Serotonin

DrAlimadadi

MD,PHD Nutrition,Psychiatrist

IUMS

• In the mid-1950s, the discovery that the pronounced behavioral effects of reserpine are accompanied by a profound decrease in brain 5-HT led to the proposal that serotonin may function as a neurotransmitter in the mammalian CNS.

• 5-hydroxytryptamine (5-HT)• The highest concentrations were found in GI mucosa, followed

by platelets and the CNS• Cell bodies are found in raphe nucleus, pons, and medulla (part

of the reticular formation)• Projections are mainly to the cerebral cortex, the

hippocampus, and basal ganglia

• In the mid-1950s, the discovery that the pronounced behavioral effects of reserpine are accompanied by a profound decrease in brain 5-HT led to the proposal that serotonin may function as a neurotransmitter in the mammalian CNS.

• 5-hydroxytryptamine (5-HT)• The highest concentrations were found in GI mucosa, followed

by platelets and the CNS• Cell bodies are found in raphe nucleus, pons, and medulla (part

of the reticular formation)• Projections are mainly to the cerebral cortex, the

hippocampus, and basal ganglia

• Numerous synthetic or naturally occurring congeners of 5-HT have pharmacological activity.

• Many of the N- and O-methylated indoleamines, such as N,N-dimethyl-tryptamine, are hallucinogens , they have long been considered candidates for endogenous psychotomimetic substances, potentially responsible for some psychotic behaviors.

• Another close relative of 5-HT, melatonin (5-methoxy-N-acetyltryptamine), is formed by sequential N-acetylation and O-methylation.• principal indoleamine in the pineal gland, where it may be said to constitute a

pigment of the imagination. Its synthesis is controlled by external factors including environmental light. • Melatonin induces pigment lightening in skin cells and suppresses ovarian

functions; it also serves a role in regulating biological rhythms and shows promise in the treatment of jet lag and other sleep disturbances.

• Tryptophan is actively transported into the brain by a carrier protein that also transports other large neutral and branched-chain amino acids.

• Competition• Tryptophan hydroxylase, a mixed-function oxidase that requires

molecular O2 and a reduced pteridine cofactor for activity, is the rate-limiting enzyme in the synthetic pathway.

• A brain-specific isoform of tryptophan hydroxylase (TPH2) is entirely responsible for the synthesis of brain 5-HT

• Brain tryptophan hydroxylase is not generally saturated with substrate; consequently, the concentration of tryptophan in the brain influences the synthesis of 5-HT.

• 5-HT, is accumulated in secretory granules by a vesicular monoamine transporter (VMAT2) a nonspecific amine carrier

• Exocytosis• In the nervous system, the action of released 5-HT is terminated via

neuronal uptake by a specific 5-HT transporter. • 5-HT transporter (SERT ) on Axon and plt membrain an especific

transporter• Most 5-HT receptors, especially the 5-HT2C receptor, can activate G-

proteins independently of agonists, a property known as constitutive activity

• Plays a role in many behaviours:– Regulation of mood– Control of eating, sleep, arousal– Regulation of pain

• Involved in higher cognition and emotion

1. Ionotropic receptor: contains a binding site and and ion channel

Binding of neurotransmitter directly opens channel2. Metabotopic receptor: contains binding site for

neurotransmitter.• Activates an enzyme that begins a series of events that

opens up a channel • Release of a G-protein that is coupled to the receptor

• Second messenger: G-proteins convey messages to other molecules that in turn produce other activating chemicals

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• 5-HT1 Receptors.• The 5-HT1-receptor subfamily consists of five members, all of which

preferentially couple to Gi/o and inhibit adenylyl cyclase. • The 5-HT1A, 5-HT1B, and 5-HT1D receptor subtypes also activate a receptor-

operated K+ channel and inhibit a voltage-gated Ca2+ channel, a common property of receptors coupled to the pertussis toxin–sensitive Gi/Go family.

• The 5-HT1A receptor is found in the raphe nuclei of the brainstem, where it functions as an inhibitory, somatodendritic autoreceptor on cell bodies of serotonergic neurons

• Another 5-HT1-receptor subtype, the 5-HT1D/1B receptor, functions as an autoreceptor on axon terminals, inhibiting 5-HT release, 5-HT1B.

• 5-HT1D receptors, abundantly expressed in the substantia nigra and basal ganglia, regulate the firing rate of DA-containing cells and the release of DA at axonal terminals.

• The 5-HT1A receptor is found in the raphe nuclei of the brainstem, where it functions as an inhibitory, somatodendritic autoreceptor on cell bodies of serotonergic neurons

• Another 5-HT1-receptor subtype, the 5-HT1D/1B receptor, functions as an autoreceptor on axon terminals, inhibiting 5-HT release, 5-HT1B.

• 5-HT1D receptors, abundantly expressed in the substantia nigra and basal ganglia, regulate the firing rate of DA-containing cells and the release of DA at axonal terminals.

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Electrophysiological properties

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