1. Central neurotransmitters
Domina Petric, MD

2. I.
Amino acids

3. Glutamate Excitatory synaptic transmission is mediated by glutamate.
Glutamate is present in very high concentrations in excitatory synaptic vesicles: 100 mM.
Glutamate is released into the synaptic cleft by Ca2+-dependent exocytosis.

4. Glutamate
The released glutamate acts on postsynaptic glutamate receptors.
It is cleared by glutamate transporters present on surrounding glia.
In glia, glutamate is converted to glutamine by glutamine synthetase, released from glia.
Glutamine is taken up by the nerve terminal and converted back to glutamate by the enzyme glutaminase.
The high concentration of glutamate in synaptic vesicles is achieved by the vesicular glutamate transporter (VGLUT).

5. Glutamate ionotropic receptors
There are three subtypes based on the action of selective agonists:
α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)
kainicacid (KA)
N-methyl-D-aspartate (NMDA)

6. Glutamate ionotropic receptors
All the ionotropic receptors are composed of 4 subunits.

7. AMPA receptors AMPA receptors are present on all neurons.
GluA1-GluA4 subunits.
The majority of AMPA receptors contain the GluA2 subunit and are permeable to Na+ and K+, but not to Ca2+.

8. AMPA receptors
Some AMPA receptors, typically present on inhibitory interneurons, lack the GluA2 subunit.
Those AMPA receptors are permeable to Ca2+.

9. Kainate receptors
Kainate receptors are expressed at high levels in the hippocampus, cerebellum and spinal cord.
They are formed from a number of subunit combination GluK1-GluK5.
Kainate receptors are permeable to Na+ and K+, and in some subunit combinations, also for Ca2+.

10. NMDA receptors
NMDA receptors are ubiquitous as AMPA receptors: they are present on all neurons in the CNS.
All NMDA receptors require the presence of the subunit GluN1.
The channel also contains one or two NR2 subunits: GluN2A-GluN2D.

11. NMDA receptors
All NMDA receptors are highly permeable to Ca2+ as well as to Na+ and K+.
In addition to glutamate binding, the channel also requires the binding of glycine to a separate site.
Glycine site appears to be saturated at normal ambient levels of glycine.

12. NMDA receptors
AMPA and kainate receptors activation results in channel opening at resting membrane potential, whereas NMDA receptor activation does not.
This is due to the voltage dependent block of the NMDA pore by extracellular Mg2+.

13. NMDA receptors
When the neuron is strongly depolarized, Mg2+ is expelled and the channel opens.
Two requirements for NMDA receptor channel opening: glutamate must bind the receptor and the membrane must be depolarized.

14. NMDA receptors
The rise in intracellular calcium ions results in a long-lasting enhancement in synaptic strength: long-term potentiation (LTP).
LTP can last for many hours or even days.
It is an important cellular mechanism underlying learning and memory.

15. Metabotropic glutamate receptors
G protein-coupled receptors that act indirectly on ion channels via G proteins.
Metabotropic receptors (mGluR1-mGluR8) are divided into three groups.

16. Metabotropic glutamate receptors
Group I receptors are typically located postsynaptically.
They cause excitation by activating a non-selective cation channel.
These receptors also activate phospholipase C, leading to inositol trisphosphate-mediated intracellular Ca2+ release.

17. Metabotropic glutamate receptors
Group II and III receptors are typically located on presynaptic nerve terminals.
They act as inhibitory autoreceptors.
Activation of these receptors causes the inhibition of Ca2+ channels, resulting in inhibition of transmitter release.

18. Metabotropic glutamate receptors
Type II and III receptors are activated only when the concentration of glutamate rises to high levels during repetitive stimulation of the synapse.
Activation of these receptors causes the inhibition of adenylyl cyclase and decreases cAMP generation.

19. Postsynaptic density
The postsynaptic membrane at excitatory synapses is thickened.
Postsynaptic density is highly complex structure containing glutamate receptors, signaling proteins, scaffolding proteins and cytoskeletal proteins.

