PSYC-2900 Chapter 4.2

neurotransmitter types

many different kinds present in the nervous system

• some found only in the CNS, some have actions in both the CNS and PNS

• excitatory or inhibitory, sometimes depends on the location and/or the receptor they bind to

amino acid neurotransmitters

a type of neurotransmitter used for protein synthesis, therefore, difficult to isolate their specific roles as neurotransmitters

• at least 8 (including glutamate and GABA, the most common) are believed to act as neurotransmitters in the mammalian CNS

glutamate

a type of amino acid neurotransmitter synthesized from glutamine by glutaminase. it is packaged by vesicle glutamate transporters into vesicles and stored until it is released from the presynaptic neuron following an action potential

glutamate receptors

4 types, including

• NMDA and AMPA receptors (ionotropic and important for learning and memory)

• kainate receptors (ionotropic)

• metabotropic glutamate receptor (autoreceptor)

drugs affecting transmission usually interact with these

AMPA

the most common type of glutamate receptor that controls a sodium channel, leading to excitatory postsynaptic potentials (EPSP)

• Kainate receptor has similar effects

NMDA

a type of glutamate receptor that is a voltage- and neurotransmitter-dependent ion channel, and requires binding by glutamate and glycine in order to open its’ Ca²⁺ channel

• has at least 6 binding sites

• when open, allows Na⁺ and Ca²⁺ to enter the cell

• blocking glutamate binding impairs plasticity and certain forms of learning

Ca²⁺ (NMDA)

a second messenger in NMDA receptors that binds and activates with enzymes, which is important for memory function. for the channel to be open, Mg²⁺ must not be attached to the binding site

• Mg²⁺ is bound at resting membrane potential, and repelled during depolarization

phencyclidine (PCP)

an indirect antagonist with a binding site in NMDA receptors that blocks Ca²⁺ from passing through the channel when it is attached

• ketamine is believed to bind to its binding site

• this molecule, as well as ketamine, were developed as anaesthetics, but have hallucinatory effects

glutamate reuptake and deactivation

the molecule is deactivated by the enzyme glutamine synthase, and transported into presynaptic cell by excitatory amino acid transporters

• too much or failure to remove can result in glutamate excitotoxicity

riluzole

a drug treatment for ALS that reduces glutamate vesicle docking at the presynaptic terminals, therefore reducing glutamte releas

GABA

a type of amino acid neurotransmitter that is produced from glutamic acid by glutamic acid decarboxylase (GAD). vesicle transporter packages it into vesicles. it produces inhibitory signalling important for modulating the spread of excitatory signals (e.g. prevents seizures)

• has several receptors

GABA_A receptor

a type of GABA receptors that has at least binding sites, of which, a primary binding site for GABA (with muscimol being a direct agonist and bicuculline blocking GABA from binding)

• other binding sites interact with different drugs such as benzodiazepines, sleep medications, barbiturates, steroid hormones (progesterone), alcohol, other steroids

• picrotoxin inhibits the activity of this receptor

GABA reuptake and deactivation

transporters remove the molecule from the synapse, deactivation is caused by GABA aminotransferase, and vigabatrin blocks enzyme activity (slows degradation)

tiagabine

a GABA transporter antagonist that is a medication that increases the availability of GABA receptor binding and reduces the likelihood of seizures

acetylcholine (ACh)

a type of classical neurotransmitter that has functions in both the CNS and PNS

• PNS: secreted by neurons terminating on muscle cells to control muscle contraction

• CNS: found in specific locations and pathways (3):

  • originating at the dorsolateral pons, role in REM sleep

  • basal forebrain (nucleus basalis), activate cerebral cortex and facilitate learning

  • medial septum, controls electrical rhythms of the hippocampus, and involved in formation of some kinds of memories

ACh production, storage, and release

• production requires 2 precursors and an enzyme

• vesicle transporters move the molecule into vesicles for storage until release

ACh inhibitors/stimulators

• Botulinum toxi (Botox), an ACh antagonist, prevents ACh release, stopping muscle contraction for a temporary period

