KENDE KANISHK LUHACH

DEPT OF PHARMACYIEC GROUP OF INSTITUTIONS.

INTRODUCTION

It is a monoamine neurotransmitter.

About 90% of body content is found/localized in the intestines: the rest in brain and platelets. It is popularly thought to be a contributor to feelings of well-being and happiness it is a key mediator in the physiology of mood, vascular function and gastrointestinal motility.

This explains the number of therapeutic agents that act targeting the serotonergic system such as: 5-HT3 antagonists, SSRIs and triptans.

Formula: C10H12N2OMolar mass: 176.2151g/molMelting point: 121 CBoiling point: 416 CIUPAC ID: 3-(2-aminoethyl)-1H-indol-5-ol, 5-Hydroxytryptamine

Biosynthetic part way of 5-HT

CLASSIFICATIONS OF 5-HT RECEPTORS Gaddum and Picarelli (1957) classified 5-HT receptors into musculotropic(D type) and neurotropic (M type) based on their blockade by Dibenzyline (phenoxybenzinamine).Modern classification is based on molecular receptor characterization and cloning.

Four families of 5-HT receptors (5-HT1, 5-HT2 , 5-HT3, 5-HT4-7) comprising of 14 subtypes have been so far recognized. However only some of these have been functionally corrected .

All 5-HT receptors ( except 5-HT 3 ) are G protein coupled receptors which functions through decrease (5-HT 1 )or increasing (5HT4 , 5HT6, 5-HT7) cAMP Production or by generating IP3/DAG as second messenger . The 5-HT3 is a ligand gated cation (Na+,k+) channel which upon activation elicits fast depolarization

PERIPHERAL MEDIATED PHYSIOLOGICAL FUNCTIONS OF 5-HT RECEPTORS

In periphery: Peristalsis Vomiting Platelet aggregation and haemostasis Inflammatory mediator Sensitization of nociceptors Microvascular control

CENTRAL MEDIATED PHYSIOLOGICAL FUNCTIONS OF 5-HT RECEPTORsMany central effects of serotonin receptors are as follows Neuronal inhibitions through decrease of cAMPBehavioral effects , sleep mood , feeding thermoregulatory , anxietyPresynaptic inhibitions Cerebral vasoconstrictions

Serotonergic Pathways In the Brain The principal centers for serotonergic neurones are the rostral and caudal raphe nuclei. From the rostral raphe nuclei axons ascend to the cerebral cortex, limbic regions and specifically to the basal ganglia.

Serotonergic nuclei in the brain stem give rise to descending axons, some of which terminate in the medulla, while others descend the spinal cord.

Drugs acting on serotonergic neurotransmissionThe figure above depicts how serotonin neurotransmission may be modified at the presynaptic level by inhibiting degradation, storage or reuptake.

MAO INHIBITORS Monoamine oxidase is a key enzyme for serotonin, dopamine and norepinephrine inactivation. MAO inhibitors prevent inactivation of monoamines within a neuron, causing excess neurotransmitter to diffuse into the synaptic space. This class of agents is used in the treatment of depression (phenelzine, tranylcypromine, selegiline) and Parkinsons disease (selegiline). Dietary restrictions (because of tyramine toxicity) limit their widespread use.Inhibitors of serotonin storageThey interfere with the ability of synaptic vesicles to store monoamines; displace serotonin, dopamine and norepinephrine from their storage in presynaptic nerve terminals. Agents that share this mechanism of action include amphetamine, methylphenidate and modafinil

SNRISNRIs mechanism involves blockade of 5-HT and norepinephrine reuptake in a concentration-dependent manner. Agents in this class include venlafaxine and duloxetine, they may be effective for the treatment of depression in patients in whom SSRIs are ineffective.SSRIs block the reuptake of serotonin, leading to increased concentrations of the neurotransmitter in the synaptic cleft and to an enhanced postsynaptic neuronal activity.

TCAsTricyclic antidepressants act by inhibiting reuptake of 5-HT and norepinephrine from the synaptic cleft by respectively blocking 5-HT and norepinephrine reuptake transporters, thereby causing enhancement of postsynaptic response.

SEROTONIN AGONIST

Serotonin receptors agonists have wide clinical applications, from treatment of depression to abortive medications for migraine headache. According to the receptor they activate, they can be divided into:

5-HT1A agonistsBuspirone is a partial 5-HT1A agonist used clinically for the treatment of anxiety and depression.

5-HT1B and 5-HT1D agonistsThe triptans are a drug class useful as abortive medication for the treatment of acute migraine headaches. They are very effective in causing cranial vasoconstriction and decreased release of neuropeptides involved in sterile inflammation.

5-HT2C agonistTrazodone was previously believed to be a 5-HT2C receptor antagonist. However, recent publications report that trazodone would behave as a 5-HT2C agonist. This drug is used generally as somnorific.

5-HT4 agonistsCisapride is a serotonin and cholinergic agonist used as a prokinetic drug, it was withdrawn from the U.S. market because of cardiovascular toxicity.

Non-selective agonistsErgotamine activates a more than one subtype of 5-HT receptor, it binds to 5-HT1A, 5-HT1D, 5-HT1B, D2 and norepinephrine receptors. Its vasoconstrictor effect makes it a suitable treatment for migraine attacks.LSD is a 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist that has psychedelic properties.

5-HT2 antagonists

Ketanserin is a 5-HT2A/2C antagonist used for the treatment of hypertension. In addition to its serotonin antagonism, it has affinity for alpha-1 receptors, which may contribute to its antihypertensive effect.

Clozapine is an atypical antipsychotic drug that acts as 5-HT2A/2C receptor antagonist with high affinity for dopamine receptors, the involvement of 5-HT has possibly increased the chances of greater efficacy and reduction in negative symptoms of schizophrenia.Agomelatine is a new antidepressant with agonist action at the melatonin receptor and antagonism at the 5-HT2C receptor.

5-HT3 antagonistsThis class includes drugs such as ondansetron, palonosetron and others. These agents are particularly useful in the treatment of chemotherapy induced nausea and vomiting .

TIPS FOR BOOSTING SEROTONIN NATURALLYGet morning sunlight, its more intense and this can boost your bodys production melatonin.Get plenty of exercise, researchers have found that exercise boost serotoninReduce your stress (both physical and emotional), prolonged stress produce adrenaline and cortisol which interfere with serotoninEating foods that are high in protein because of high percentage of tryptophanAlso food containing carbohydrates as they produce insulin which helps tryptophan go into the brain

CONCLUSION

From the above presentations we can conclude the following 5-HT is one of the most important neurotransmitters in the CNS and PNS as well

It also plays a major role in the maintenance of homeostasis , control of appetite, sleep, mood, hallucinations, stereotyped behavior, pain perception and vomiting.

Looking into the drugs which acts on 5-HT receptors it becomes very clear that for a effective and save management of any neurological conditions use of drugs which affect serotonin is of great importance .

Drugs which acts on serotonin are relatively safer than those acting on dopamine and nor epinephrine

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