1. Neurotransmitters

2. Definition
They are chemical messengers which released from neurons to act on adjacent cells which are usually also neurons
Peripherally,adjacent effector's cell may be a muscle or glandular cell

3. Differences
Hormones: produced by ductless glands,secreted into circulation, go to distance target cells,to act via specific protein receptors at these cells e.g: Aldosterone,Insulin,ADH,Thyroxin
Autacoids : act on target cells close to their site of release,called “local hormones” or “paracrine secretions” e.g: Histamine,prostaglandin

4. Criteria The substance must be present within the presynaptic neuron
The substance must be released in response to presynaptic depolarization, and the release must be Ca2+-dependent
Specific receptors for the substance must be present on the postsynaptic cell

5. Major classes of NT Amino Acids Acetylcholine (excitatory)
Glutamate (excitatory)
GABA (inhibitory)
Acetylcholine (excitatory)
Monoamine (excitatory)
Catecholamine: Dopamine, Norepinephrine
Indolamine: Serotonin

6. Neural organization of NT systems
I, II, & III are different CNS areas, e.g.
cortex, brainstem, spinal cord I II
III
Communication
(GLT & GABA)
Coordination
(GLT & GABA)
Modulation
(Ach, NE, DA,5HT

7. 1. Amino acids Glutamate (GLT) & ɣ-aminobutyric acid (GABA)
Main excitatory (GLT) and inhibitory (GABA) NTs in CNS
Found throughout CNS in long axon and intrinsic neurons
Interacts with / modulate activity within other NT systems

8. AA synthesis and metabolism
Glucose OR glutamine
Kribs cycle
Glutamate (GLT)
Glutamic acid decarboxylase (GAD)
γ- aminobutyric acid (GABA)
Metabolism
Reuptake by presynaptic neuron and glial cells
Recycled into glutamate (& GABA)

9. 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

10. Glutamate Receptors

11. GLT 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)

12. GABA Major inhibitory neurotransmitter in CNS
Hyperpolarizes postsynaptic membrane
Two types of GABA Receptors:
GABA-A
Cl- channel  binding Cl- conductance in presynaptic neurons
“fast” response (1msec)
Benzodiazepines, barbiturates
GABA-B
G-protein coupled receptor
K+ conductance
“slow” response (1sec)
The first nt that I am going to discuss is GABA…

13. GABA Receptors
This slide shows a schematic diagram of the GABA A receptor. As you can see, it is made up of 5 membrane spanning subunits.
This diagram also shows some of its pharmacological binding sites.

14. GABA functions & effect
Main inhibitory NT within CNS
synchronize local neural activity
modulation of motor control in basal ganglia
broad distribution underlies importance of tonic inhibition in CNS
Dysfunction = Epilepsy

15. 2. Acetylcholine (Ach) Earliest discovered neurotransmitter
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

17. ACh synthesis and metabolism
choline
Choline acetyltransferase (ChAT)
acetylcholine (ACh)
Acetylcholinesterase (AChE)
choline [reuptake into presynaptic neuron] + acetate [to blood]

18. Ach function & effect (brain)
Pedunculopontine – lateral dorsal pathway
Sleep / wake (REM sleep); motor (ACh →DA)
Basal forebrain cholinergic pathways
Medial septal nucleus →HC + amygdala
Learning and memory
Nucleus basalis of Maynert → cortex
Attention and memory

19. Ach circuit in brain

20. 3. Monoamines
Catecholamines
Indolamine(s)

21. 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

22. DA synthesis and metabolism
Tyrosine (amino acid from diet)
Tyrosine hydroxylase
Dopa
Dopa decarboxylase on postsynaptic membrane
Dopamine (DA)
Monoamine oxidase (MAO) in presynaptic neuron [after reuptake]
Catechol-O-methyl transferase (COMT)
DOPAC + HVA

23. Wait a minute !!
If dopamine is too polar to cross the BBB, how can L-DOPA cross it?

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

25. DA function & effect Nigrostriatal pathway
Motor function
Mesolimbic and Mesocortical pathways
Pleasure & Reward, reinforcement, motivation
Attentional and behavioural control
Endocrine regulation (Prolactin)
Psychosis
Schizophrenia, hallucinatory drugs