20. Postsynaptic density
A typical excitatory synapse contains AMPA receptors, which tend to be located toward the periphery, and NMDA receptors.
NMDA receptors are concentrated in the center.
Kainate receptors are present at a subset of excitatory synapses.

21. Postsynaptic density
Metabotropic glutamate receptors (group I) are localized just outside the postsynaptic density.
These receptors are also present at some excitatory synapses.

22. GABA and glycine
Inhibitory neurotransmitters released from local interneurons.
Interneurons that release glycine are restricted to the spinal cord and brainstem.
Interneurons releasing GABA are present throughout the CNS, including the spinal cord.

23. GABA and glycine
Some interneurons in the spinal cord can release both GABA and glycine.
Glycine receptors are pentameric structures that are selectively permeable to Cl-.
Strychnine selectively blocks glycine receptors.

24. GABA receptors GABAA and GABAB receptors.
Inhibitory postsynaptic potentials in many areas of the brain have a fast and slow component.
The fast component is mediated by GABAA receptors.
The slow component is mediated by GABAB receptors.

25. GABA receptors GABAA receptors are ionotropic receptors.
These receptors are pentameric structures that are selectively permeable to Cl-.
GABAA receptors are selectively inhibited by picrotoxin and bicuculline: generalized convulsions.

26. GABA receptors
GABAB receptors are metabotropic receptors that are selectively activated by the antispastic drug baclofen.
These receptors are coupled to G proteins, that either inhibit Ca2+ channels or activate K+ channels, wich depends on their cellular location.

27. GABA receptors
The GABAB component of the inhibitory postsynaptic potential is due to a selective increase in K+ conductance.
This inhibitory postsynaptic potential is long-lasting and slow because the coupling of receptor activation of K+ channel opening is indirect and delayed.

28. GABA receptors
GABAB receptors are localized to the perisynaptic region and require the spillover of GABA from the synaptic cleft.
GABAB receptors are also present on the axon terminals of many excitatory and inhibitory synapses.
These receptors also inhibit adenylyl cyclase and decrease cAMP generation.

29. II.
acetylcholine

30. Acetylcholine
Most CNS responses to acetylcholine are mediated by a large family of G protein-coupled muscarinic receptors.
At a few sites, acetylcholine causes slow inhibition of the neuron by activating the M2 subtype of receptor, which opens potassium channels.

31. Acetylcholine
A far more widespread muscarinic action in response to acetylcholine is a slow excitation.
This slow excitation is in some cases mediated by M1 receptors.

32. Acetylcholine
A number of pathways contain acetylcholine, including neurons in the neostriatum, the medial septal nucleus and the reticular formation.
Cholinergic pathways are important for cognitive function, especially memory.
Presenile dementia of the Alzheimer type is associated with a profound loss of cholinergic neurons.

33. III.
monoamines

34. Monoamines Catecholamines: dopamine and norepinephrine.
5-hydroxytryptamine (serotonin)

35. Dopamine The major pathways are:
the projection linking the substantia nigra to the neostriatum (target for drug levodopa)
the projection linking the ventral tegmental region to limbic structures, particularly the limbic cortex (target of antipsychotic drugs)

36. Dopamine
Dopamine-containing neurons in the tuberobasal ventral hypothalamus play an important role in regulating hypothalamohypophysial function.
Dopamine receptors are D1-like (D1 and D5) and D2-like (D2, D3, D4).

37. Dopamine All dopamine receptors are metabotropic.
Dopamine generally exerts a slow inhibitory action on CNS neurons.

38. Norepinephrine
Most noradrenergic neurons are located in the locus caeruleus or the lateral tegmental area of the reticular formation.
Most regions of the CNS receive diffuse noradrenergic input.
All noradrenergic receptor subtypes are metabotropic.

39. Norepinephrine
Norepinephrine can hyperpolarize neurons by increasing potassium conductance.
This effect is mediated by α2 receptors.
In many regions of the CNS, norepinephrine enhances excitatory inputs by both indirect and direct mechanisms.

