NeurotransmittersNeurotransmitters

DefinitionDefinition

They are They are chemical messengerschemical messengers which which released from released from neuronsneurons to act on adjacent to act on adjacent cells which are cells which are usuallyusually also neurons also neurons

Peripherally,adjacent effector's cell Peripherally,adjacent effector's cell may may bebe a muscle or glandular cell a muscle or glandular cell

DifferencesDifferences

HormonesHormones: : produced by ductless produced by ductless glands,secreted into circulation, go to distance glands,secreted into circulation, go to distance target cells,to act via specific protein receptors target cells,to act via specific protein receptors at these cells e.g: at these cells e.g: Aldosterone,Insulin,ADH,ThyroxinAldosterone,Insulin,ADH,Thyroxin

AutacoidsAutacoids : : act on target cells close to act on target cells close to their site of release,called “local hormones” or their site of release,called “local hormones” or “paracrine secretions” e.g: “paracrine secretions” e.g: Histamine,prostaglandinHistamine,prostaglandin

CriteriaCriteria

1.1. The substance must be present within the The substance must be present within the presynaptic neuronpresynaptic neuron

2.2. The substance must be released in response The substance must be released in response to presynaptic depolarization, and the release to presynaptic depolarization, and the release must be Ca2+-dependentmust be Ca2+-dependent

3.3. Specific receptors for the substance must be Specific receptors for the substance must be present on the postsynaptic cellpresent on the postsynaptic cell

Major classes of NTMajor classes of NT

Amino AcidsAmino Acids GlutamateGlutamate ( (excitatoryexcitatory)) GABAGABA ( (inhibitoryinhibitory) )

Acetylcholine Acetylcholine ((excitatoryexcitatory))

Monoamine Monoamine ((excitatoryexcitatory)) Catecholamine: Catecholamine: DopamineDopamine, , NorepinephrineNorepinephrine Indolamine: Indolamine: SerotoninSerotonin

Neural organization of NT systems

Communication

(GLT & GABA)

Coordination

(GLT & GABA)

Modulation

(Ach, NE, DA,5HT

III III

I, II, & III are different CNS areas, e.g.cortex, brainstem, spinal cord

1. Amino acids1. Amino acids

Glutamate (GLT) & ɣ-aminobutyric acid Glutamate (GLT) & ɣ-aminobutyric acid (GABA)(GABA)

Main excitatory (GLT) and inhibitory Main excitatory (GLT) and inhibitory (GABA) NTs in CNS(GABA) NTs in CNS Found throughout CNS in long axon and Found throughout CNS in long axon and

intrinsic neuronsintrinsic neurons Interacts with / modulate activity within other Interacts with / modulate activity within other

NT systemsNT systems

AA synthesis and AA synthesis and metabolismmetabolismGlucose OR glutamine

Glutamate (GLT)

γ- aminobutyric acid (GABA)

Glutamic acid decarboxylase (GAD)

Kribs cycle

• Metabolism• Reuptake by presynaptic neuron and glial cells

• Recycled into glutamate (& GABA)

Glutamate receptors

Ionotropic (fast): Na+ in AMPA: fast excitatory signals Kainate: fast excitatory, autoreceptor (↑ GLT

release) Ionotropic (slow): Na+, Ca2+ in

NMDA: sustained, high-frequency excitatory signals

Activated by repeated excitatory stimulation: escalation

Metabotropic (slow): K+ out; Ca2+ in

Glutamate ReceptorsGlutamate Receptors

GLT function & effectGLT function & effect

Main excitatory NT within CNS Pain perception:

Acute: AMPA / kainate (co-transmission substance P)

Chronic (neuropathic): NMDA

Memory: long-term potentiation (LTP) Epilepsy, excitotoxicity (ischemic episodes)

GABAGABA Major inhibitory neurotransmitter in CNSMajor inhibitory neurotransmitter in CNS

Hyperpolarizes postsynaptic membraneHyperpolarizes postsynaptic membrane

Two types of GABA Receptors:Two types of GABA Receptors: GABA-AGABA-A

ClCl-- channel channel binding Cl binding Cl-- conductance in presynaptic conductance in presynaptic neuronsneurons