• black widow spider venom, an ACh agonist, stimulates the release of ACh

ACh receptors

two types:

• nicotinic receptors, ionotropic and stimulated by nicotine, blocked by curare, allow muscle fibres to contract fast

  • found on axoaxonic synapses (presynaptic facilitation) in the CNS

• muscarinic receptors, metabotropic and stimulated by muscarine, blocked by atropine

  • more predominate in the CNS

ACh reuptake and deactivation

deactivated by acetylcholinesterase (AChE) by breaking it down into precursors. only Choline is recycled by cholinergic cells, but hemicholinium-3 blocks the choline transporter

• neostigmine, an AChE inhibitor, used to treat symptoms of myasthenia gravis

types of monoamine neurotransmitters

catecholamines

• dopamine, norepinephrine, epinephrine

indolamine

• serotonin

ethylamine

• histamine

monoamine neurotransmitters

a type of neurotransmitter that is present in several systems, most consisting of a smaller number of cell bodies in the brainstem with large numbers and distribution of terminal buttons. it modulates functions of widespread regions of the brain, either increasing or decreasing brain functions, but the action depends on the postsynaptic receptor it binds to

dopamine

a type of monoamine neurotransmitter that has pathways related to movement, attention, learning, and reenforcing pleasure-seeking behaviours. 3 pathways originate in the substantia nigra and ventral tegmental area of the midbrain

nigrostriatal system

a dopamine pathway from the substantia nigra to the neostriatum (caudate nucleus & putamen)

• degradation of these neurons occurs in Parkinson’s disease

mesolimbic system

a dopamine pathway from the ventral tegmental area to several limbic areas (nucleus accumbens, amygdala, hippocampus)

mesocortical system

a dopamine pathway from the ventral tegmental area to the prefrontal cortex

dopamine production, storage, and release

produced by catecholamine synthesis, a multi-step process with each step controlled by a different enzyme to slightly modify the precursor

• tyrosine (+ tyrosine hydroxylase) → L-DOPA (+ DOPA decarboxylase) → dopamine (+ Dopamine β-hydroxylase) → norepinephrine

• AMPT inactivates tyrosine hydroxylase

• L-DOPA is given to patients with Parkinson’s disease (crosses BBB)

• reserpine blocks vesicle monoamine transporters, previously used to treat high blood pressure

dopamine receptors

several different types, 5 metabotropic receptors:

• D₁ & D₂ are most common

• D₂, D₃, and D₄ decrease the productionn of cyclic AMP

• D₅ & D₁ increase the production of cyclic AMP (second messenger)

receptors have certain unique binding properties, and autoreceptors resemble D₂ receptors, but have a higher affinity

apomorphine

a drug in which a low dose will bind to the presynaptic dopamine receptors, produceing an antagonistic effect, and a higher dose serves as an agonist

dopamine reuptake and deactivation

• transporters remove the neurotransmitter from the synapse

• several drugs inhibit reuptake, and therefore serve as agonists (amphetamine, methamphetamine, cocaine, methylpenidate/Ritalin)

• deactivation of catecholamines is regulated by the enzyme monoamine oxidase (MAO), found in monoaminergic terminal buttons, which deactivates excess enzyme

  • MAO inhibitors can be used to slow down dopamine deactivation (deprenyl, used in Parkinson’s)

norepinephrine/noradrenaline

a type of monoamine neurotransmitter found in the CNS and PNS. cell bodies are located in the pons (mostly locus coeruleus (dorsal pons)), medulla, and one area of the thalamus. its’ primary effect of activation is an increase in vigilance

production, storage, and release of norepinephrine/noradrenaline

• same production pathway as dopamine, the final step takes place inside dopamine-filled vesicles (rather than the cytoplasm), where the enzyme dopamine-β hydroxylase transforms dopamine into norepinephrine

fusaric acid

inhibits dopamine-β hydroxylase, used for research in which they want to study the norepinephrine system without affecting dopamine

norepinephrine/noradrenaline receptors

four types found in different parts of the CNS and organs of the body, sensitive to both norepinephrine and epinephrine:

• α₁ adrenergic receptors

• α₂ adrenergic receptors

• β₁ adrenergic receptors

• β₂ adrenergic receptors

norepinephrine/noradrenaline reuptake and deactivation

• transporter removes excess from the synapse

• deactivated by monoamine oxidase (MAO-A)

serotonin/5-HT

a type of monoamine neurotransmitter found in 9 clusters, most located in the raphe nuclei of the midbrain, pons, and medulla

• released from varicosites (rather than terminal buttons), like norepinephrine

• role in regulation of mood, control of eating, sleep/arousal, pain regulation, and dreaming

serotonin production, storage, and release

• tryptophan (+ tryptophan hydroxylase) → 5-hydroxytryptphan (5-HTP) (+ 5-HTP decarboxylase) → 5-hydroxytryptamine (5-HT/serotonin)

• PCPA blocks tryptophan hydrolase activity

• vesicle monoamine transporters load the neurotransmitter into vesicles

serotonin receptors

at least 9 types exist, and follow a number + letter naming convention

• some are autorteceptors, others are postsynaptic receptors

• all are metabotropic, except 5-HT₃, which is an ionotropic receptor controlling a Cl^- channel (produces an inhibitory postsynaptic potential)

• 5-HT³ antagonists help reduce nausea following cancer treatments

• drugs bind selectively to other receptor subtypes (Busipirone, LSD)

serotonin reuptake and deactivation

• transport removes from the synapse

• drugs that inhibit reuptake play an important role in treatment of mental illness (e.g. Fluoxetine)

• MDMA/ecstasy has excitatory and hallucinogenic effects

• deactivated by monoamine oxidase

histamine

a type of monoamine neurotransmitter

• cell bodies found only in the tuberomammillary nucleus

• send axons to widespread regions of the cortex and brainstem

• role in wakefulness, antihistamines are antagonists

• produced from the amino acid precursor histidine by histidine decarboxylase

• stored in vesicles until release

histamine receptors

4 types in the CNS:

• H_1, H_2, H_3, H₄

• sleep aids often cross the BBB to act on their receptors

peptides

a type of neurotransmitter that consists of 2 or more amino acids linked by peptide bonds:

• produced in the soma from precursor molecules (large polypeptides that are broken down by enzymes)

• released from all parts of terminal buttons (not just the active zone), and are therefore not only released into the synaptic cleft

• often released with a classical neurotransmitter to regulate the sensitivity of the pre/postsynaptic receptors to the transmitter

• most serve as neuromodulators, but some as neurotransmitters

peptide reuptake and deactivation

• excess deactivated by enzymes, therefore no reuptake

opioid peptide receptors

3 different types:

• M (mu), δ (delta), K (kappa)

• enkephalins are natural ligands for receptors

• agonists include synthetic varieties (heroin, methadone, oxycodone)

• naloxone is an antagonist used clinically to reverse overdose

several neural systems are activated upon stimulation:

• analgesia

• inhibition of defensive responses

• reinforcement (can lead to abuse)

lipids

a type of neurotransmitter:

• derived substances can transmit messages within/between cells (e.g. endocannabinoids from THC)

• anadamide is the first natural ligand for the THC receptor

• appear to be synthesized on demand, produced an released as needed

• not stored in synaptic vesicles

cannabinoid lipid receptors

two types, both of which are metabotropic:

• CB₁, found on the terminal buttons of different types of neurons regulating neurotransmitter release, and open potassium channels to shorten the period of action potentials

• acetaminophen is converted several times to produce anadamide to bind with CB₁ receptors

• CB₂

cannabinoid lipid reuptake and deactivation

• anadamide is deactivate by the enzyme FAAH, present in anandamide-secreting neurons

• anadamide transporters are responsible for reuptake of anandamide to the presynaptic cell