40. Norepinephrine
The indirect mechanism involves disinhibition: inhibitory local circuit neurons are inhibited.
The direct mechanism involves blockade of potassium conductances that slow neuronal discharge, which is mediated by either α1 or β receptors.

41. Norepinephrine
Facilitation of excitatory synaptic transmission is in accordance with many of the behavioral processes: attention and arousal.

42. 5-hydroxytryptamine
5-HT, serotonin pathways originate from neurons in the raphe or midline regions of the pons and upper brainstem.
Serotonin is contained in unmyelinated fibers that diffusely innervate most regions of the CNS, but the density of the innervation varies.

43. 5-hydroxytryptamine
All of serotonine receptors, except 5-HT3 receptor, are metabotropic.
The ionotropic 5-HT3 receptor exerts a rapid excitatory action at a very limited number of sites in the CNS.
In most areas of the CNS, 5-HT has a strong inhibitory action.

44. 5-hydroxytryptamine
Strong inhibitory action is mediated by 5-HT1A receptors and is associated with membrane hyperpolarization: an incrase in potassium conductance.
5-HT1A receptors and GABAB receptors activate the same population of potassium channels.

45. 5-hydroxytryptamine
Some cell types are slowly excited by serotonin owing to its blockade of potassium channels via 5-HT2 or 5-HT4 receptors.
Both excitatory and inhibitory actions can occur on the same neuron.

46. neuroendocrine control
5-hydroxytryptamine
Regulatory functions of serotonin-containing neurons are:
sleep
temperature
appetite
neuroendocrine control

47. IV.
peptides

48. Peptides opioid peptides (enkephalins, endorphins) neurotensin
substance P
somatostatin
cholecystokinin
vasoactive intestinal polypeptide
neuropeptide Y
thyrotropin-releasing hormone…

49. Peptides
Peptides often coexist with a conventional nonpeptide transmitter in the same neuron.
Substance P is contained in and released from small unmyelinated primary sensory neurons in the spinal cord and brainstem: slow excitatory postsynaptic potential in target neurons.

50. Peptides These sensory fibers transmit noxious stimuli.
Substance P receptor antagonists can modify responses to certain types of pain, but do not block the response.
Glutamate is released with substance P from these synapses: role in transmitting pain stimuli.

51. V.
Nitric oxide

52. Neuronal NOS is an enzyme activated by calcium-calmodulin.
Nitric oxide
The CNS contains a substantial amount of nitric oxide synthase (NOS) within certain classes of neurons.
Neuronal NOS is an enzyme activated by calcium-calmodulin.
Activation of NMDA receptors, which increases intracellular calcium, results in the generation of nitric oxide.

53. Nitric oxide
Role of nitric oxide in neuronal signaling in the CNS may be long-term depression of synaptic transmission in the cerebellum.

54. VI.
endocannabinoids

55. Endocannabinoids
The primary psychoactive ingredient in cannabis, ∆9-tetrahydrocannabinol (∆9-THC), affects the brain mainly by activating a specific cannabinoid receptor, CB1.
CB1 receptors are expressed at high levels in many brain regions.
They are primarily located on presynaptic terminals.

56. Endocannabinoids
Several endogenous brain lipids, like anandamide and 2-arachidonylglycerol (2-AG), are CB1 ligands.
These ligands are not stored, but are rapidly synthesized by neurons in response to depolarization and consequent calcium influx.

57. Endocannabinoids
Activation of metabotropic receptors (by acetylcholine and glutamate) can also activate the formation of 2-AG.
Endogenous cannabinoids can function as retrograde synaptic messengers.

58. Endocannabinoids
Endogenous cannabinoids are released from postsynaptic neurons and travel backward across synapses, activating CB1 receptors on presynaptic neurons and suppressing transmitter release: retrograde synaptic messengers.

59. Endocannabinoids
This suppression can be transient or long lasting, depending on the pattern of activity.
Cannabinoids may affect memory, cognition and pain perception by this mechanism.

60. Literature
Katzung, Masters, Trevor. Basic and clinical pharmacology.