““fast” response (1msec)fast” response (1msec) Benzodiazepines, barbituratesBenzodiazepines, barbiturates

GABA-BGABA-B G-protein coupled receptorG-protein coupled receptor K+ conductanceK+ conductance ““slow” response (1sec)slow” response (1sec)

GABA ReceptorsGABA Receptors

GABA functions & effectGABA functions & effect

Main inhibitory NT within CNSMain inhibitory NT within CNS synchronize local neural activity synchronize local neural activity modulation of motor control in basal gangliamodulation of motor control in basal ganglia broad distribution underlies importance of broad distribution underlies importance of

tonic inhibition in CNStonic inhibition in CNS

Dysfunction = EpilepsyDysfunction = Epilepsy

2. Acetylcholine (Ach)2. Acetylcholine (Ach) Earliest discovered neurotransmitter

NT @ ALL first synapses outside CNS (autonomic ganglia)

Terminal NT: parasympathetic NS; skeletal muscle

2 receptor families Muscarinic: metabotropic

PNS: parasympathetic NS terminals CNS cortex, hippocampus (HC), striatum

Nicotonic: ionotropic (Na+ in) CNS cortex, hippocampus (HC), ventral tegmental area (VTA) PNS: autonomic ganglia, skeletal muscle junctions

ACh synthesis and metabolism

choline

acetylcholine (ACh)

choline [reuptake into presynaptic neuron] + acetate [to blood]

Acetylcholinesterase (AChE)

Choline acetyltransferase (ChAT)

Ach function & effect Ach function & effect (brain)(brain)

1. Pedunculopontine – lateral dorsal pathway Sleep / wake (REM sleep); motor (ACh →DA)

2. Basal forebrain cholinergic pathways Medial septal nucleus →HC + amygdala Learning and memory

3. Nucleus basalis of Maynert → cortex Attention and memory

Ach circuit in brainAch circuit in brain

3. Monoamines3. Monoamines

Catecholamines

Indolamine(s)

Dopamine (DA) Found only in CNS (not PNS): widely

distributed via pathways ascending from midbrain

Can be excitatory or inhibitory [location, receptors,interactions w other NTs]

2 receptor families: D1 (D5) & D2 (D3, D4) D1 striatum; (D5) hippocampus, hypothalamus D2 striatum; substantia nigra (SN) & VTA

[autoreceptors] D3 limbic, striatum, cortex; SN [autoreceptors] D4 limbic, frontal cortex

DA synthesis and metabolism

Tyrosine (amino acid from diet)

Dopa

Dopamine (DA)

DOPAC + HVA

Tyrosine hydroxylase

Dopa decarboxylase on postsynaptic membrane

Monoamine oxidase (MAO) in presynaptic neuron [after reuptake]Catechol-O-methyl transferase (COMT)

Wait a minute !!Wait a minute !!

HO

HO

NH3+

Dopamine

Polar groups Mostly protonatedto the correspondingammonium salt

HO

HO

NH3+

L-DOPA

Polar groups Mostly protonatedto the correspondingammonium saltO O

H

Polar group

If dopamine is too polar to cross the BBB, If dopamine is too polar to cross the BBB, how can L-DOPA cross it?how can L-DOPA cross it?

Answer !Answer !

L-DOPA is transported across the BBB L-DOPA is transported across the BBB by an amino acid transport system (same by an amino acid transport system (same one used for tyrosine and phenylalanine)one used for tyrosine and phenylalanine)

DA function & effectDA function & effect

Nigrostriatal pathwayMotor function

Mesolimbic and Mesocortical pathways Pleasure & Reward, reinforcement, motivation Attentional and behavioural control Endocrine regulation (Prolactin)

PsychosisSchizophrenia, hallucinatory drugs

DA circuit in brainDA circuit in brain

Reward circuitryReward circuitryPrefront

alcortex

dopamine

nucleus accumbe

ns

dopamine

VTA

dopamine

Reward Reward PathwayPathway

?