26. DA circuit in brain

29. Reward circuitry Prefrontal cortex nucleus accumbens VTA dopamine
SLIDE 16:
Introduce the pleasure centres of the brain affected by drugs:
This is a mid-sagittal view of the brain, as seen if you were to cut down the middle of the brain. The major structures of the reward pathway are the ventral tegmental area (VTA), the nucleus accumbens, and the prefrontal cortex. When you are engaged in something pleasurable, this circuitry of your brain is activated causing you to experience pleasure and thus making it more likely that you will engage in this pleasurable activity again.
The nucleus accumbens plays a central role in the reward circuit. Its operation is based chiefly on two essential neurotransmitters: dopamine, which promotes desire (Well, the specific role of dopamine in this reward circuit is not fully known. Dopamine promotes the link between behavior and learned rewarding stimuli, rather than having a direct association with pleasure), and serotonin, whose effects include satiety and inhibition. Many animal studies have shown that all drugs increase the production of dopamine in the nucleus accumbens, while reducing that of serotonin. The nucleus accumbens maintains close relations the ventral tegmental area (VTA). Located in the midbrain, at the top of the brainstem, the VTA is one of the most primitive parts of the brain. It is the neurons of the VTA that synthesize dopamine, which their axons then send to the nucleus accumbens. The VTA is also influenced by endorphins whose receptors are targeted by opiate drugs such as heroin and morphine.
Another structure involved in pleasure mechanisms is the prefrontal cortex, whose role in planning and motivating action. The prefrontal cortex is a significant relay in the reward circuit and also is modulated by dopamine.
Taken from
VTA
dopamine

30. ? Reward Pathway SLIDE 17: How the reward pathway was discovered:
The pleasure and reward pathway of the brain was discovered through research on laboratory rats. In these experiments researchers implanted electrodes into the structures of the rat reward pathway, such as the nucleus accumbens. This allowed them to administer small electrical stimuli to these structures that were reinforcing to the animals. Rats were then trained to press a lever in order to obtain the rewarding electrical stimulation. This reward proved so powerful that the animals would lever press at very high rates (> 6,000 times per hour). Moreover, this reinforcement was more potent than other rewards, such as food or water. For example, in a classic experiment, animals suffered self-imposed starvation when forced to make a choice whether to obtain food and water or electrical brain stimulation. Research has shown that electrical stimulation of the pleasure and reward pathway is intensely pleasurable to humans, as well.
So to summarize, both natural and artificial rewards exert their reinforcing effects through activating the pleasure and reward circuitry of the brain. Activation of this circuitry causes us to experience pleasure, and increases the likelihood of our repeating the behavior that led to that pleasurable experience. When a drug causes an activation of the pleasure and reward pathway, it initiates changes in the brain that reinforce the use of the drug. We know many drugs that can cause addiction. Even you can name a few (ask the students). For example: nicotine in cigarettes, alcohol, opiates like heroin and morphine, marijuana (yes, it does), cocaine and its derivatives, ecstasy, etc. In the next few slides, we’ll see how drugs can lead to addiction.

31. 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

33. NE in PNS: Autonomic (sympathetic) NS
Sympathetic NS terminals and adrenal medulla
Fight-or-flight response

34. 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

35. NE 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

36. Serotonin (5-HT) 5-hydroxytryptamine Found in both PNS and CNS
CNS contains < 2% total 5-HT in body
Outside CNS: broad range physiological functions
7 (!) receptor subtypes (ionotropic and metabotropic)
Not clearly associated with specific brain regions
Some functional specificity (with overlap)

37. Serotonin Receptors
5-HT1A CNS: neuronal inhibition, behavioral effects (sleep, feeding, thermoregulation, anxiety)
5-HT1B CNS: presynaptic inhibition, behavioral effects; vascular: pulmonary vasoconstriction ergotamine
5-HT1D CNS: locomotion; vascular: cerebral vasoconstriction
5-HT2A CNS: neuronal excitation, behavioral effects; smooth muscle: contraction, vasoconstriction / dilatation; platelets: aggregation α-methyl-5-HT
5-HT2B stomach: contraction α-methyl-5-HT
5-HT2C CNS, choroid plexus: (CSF) secretion α-methyl-5-HT, LSD
5-HT3 CNS, PNS: neuronal excitation, anxiety, emesis
5-HT4 GIT, CNS: neuronal excitation, gastrointestinal motility
5-Ht5 CNS: unknown
5-Ht6 CNS: unknown
5-HT7 CNS, GIT, blood vessels: unknown
There are many 5HT receptors subtypes found with in and outside the nervous system. Different receptor subtypes are implicated in mediating various functions. Please do not try to memorize this chart!
A few of these subtypes you will hear about repeatedly. For example, the 5HT 1A receptor….., the 5HT 1B R….., the 5HT 2AR…., and the 5HT 2C R….

38. 5-HT synthesis and metabolism
Tryptophan (amino acid from diet)
Tryptophan hydroxylase
5-hydroxytryptophan
L-aromatic acid decarboxylase
Serotonin (5-HT)
Monoamine oxidase (MAO) in presynaptic neuron [after reuptake]
Aldehyde dehydrogenase
5-HIAA

40. 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)

41. 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

42. 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