Norepinephrine (NE)

Found in both PNS (sympathetic NS), and widely distributed in CNS

3 receptor families (all metabotropic): Alpha-1: excitatory postsynaptic (↑Ca2+ flow) Alpha-2: inhibitory presynaptic [autoreceptor] (↑K+,

↓Ca2+) Beta: excitatory presynaptic [autoreceptors] &

postsynaptic

Synthesized from DA in NE axon terminals; metabolized (after reuptake) by MAO / COMT

NE in PNS:Autonomic (sympathetic) NS

Sympathetic NS terminals and adrenal medulla Fight-or-flight

response

NE pathways in brain

2 major groups of NE neurons ascending from pontine locus coeruleus (LC) and lateral tegmental nuclei (LTN) some overlap, together

innervate whole brain

NE function & effectNE function & effect Arousal: LC sleep/wake state Arousal ↔ attention

Tonic NE activity in LC = vigilant attention Scanning, high behavioural flexibility

Phasic NE activity in LC = focused attention Selective attention, response inhibition

Also involved in nociception, memory, and control of autonomic & endocrine function

Serotonin (5-HT)

5-hydroxytryptamine Found in both PNS and CNS

CNS contains < 2% total 5-HT in bodyOutside CNS: broad range physiological functions

7 (!) receptor subtypes (ionotropic and metabotropic)Not clearly associated with specific brain regionsSome functional specificity (with overlap)

Serotonin ReceptorsSerotonin Receptors 5-HT5-HT1A1A CNS: neuronal inhibition, behavioral effects (sleep, feeding, CNS: neuronal inhibition, behavioral effects (sleep, feeding,

thermoregulation, anxiety) thermoregulation, anxiety) 5-HT5-HT1B1B CNS: presynaptic inhibition, behavioral effects; vascular: CNS: presynaptic inhibition, behavioral effects; vascular:

pulmonary vasoconstriction ergotaminepulmonary vasoconstriction ergotamine 5-HT5-HT1D1D CNS: locomotion; vascular: cerebral vasoconstrictionCNS: locomotion; vascular: cerebral vasoconstriction 5-HT5-HT2A2A CNS: neuronal excitation, behavioral effects; smooth muscle: CNS: neuronal excitation, behavioral effects; smooth muscle:

contraction, vasoconstriction / dilatation; platelets: aggregation α-contraction, vasoconstriction / dilatation; platelets: aggregation α-methyl-5-HTmethyl-5-HT

5-HT5-HT2B2B stomach: contraction α-methyl-5-HTstomach: contraction α-methyl-5-HT 5-HT5-HT2C2C CNS, choroid plexus: (CSF) secretion α-methyl-5-HT, LSDCNS, choroid plexus: (CSF) secretion α-methyl-5-HT, LSD 5-HT5-HT33 CNS, PNS: neuronal excitation, anxiety, emesisCNS, PNS: neuronal excitation, anxiety, emesis 5-HT5-HT44 GIT, CNS: neuronal excitation, gastrointestinal motilityGIT, CNS: neuronal excitation, gastrointestinal motility 5-Ht5-Ht55 CNS: unknown CNS: unknown 5-Ht5-Ht66 CNS: unknown CNS: unknown 5-HT5-HT77 CNS, GIT, blood vessels: unknownCNS, GIT, blood vessels: unknown

5-HT synthesis and metabolism

Tryptophan (amino acid from diet)

5-hydroxytryptophan

Serotonin (5-HT)

5-HIAA

Tryptophan hydroxylase

L-aromatic acid decarboxylase

Monoamine oxidase (MAO) in presynaptic neuron [after reuptake]

Aldehyde dehydrogenase

5-HT functions: ‘body’

Coordinate physiological functioning Physiological regulation

Thermoregulation, appetite and digestion, cardiovascular activity, sexual functioning, pain perception

Circadian rhythms Sleep/wake cycle: precursor of melatonin

(pineal gland)

5-HT functions: ‘mind’

Affect regulation and cognitive function Learned helplessness Anticipatory anxiety Inhibit pain sensation 5-HT contributes to (declarative)

memory, particularly for emotional stimuli

Summary Neural signaling occurs via electrical impulse

down the axon, causing NT release Amino acids glutamate and GABA are the major

excitatory and inhibitory NTs in the CNS, modulating activity via long-axon and intrinsic neurons

Ach, DA, NE, and 5-HT systems originate in subcortical nuclei and project along organized pathways to modulate brain activity; although interactive, each is associated with certain functions and neuromodulatory disorders